Abstract:
The present invention features methods and pharmaceutical compositions for the treatment of Hepatitis C in a human in need thereof comprising administering a compound of Formula (I), (II), (III), (IV), (V), or (VI) described herein or a pharmaceutically acceptable salt thereof in combination with one or more additional Hepatitis C therapeutic agents.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims priority of the following co-pending U.S. Provisional patent applications: (1) U.S. Provisional Application Ser. No. 61/535,900, titled, “Fluid Exchange Apparatus and Methods,” filed on Sep. 16, 2011; and (2) U.S. Provisional Application Ser. No. 61/595,604, titled, “Fluid Exchange Apparatus and Methods,” filed on Feb. 6, 2012. The disclosures of the Provisional patent applications are hereby incorporated by reference in their entirety. 
     
    
     BACKGROUND 
       [0002]    The present disclosure is generally directed to methods and apparatus to exchange a fluid of an implantable device. 
         [0003]    Implantable devices can be used to provide a therapeutic agent to one or more portions of a body of a patient. The implantable device may have a chamber for storing the therapeutic agent, and the agent can be released into the patient to provide a therapeutic benefit. After an amount of time, the amount of fluid release can be less than ideal, and the fluid of the implantable device may be replaced, refilled, or exchanged to provide additional amounts of therapeutic agent to extend the therapy. 
         [0004]    Work in relation to embodiments of the present disclosure indicates that the prior methods and apparatus to place a fluid in a device implanted in the body can be less than ideal in at least some instances. For example, the amount of therapeutic fluid placed in an implanted therapeutic device with injection can be less than ideal in at least some instances. The therapeutic fluid placed in the implantable device may mix with a fluid already present in the implantable device, such that the amount of therapeutic fluid placed in the implantable devices can be less than ideal in at least some instances. Also, mixing of the implantable device fluid with the therapeutic fluid during exchange can provide a less than ideal sample of the fluid from the implantable device in at least some instances. At least some of the prior injections may at least partially damage the implantable device, for example with repeated injection of a needle through a septum. Further, as the implantable device may be small, the amount of pressure within a chamber of the implantable device may substantially exceed atmospheric pressure in order to provide a clinically acceptable amount of time to place the therapeutic fluid in the implanted device. In at least some instances the seal between the injector apparatus and implantable therapeutic device may be absent or inadequate and the exchanged fluids may leak from one or more of the injector apparatus or the implantable device in at least some instances. 
         [0005]    Refilling devices implanted in the eye may present additional challenges in at least some instances. At least some of the prior devices implanted in the eye can be small to decrease interference with vision, and the refill port of such devices can be small and the eye can move rapidly in at least some instances. Alignment of the injection apparatus with the refill port of the implanted device can be more difficult than would be ideal in at least some instances. 
         [0006]    Work in relation to embodiments suggests that at least some prior injector apparatus may be reused among patients, for example needles, and it may be helpful to limit reuse of the injector apparatus. 
         [0007]    At least some of the prior methods and apparatus to diagnose a patient have been less than ideal in at least some respects. In at least some instances, the eye disease may have progressed more than would be ideal. Although tissue can be removed from the patient with a biopsy or vitreous humor removed with a vitreal tap, such procedures can be more invasive than would be ideal. It would be helpful to provide methods and apparatus to obtain a sample from a patient that is less invasive than prior methods and apparatus. 
       SUMMARY 
       [0008]    In light of the above, it would be desirable to provide improved treatments for the eye and improved methods and apparatus to place therapeutic fluids in a device implanted in the eye. These treatments and methods and apparatus would decrease at least some of the deficiencies of the prior art, and would provide improved replacement and sampling of a fluid of a device implanted within the body, improved ease of alignment, improved exchange efficiency, little or no leakage resulting from pressure of the injection, and a clinically acceptable exchange time. 
         [0009]    Embodiments disclosed herein provide improved methods and apparatus to treat a patient having a device implanted in the body. The apparatus may comprise an exchange apparatus having an elongate structure capable of extending into the implantable device when implanted, and the elongate structure may comprise an opening to place a therapeutic fluid in the implanted device and one or more openings to receive an implantable device fluid from the implantable device. The implantable device may comprise a lock, and the exchange apparatus may comprise a key, so as to limit access to appropriate apparatus and formulations appropriate for the implantable device. The implantable device fluid may comprise air, or a liquid such as saline or a fluid comprising a component of the patient. The elongate structure of the exchange apparatus may comprise a needle and a sheath, in which the sheath extends over a proximal portion of the needle so that the needle and the sheath can be advanced through a penetrable barrier and into a reservoir of the implantable device. The sheath extending over at least a portion of the needle can maintain integrity of the penetrable barrier, and can provide an outflow path having a low resistance to flow so that the fluid within the implantable device can be displaced with decreased pressure. The outflow path can extend from the one or more openings to a receiver container configured to receive the fluid of the implantable device. The implantable device may comprise a porous structure to release therapeutic agent for an extended time. The porous structure may comprise a resistance to fluid flow greater than the resistance to flow of the outflow path from the one or more openings to the receiver container, so that the fluid of the implantable device can be displaced to the receiver container and flow through the porous structure inhibited. The exchange apparatus may comprise a receiver container to receive a sample of the implantable device fluid when the therapeutic fluid is placed in the implantable device. In many embodiments, the exchange apparatus is configured to separate at least a portion of the implantable device fluid from the therapeutic fluid. The separation of at least a portion of the implantable device fluid from the therapeutic fluid can provide a sample of the implantable device fluid useful for analysis and may increase the amount of therapeutic fluid placed in the implantable device. 
         [0010]    The one or more openings may comprise a plurality of openings to receive the implantable device fluid. In many embodiments, an injector apparatus comprises an elongate structure having a plurality of openings positionable near a penetrable barrier of the implantable device so as to receive fluid of the implantable device and increase exchange efficiency and decrease refill pressure. The elongate structure may comprise a distal tip to penetrate tissue and the penetrable barrier, and a distal opening near the tip to release therapeutic fluid into the implantable chamber. In many embodiments the distal tip, the distal opening, and the plurality of openings are separated from a stop that engages a tissue of the patient and limits penetration depth such that the distal opening and the plurality of openings are located along an axis of the implantable device so as to increase efficiency of the exchange. A tapered portion of the elongate structure can extend between the distal opening and the plurality of openings so as to stretch a penetrable barrier when the elongate structure is advanced. The plurality of openings can be located away from the tapered portion along a proximal portion so as to maintain integrity of the penetrable barrier and so that leakage can be inhibited. The penetrable barrier can be used repeatedly with pressure for subsequent fluid exchange which can extend the lifetime of the device implanted in the eye. The proximal portion of the elongate structure may comprise an extension without openings extending from the stop to the plurality of openings so as to inhibit leakage through the penetrable barrier and place the plurality of openings away from a proximal side of the penetrable barrier. The extension without openings may extend from the stop to the plurality of openings a distance corresponding substantially to a thickness of the penetrable barrier, such that at least one of the plurality of openings is placed near an inner surface of the penetrable barrier so as to receive fluid near the surface of the penetrable barrier and increase an efficiency of the exchange. The plurality of openings can be distributed along an axis of the elongate structure and may be distributed circumferentially around the elongate structure so as to receive fluid from a plurality of axial and circumferential locations of the reservoir chamber of the implantable device. 
         [0011]    The fluid initially within the implantable device may comprise a density less than a therapeutic fluid, and the distal tip and plurality of openings can be configured to at least partially separate the fluid injected through the distal tip from the fluid received through the plurality of openings. The distal opening may be placed below the plurality of openings so as to increase separation and the efficiency of the exchange. The distal opening can be placed below the plurality of openings with a distance from the stop shorter than a length of the implantable device. The distance from the distal opening to the stop may correspond to a length of the reservoir chamber of the implantable device so as to position the distal tip having the opening near a distally located porous structure of the implantable device. In many embodiments the distance from the distal opening to the stop can be no more than about half the distance of the reservoir chamber of the implant so as to facilitate alignment and provide high exchange efficiency with the distal opening placed below the proximal plurality of openings. 
         [0012]    In many embodiments, the exchange apparatus comprises one or more structures to separate at least a portion of the implantable device fluid from the therapeutic fluid. The one or more structures may comprise a valve, fluid separator, a separator fluid or combinations thereof. The separator fluid may comprise a fluid miscible with the therapeutic fluid and the implantable device fluid, or a fluid immiscible with the therapeutic fluid and the implantable device fluid such as an immiscible fluid comprising one or more of an oil, a hydrophobic liquid, a gas, or air. The separator fluid can be contained in the fluid separator to inhibit mixing of the implantable device fluid with the therapeutic fluid. The valve may be coupled to a first receiver container and a second receiver container such that a first portion of the implantable device fluid can be placed in the first container without substantial amounts of therapeutic fluid. A second portion of the implantable device fluid mixed with the placed therapeutic fluid can be placed in the second receiver container to inhibit mixing of the therapeutic fluid with the sample contained in the first container. The fluid separator may comprise a structure configured to contain the separator fluid between the implantable device fluid and the therapeutic fluid to inhibit mixing. 
         [0013]    While the elongate structure can be configured in many ways, in many embodiments the elongate structure comprises a needle extending from the proximal stop to the distal tip and a sheath placed over the needle to provide the plurality of openings and the tapered intermediate portion. The sheath may comprise a distal portion to engage the needle and an increased cross sectional size to provide the taper. In many embodiments the sheath located over the needle provides one or more channels coupled to the plurality of opening to receive the fluid from the implantable device. The one or more channels may extend proximally from the plurality of openings to a container to receive the fluid from the implantable device. 
         [0014]    The exchange apparatus can be coupled to an injector in many ways and may comprise an injector, such as a syringe. In many embodiments the exchange apparatus comprises a connector to couple to a syringe. The connector may comprise a known standard connector, such as a Luer connector, or may comprise a custom connector, such as a keyed connector, to inhibit inappropriate access to the implantable device. The connector may comprise a lock and key mechanism. The connector of the implantable device may comprise a lock and the connector of the syringe may comprise a key to access the exchange apparatus. Alternatively, the injector can be integrated with the exchange apparatus, and the injector may comprise an amount of therapeutic agent to inject into the implantable device. 
         [0015]    In many embodiments, the receiver container comprises one or more channels that vent to atmospheric pressure such that a gas within the receiver container can be displaced with fluid comprising liquid from the implantable device. The receiver container may comprise a porous structure that readily allows passage of the gas from the receiver container with a low resistance to flow and substantially inhibits passage of the liquid from the implantable device chamber with a substantially greater resistance to flow. The receiver container may comprise a volume to inhibit re-use of the exchange apparatus, such that the injector apparatus can be a single-use device. The volume of the receiver container may be no more than about twice a volume of the reservoir chamber of the implantable device, for example. 
         [0016]    The container of the exchange apparatus can be configured to receive a sample from the implantable device container, and to provide access to the fluid stored in the receiver container. The fluid from the receiver container can be removed from the receiver container for analysis to determine the health of the eye of the patient. The receiver container may comprise a penetrable barrier to access the fluid sample within the receiver container with a needle. The receiver container may be separated from the exchange apparatus to provide the sample from the container. Alternatively or in combination, the receiver container may be pressurized to displace the sample fluid from the reservoir container. 
         [0017]    In many embodiments, a sample container can be coupled to the receiver container so as to receive the implantable device fluid from the receiver container. The exchange apparatus may comprise an elongate structure having one or more openings to receive the implantable device fluid, and the implantable device fluid can be displaced from the receiver container so as to pass through the one or more openings and into the sample container. The implantable device fluid can be displaced from the receiver container in many ways. A pressure source or a vacuum source such as a syringe can be coupled to the one or more openings to urge the implantable device fluid from the receiver container to the sample container. The implantable device fluid can be urged, for example drawn, into the sample container with aspiration from the vacuum source comprising the syringe. Alternatively or in combination, the implantable device fluid can be urged, for example pushed, with pressurization of the receiver container, for example from a pressure source comprising a syringe. A channel may extend from the receiver container to an opening that vents to atmospheric pressure during exchange, and the opening can be coupled to the syringe with pressurization subsequent to exchange, such that the channel and receiver container can be pressurized so as to urge fluid from the receiver container through the one or more openings. The receiver container and sample container may be placed in a centrifuge to urge implantable device fluid through the one or more openings onto an inner surface of the sample container. The sample container may comprise a penetrable barrier such as a septum, and the elongate structure may be advanced to place the one or more openings within a chamber of the sample container such that the implantable device fluid can be displaced from the receiver container. 
         [0018]    Additional aspects of the present disclosure are recited in the claims below, and can provide additional summary in accordance with embodiments. It is contemplated that the embodiments as described herein and recited in the claims may be combined in many ways, and any one or more of the elements recited in the claims can be combined together in accordance with embodiments of the present disclosure and teachings as described herein. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0019]      FIG. 1  shows an eye suitable for incorporation of the therapeutic device; 
           [0020]      FIG. 2  shows a therapeutic device implanted under the conjunctiva and extending through the sclera to release a therapeutic agent into vitreous humor of the eye so as to treat the retina of the eye; 
           [0021]      FIG. 3A  shows an embodiment of a therapeutic device comprising a container having a penetrable barrier disposed on a first end, a porous structure disposed on a second end to release therapeutic agent for an extended time; 
           [0022]      FIG. 3B  shows an embodiment of a porous structure comprising a plurality of channels extending substantially straight through a disk; 
           [0023]      FIG. 4  shows an embodiment of an apparatus to exchange fluid of a device implanted in a an eye; 
           [0024]      FIG. 5  shows an embodiment of an apparatus to exchange fluid coupled to an implanted device; 
           [0025]      FIG. 6  shows an embodiment of an elongate structure of the apparatus to exchange fluid as in  FIG. 5 ; 
           [0026]      FIG. 7  shows a cross-sectional view of an embodiment of an elongate structure of the apparatus exchange fluid comprising a sheath over a needle; 
           [0027]      FIG. 7A  shows an embodiment of an exchange apparatus comprising a locking connector to couple to a syringe; 
           [0028]      FIG. 7B  shows an embodiment of an elongate structure and receiver container of the exchange apparatus of  FIG. 7A ; 
           [0029]      FIG. 7C  shows embodiments of sheaths suitable for combination with the exchange apparatus of  FIGS. 7A and 7B ; 
           [0030]      FIG. 7D  shows an embodiment of a sheath opening having a beveled channel surface to inhibit degradation of the penetrable barrier; 
           [0031]      FIG. 7E  shows an embodiment of a sheath opening having a rounded channel surface and edge to inhibit degradation of the penetrable barrier; 
           [0032]      FIG. 7F  shows an embodiment of schematic illustration of the pressure drops across the porous structure and the one or more channels extending from the plurality of openings to the receiver container; 
           [0033]      FIG. 8A  shows a cross-sectional view of an embodiment of the apparatus to exchange fluid as in  FIGS. 5 and 6  coupled to a syringe; 
           [0034]      FIG. 8B  shows an embodiment of an implantable therapeutic device comprising a lock and an exchange apparatus comprising a key to the lock; 
           [0035]    FIG.  8 B 1  shows an embodiment of a deflectable elongate structure in an unloaded configuration prior to insertion in the lock of  FIG. 8B ; 
           [0036]    FIG.  8 B 2  shows an embodiment of a deflected elongate structure in an unloaded configuration prior to insertion in the lock of  FIG. 8B ; 
           [0037]    FIG.  8 C 1  shows an embodiment of an implantable therapeutic device comprising a lock and an exchange apparatus comprising a rotatable key to the lock; 
           [0038]    FIG.  8 C 2  shows an embodiment of an implantable therapeutic device of FIG.  8 C 1  in a locked configuration in which the elongate structure extends through the open lock to access the reservoir chamber of the implantable device; 
           [0039]    FIG.  8 D 1  shows an embodiment of an implantable therapeutic device comprising a lock and an exchange apparatus comprising a slidable key to the lock; 
           [0040]    FIG.  8 D 2  shows an embodiment of an implantable therapeutic device of FIG.  8 D 1  in a locked configuration in which the elongate structure extends through the open lock to access the reservoir chamber of the implantable device; 
           [0041]      FIG. 8E  shows an embodiment of an implantable therapeutic device comprising a lock and an exchange apparatus comprising an elongate structure having engagement structures to open the lock; 
           [0042]      FIG. 9  shows an embodiment of a container to receive and store the exchange apparatus; 
           [0043]      FIG. 10  shows an embodiment of an exchange apparatus having a fluid sample within the receiver container; 
           [0044]      FIG. 11  shows an embodiment of the exchange apparatus having the fluid sample placed partially within the storage container; 
           [0045]      FIG. 12  shows an embodiment of a cap of the storage container placed over an outlet channel of the exchange apparatus to inhibit leakage; 
           [0046]      FIG. 13  shows an embodiment of an elongate structure of the exchange apparatus placed within a soft penetrable material near the bottom of the storage container and the cap placed over the container so as to seal the exchange apparatus within the container; 
           [0047]      FIG. 14  shows an embodiment of an apparatus to remove the sample fluid from the receiver container; 
           [0048]      FIG. 15  shows an embodiment of a cap placed on a connector to couple a syringe to the exchange apparatus; 
           [0049]      FIG. 16  shows an embodiment of the exchange apparatus placed within a receptacle to couple the receiver container with a syringe to displace the sample fluid from the receiver container into a sample container for analysis; 
           [0050]      FIG. 17  shows an embodiment of an exchange apparatus coupled to a removable receiver container; 
           [0051]      FIG. 18  shows an embodiment of the exchange apparatus coupled to an implanted device to exchange fluid and receive fluid from the implanted device; 
           [0052]      FIG. 19  shows an embodiment of the exchange apparatus removed from the implanted device and the receiver container detached from the exchange apparatus; 
           [0053]      FIG. 20A  shows an embodiment of components of a container to remove a sample fluid from an exchange apparatus; 
           [0054]      FIG. 20B  shows an embodiment of an exchange apparatus placed in the container having components as in  FIG. 20A ; 
           [0055]      FIGS. 20C and 20D  show an embodiment of removal of a sample fluid from an exchange apparatus with the sample fluid drawn into the container as in  FIG. 20B ; 
           [0056]      FIG. 21  shows an embodiment of a method of removal from an exchange apparatus with a removal container as in  FIGS. 20A to 20D ; 
           [0057]      FIG. 22  shows an embodiment of an exchange apparatus having a receiver container comprising a penetrable barrier on a side port to remove a sample from the receiver container with a needle and syringe; 
           [0058]      FIG. 23A  shows an embodiment of an exchange apparatus having a receiver container coupled to a sample container and a syringe to displace fluid from the receiver container; 
           [0059]      FIG. 23B  shows the sample container of  FIG. 23A  placed over the plurality of openings of the exchange apparatus; 
           [0060]      FIG. 24A  shows an embodiment of an exchange apparatus having a receiver container coupled to a syringe with a sample container placed over openings of the exchange apparatus so as to remove a sample from the receiver container; 
           [0061]      FIG. 24B  shows an embodiment of the sample container of  FIG. 24A  placed over the plurality of openings of the exchange apparatus and the opening to the injection needle; 
           [0062]      FIG. 25A  shows an embodiment of an exchange apparatus comprising a removable receiver container comprising a removable sheath placed over a needle; 
           [0063]      FIG. 25B  shows an embodiment of the removable container of  FIG. 25A  with a plug placed over the sheath and the needle removed; 
           [0064]      FIG. 25C  shows an embodiment of the removable container of  FIGS. 25A and 25B  with a plug placed over the sheath and a cap over the removable receiver container; 
           [0065]      FIGS. 26A ,  26 B,  26 C,  26 D and  26 E show an embodiment of a centrifuge used to remove the fluid sample from the receiver container of the exchange apparatus; 
           [0066]      FIG. 26F  shows an embodiment comprising an exchange apparatus placed in a sample container comprising a centrifuge tube; 
           [0067]      FIG. 26G  shows an embodiment comprising an exchange apparatus placed in a sample container comprising a centrifuge tube, in which the centrifuge tube comprises a support comprising a narrow shoulder portion of the tube to hold the exchange apparatus; 
           [0068]      FIG. 26H  shows an embodiment comprising an exchange apparatus placed in a sample container comprising a centrifuge tube, in which the centrifuge tube comprises a support comprising restricted portion to hold the exchange apparatus; 
           [0069]      FIG. 27A  shows an embodiment of a collapsible fluid separator for use with a therapeutic device; 
           [0070]      FIG. 27B  shows an embodiment of a plunger comprising an exchange needle and a shoulder suitable for use with the collapsible fluid separator as in  FIG. 27A  and a therapeutic device; 
           [0071]      FIG. 27C  shows an embodiment of the collapsible fluid separator as in  FIG. 27B  placed within a reservoir chamber of a therapeutic device; 
           [0072]      FIG. 27D  shows an embodiment of the plunger comprising the exchange needle and the shoulder as in  FIG. 27B  advanced into the access port of the therapeutic device having the collapsible fluid separator placed within the reservoir chamber of the therapeutic device as in  FIG. 27C ; 
           [0073]      FIG. 27E  shows an embodiment of the collapsible fluid separator advanced within the reservoir chamber of the therapeutic device as in  FIG. 27D  so as to displace the implantable device fluid from the reservoir chamber through the needle; 
           [0074]      FIG. 27F  shows an embodiment of the collapsible fluid separator advanced within the reservoir chamber to a location near the distal end of the reservoir chamber so as to displace most of the implantable device fluid from the reservoir chamber through the needle; 
           [0075]      FIG. 27G  shows an embodiment of the collapsible fluid separator moved from the distal end of the reservoir chamber so as to place therapeutic device fluid in the reservoir chamber; 
           [0076]      FIG. 27H  shows an embodiment of the collapsible fluid separator moved from the distal end of the reservoir chamber to the proximal end of the reservoir chamber so as to fill substantially the reservoir chamber; 
           [0077]      FIG. 27I  shows an embodiment of a substantially non-collapsible fluid separator placed within a rigid walled container of a therapeutic device having a substantially fixed cross sectional size; 
           [0078]      FIG. 28A  shows an embodiment of an exchange apparatus comprising a balloon supported on an elongate tubular member capable of introduction into an implantable therapeutic device to exchange the implantable device fluid with a therapeutic fluid; 
           [0079]      FIG. 28B  shows an embodiment of the balloon as in  FIG. 28A  inflated within the therapeutic device to displace the implantable device fluid; 
           [0080]      FIG. 28C  shows an embodiment of the balloon deflated within the therapeutic device to provide space for the therapeutic fluid; 
           [0081]      FIG. 28D  shows an embodiment of the balloon punctured within the therapeutic device to release the therapeutic fluid from the balloon to the reservoir chamber of the therapeutic device; 
           [0082]      FIG. 29A  shows an embodiment of a deflectable fluid separator placed within an implantable therapeutic device; 
           [0083]      FIG. 29B  shows an embodiment of the deflectable fluid separator as in  FIG. 29A  displaced to a second side of the reservoir chamber to remove fluid from the second side of the reservoir chamber; 
           [0084]      FIG. 29C  shows an embodiment of the deflectable fluid separator as in  FIG. 29B  displaced to a first side of the reservoir chamber with the therapeutic fluid placed in the second side; 
           [0085]      FIG. 30A  shows an embodiment of an exchange apparatus comprising a valve to direct flow toward a second receiver container when a sample of the implantable device fluid has been placed in a first receiver container; 
           [0086]      FIG. 30B  shows an embodiment of an exchange apparatus having a valve comprising a porous structure to direct flow toward a second receiver container when a sample of the implantable device fluid has been placed in a first receiver container; 
           [0087]      FIG. 30C  shows an embodiment of an exchange apparatus having a float valve comprising a ball to direct flow toward a second receiver container when a sample of the implantable device fluid has been placed in a first receiver container; 
           [0088]      FIG. 30D  shows an embodiment of an exchange apparatus having a float valve comprising a sliding annular structure to direct flow toward a second receiver container when a sample of the implantable device fluid has been placed in a first receiver container; 
           [0089]      FIG. 30E  shows an embodiment of an exchange apparatus having a float valve comprising a flap to direct flow toward a second receiver container when a sample of the implantable device fluid has been placed in a first receiver container; 
           [0090]    FIG.  31 A 1  shows an embodiment of an exchange apparatus having a fluid separator comprising an internal channel sized to support the implantable device fluid with a pocket of air; 
           [0091]    FIG.  31 A 2  shows an embodiment of the exchange apparatus of FIG.  31 A 1  having the implantable device fluid supported with a pocket of air to separate the implantable device fluid from the therapeutic fluid; 
           [0092]    FIG.  31 B 1  shows an embodiment of an exchange apparatus having a fluid separator comprising an internal channel having a first portion sized to support the implantable device fluid with a pocket of air and a second portion sized to pass air through the implantable device fluid; 
           [0093]    FIG.  31 B 2  shows an embodiment of the exchange apparatus of FIG.  31 B 1  having the first portion supporting the implantable device fluid contained in the second portion with the pocket of air within the first portion; 
           [0094]    FIG.  31 B 3  shows an embodiment of the exchange apparatus of FIGS.  31 B 1  and  31 B 2  having the first portion supporting the implantable device fluid with the pocket of air and therapeutic fluid; 
           [0095]      FIG. 31C  shows an embodiment of an exchange apparatus coupled to a syringe to inject a displacement fluid comprising air into a therapeutic device to collect a sample of implantable device fluid; 
           [0096]      FIG. 32  shows an embodiment of an exchange apparatus coupled to a syringe to draw therapeutic fluid into the implantable device with aspiration of the implantable device fluid into the syringe; 
           [0097]      FIG. 33  shows an embodiment of a curved needle of an exchange apparatus to direct therapeutic fluid toward a wall of a container; 
           [0098]      FIG. 34  shows an embodiment of a covering on a porous structure of a therapeutic device to inhibit bolus release when the therapeutic fluid is introduced and a needle of an exchange apparatus oriented toward the covering; 
           [0099]      FIG. 35  shows an embodiment of a first exchange apparatus coupled to a double barrel syringe to exchange a first exchange fluid with the implantable device fluid, and a second exchange apparatus to exchange the first exchange fluid placed in the therapeutic device with a therapeutic fluid; 
           [0100]      FIG. 36  shows an embodiment of an experimental test apparatus; 
           [0101]      FIG. 37  shows experimental results obtained with the test apparatus of  FIG. 36 . 
       
    
    
     DETAILED DESCRIPTION 
       [0102]    Embodiments of the present disclosure as described herein can be combined in many ways to treat one or more diseases of a patient such as a disease of the eye. The embodiments as described herein are well suited to treat patients with a therapeutic agent for an extended time, such as may be provided with a device that can be at least partially implanted into the eye. Although specific reference is made to ophthalmic treatment of the eye, the methods and apparatus to place a therapeutic fluid in implantable device can be used with many implantable devices and treatments of one or more of many diseases, such as systemic medication to treat systemic disease, orthopedic treatment to treat orthopedic disorders, or dental treatment, for example. The exchange apparatus and methods as described herein are well suited for use with many drug delivery devices, such as refillable diffusion based devices, and can be exceptionally well suited for diffusion devices having a porous drug release structure configured for extended release in which the porous structure inhibits flow of fluid during exchange. 
         [0103]    The exchange apparatus and methods as described herein are well suited for diagnoses and treatment of the eye, for example with diagnosis and treatment of the eye based on the implantable device fluid received with the exchange apparatus with the fluid is injected. The implantable device can be combined with one or more known methods of analysis of biomarkers, for example commercially available beads and arrays to detect and measure biomarkers. The methods and apparatus as described herein are well suited for combination with analysis of samples as described in U.S. Pat. App. Ser. No. 61/538,736, entitled “Diagnostic Methods and Apparatus”, Filed: Sep. 23, 2011 (attorney docket no. 93161-821804 (000140US), the full disclosure of which is incorporated herein by reference. Examples of injector apparatus, therapeutic devices, valves and mechanisms to provide the bolus injection are described in U.S. patent application Ser. No. 12/696,678, filed on Jan. 29, 2010, entitled “Posterior Segment Drug Delivery”, Publication No. 2010/0255061; and U.S. PCT Pat. App. No. PCT/US2011/046812, filed Aug. 5, 2011, entitled “Injector Apparatus and Method for Drug Delivery”, the entire disclosures of which are incorporated herein by reference. PCT Patent Application No. PCT/US2012/049654, filed Aug. 3, 2012 entitled “Small Molecule Delivery with Implantable Therapeutic Device” is also incorporated herein by reference in its entirety. 
         [0104]    As used herein like numerals and/or letters denote like elements in the drawings and text as will be apparent to a person of ordinary skill in the art. 
         [0105]      FIG. 1  shows an eye  10  suitable for incorporation of the therapeutic device. The eye has a cornea  12  and a lens  22  configured to form an image on the retina  26 . The cornea extends to a limbus  14  of the eye, and the limbus connects to a sclera  24  of the eye. A conjunctiva  16  of the eye is disposed over the sclera  24 . A Tenon&#39;s capsule  17  extends between the conjunctiva  16  and the sclera  24 . The lens can accommodate to focus on an object seen by the patient. The eye has an iris  18  that may expand and contract in response to light. 
         [0106]    The eye also comprises a choroid  28  disposed between the sclera  24  and the retina  26 . The retina comprises the macula  32 . The eye comprises a pars plana, which comprises an example of a region of the eye suitable for placement and retention, for example anchoring, of the therapeutic device as described herein. The pars plana region may comprise sclera  24  and conjunctiva  16  disposed between the retina  26  and cornea  12 . The therapeutic device can be positioned so as to extend from the pars plana region into the vitreous humor  30  to release the therapeutic agent. The therapeutic agent can be released into the vitreous humor  30 , such that the therapeutic agent arrives at the retina  26  and choroid  28  for therapeutic effect on the macula  32 . The vitreous humor of the eye  30  comprises a liquid disposed between the lens  22  and the retina  26 . The vitreous humor  30  may comprise convection currents to deliver the therapeutic agent to the macula  32 . 
         [0107]      FIG. 2  shows a therapeutic device  100  implanted under the conjunctiva  16  and extending through the sclera  24 .  FIG. 3A  shows an exemplary embodiment of the therapeutic device  100 . The device  100  is configured to release a therapeutic agent  110  into vitreous humor  30  of the eye  10  so as to treat the retina of the eye. The therapeutic device  100  may comprise a retention structure  120  such as a smooth protrusion configured for placement along the sclera  24  and under the conjunctiva  16 , such that the conjunctiva  16  can cover and protect the therapeutic device  100 . When the therapeutic agent  110  is inserted into the device  100 , the conjunctiva  16  may be lifted away, incised, or punctured with a needle to access the therapeutic device  100 . The eye  10  may comprise an insertion of the tendon of the superior rectus muscle to couple the sclera of the eye to the superior rectus muscle. The device  100  may be positioned in many locations of the pars plana region, for example away from tendon and one or more of posterior to the tendon, anterior to the tendon, under the tendon, or with nasal or temporal placement of the therapeutic device. 
         [0108]    While the implant can be positioned in the eye in many ways, work in relation to embodiments suggests that placement in the pars plana region  25  can release therapeutic agent into the vitreous  30  to treat the retina  26 , for example therapeutic agent comprising an active ingredient composed of large molecules. 
         [0109]    Therapeutic agents  110  suitable for use with device  100  include many therapeutic agents, for example as listed in Table 1A, herein below. The therapeutic agent  110  of device  100  may comprise one or more of an active ingredient of the therapeutic agent, such as a formulation of the therapeutic agent, a commercially available formulation of the therapeutic agent, a physician prepared formulation of therapeutic agent, a pharmacist prepared formulation of the therapeutic agent, or a commercially available formulation of therapeutic agent having an excipient. The therapeutic agent may be referred to with generic name or a trade name, for example as shown in Table 1A. 
         [0110]    The therapeutic device  100  can be implanted in the eye to treat the eye for as long as is helpful and beneficial to the patient. For example the device can be implanted for at least about 5 years, such as permanently for the life of the patient. Alternatively or in combination, the device can be removed when no longer helpful or beneficial for treatment of the patient. 
         [0111]    The therapeutic agent  110  can be placed in the therapeutic device  100  in many ways. In many embodiments, a therapeutic fluid  260  ( FIG. 2 ) comprising therapeutic agent  110  is exchanged with an implantable device fluid  262  contained within therapeutic device  100 , as shown in  FIG. 2 . An exchange apparatus  200  can be configured to place the therapeutic fluid  260  and to receive the implantable device fluid displaced from the implantable device when the therapeutic fluid is placed. 
         [0112]    With reference to  FIG. 2 , an exemplary embodiment of the exchange apparatus  200  comprises an elongate structure  201  that can be placed substantially within the implantable device. The elongate structure  201  comprises an opening to place the therapeutic fluid in the reservoir chamber of the implantable device and one or more openings to receive the implantable device fluid from the reservoir chamber. The exchange apparatus  200  may comprise the therapeutic fluid  260  and the receiver container  250  to receive fluid  262  of the implantable device. The therapeutic device  100  may comprise a reservoir chamber to store an amount of the therapeutic agent  110 . The reservoir chamber may comprise a fluid  262  of the implantable device  100 . The fluid  262  of the implantable device can be displaced when the therapeutic fluid  260  is injected, for example, and a receiver container  250  can be provided to receive the implantable fluid  262  from the implantable device. The reservoir chamber of the implantable device may comprise a substantially rigid walls and a substantially fixed volume, for example. 
         [0113]    The exchange apparatus  200  can be configured in many ways, and may be coupled to a syringe  300  with one or more of many connectors, such as a Luer connector, a Luer-Lok™ connector, for example. Alternatively or in combination, the exchange apparatus may comprise syringe  300 , for example. The exchange apparatus  200  may comprise an elongate structure  201  to for insertion into the reservoir chamber of the implantable device, and a stop  240  to limit a depth of insertion of the elongate structure  201  into the reservoir chamber of the implantable device. The exchange apparatus  200  may comprise a receiver container  250  to receive the implantable device fluid from the reservoir chamber of the implantable device, and the elongate structure may comprise a plurality of openings coupled to the receiver container so as to receive the fluid of the implantable device through the plurality of openings when the fluid is injected. Alternatively, the therapeutic fluid may be drawn into the reservoir chamber of the implantable device with aspiration of the implantable device fluid into chamber  310  of the syringe, such that the therapeutic fluid placed in chamber  250  can be drawn into the reservoir chamber of the implantable device, for example. 
         [0114]      FIG. 3A  shows a therapeutic device  100  comprising a container  130  having a penetrable barrier  184  disposed on a first end, a porous structure  150  disposed on a second end to release therapeutic agent for an extended period, and a retention structure  120  comprising an extension protruding outward from the container to couple to the sclera and the conjunctiva. The container  130  may comprise an axis  100 A. The inner surfaces of the container  130  may define a reservoir chamber having a volume sized to provide therapeutic amounts of the therapeutic agent for the extended time. The extending protrusion of the retention structure may comprise a diameter  120 D. The retention structure may comprise an indentation  120 I sized to receive the sclera. 
         [0115]    The container may comprise a tubular barrier  160  that defines at least a portion of the reservoir, and the container may comprise a width, for example a diameter  134 . The diameter  134  can be sized within a range, for example within a range from about 0.5 to about 4 mm, for example within a range from about 1 to 3 mm and can be about 2 mm, for example. The container may comprise a length  136  sized so as to extend from the conjunctive to the vitreous along axis  100 A to release the therapeutic agent into the vitreous. The length  136  can be sized within a range, for example within a range from about 2 to about 1 4 mm, for example within a range from about 4 to 10 mm and can be about 7 mm, for example. The volume of the reservoir may be substantially determined by an inner cross sectional area of the tubular structure and distance from the porous structure to the penetrable barrier. The retention structure may comprise an annular extension having a retention structure diameter greater than a diameter of the container. The retention structure may comprise an indentation configured to receive the sclera when the extension extends between the sclera and the conjunctive. The penetrable barrier may comprise a septum disposed on a proximal end of the container, in which the septum comprises a barrier that can be penetrated with a sharp object such as a needle for injection of the therapeutic agent. The porous structure may comprise a cross sectional area  150 A sized to release the therapeutic agent for the extended period. 
         [0116]    The porous structure  150  may comprise a control release mechanism. The porous structure  150  can be configured in many ways to provide controlled sustained release, for example with a release rate index, or a size and number of openings, for example. The porous structure  150  may comprise a first side  150 S 1  coupled to the reservoir and a second side  150 S 2  to couple to the vitreous. The first side may comprise a first area  150 A 1  and the second side may comprise a second area  150 A 2 . The porous structure may comprise a thickness  105 T. The porous structure many comprise a diameter  150 D. 
         [0117]    The porous structure  150  may comprise one or more of a release control element, a release control mechanism, permeable membrane, a semipermeable membrane, a material having at least one hole disposed therein, channels formed in a rigid material, straight channels, nano-channels, nano-channels etched in a rigid material, laser drilled holes, laser etched nano-channels, a capillary channel, a plurality of capillary channels, one or more tortuous channels, sintered material, sintered rigid material, sintered glass, sintered ceramic, sintered metal, tortuous micro-channels, sintered nano-particles, an open cell foam or a hydrogel such as an open cell hydrogel. Additional examples of porous structures are described in U.S. patent application Ser. No. 12/696,678, filed on Jan. 29, 2010, entitled “Posterior Segment Drug Delivery”, Publication No. 2010/0255061; and U.S. PCT Pat. App. No. PCT/US2011/046812, filed Aug. 5, 2011, entitled “Injector Apparatus and Method for Drug Delivery”, the entire disclosures of which have been previously incorporated herein by reference. 
         [0118]    The volume of the reservoir chamber may comprise from about 5 μL to about 2000 μL of therapeutic agent, or for example from about 10 μL to about 200 μL of therapeutic agent. The reservoir may comprise an axial length  136 C extending between the penetrable barrier  184  and the porous structure  150 . 
         [0119]    The therapeutic agent stored in the reservoir of the container comprises at least one of a solid comprising the therapeutic agent, a solution comprising the therapeutic agent, a suspension comprising the therapeutic agent, particles comprising the therapeutic agent adsorbed thereon, or particles reversibly bound to the therapeutic agent. For example, reservoir may comprise a suspension of a cortico-steroid such as triamcinolone acetonide to treat inflammation of the retina. The reservoir may comprise a buffer and a suspension of a therapeutic agent comprising solubility within a range from about 1 μg/mL to about 100 μg/mL, such as from about 1 μg/mL to about 40 μg/mL. For example, the therapeutic agent may comprise a suspension of triamcinolone acetonide having a solubility of approximately 19 μg/mL in the buffer at 37° C. when implanted. 
         [0120]    The release rate index may comprise many values, and the release rate index with the suspension may be somewhat higher than for a solution in many embodiments, for example. The release rate index may be no more than about 5, and can be no more than about 2.0, for example no more than about 1.5, and in many embodiments may be no more than about 1.2, so as to release the therapeutic agent with therapeutic amounts for the extended time. The release rate index can be at about 0.01, for example. 
         [0121]    The therapeutic device, including for example, the retention structure and the porous structure, may be sized to pass through a lumen of a catheter. 
         [0122]    The porous structure may comprise a needle stop that limits penetration of the needle. The porous structure may comprise a plurality of channels configured for the extended release of the therapeutic agent. The porous structure may comprise a rigid sintered material having characteristics suitable for the sustained release of the material. 
         [0123]      FIG. 3B  shows a porous structure comprising a plurality of substantially straight channels  150 SC extending substantially straight through a disk. The channels  150 SC can extend from a first side  150 S 1  to a second side  150 S 2  a distance comprising thickness  150 T of the porous structure. Each of the channels comprises a cross-sectional dimension across, for example a diameter, and a corresponding area across the cross section. The combined cross-sectional area of the plurality of channels, the thickness  150 T, the diffusion coefficient of the therapeutic agent, the concentration of therapeutic agent within the reservoir chamber and the volume of the reservoir chamber determine substantially the release rate profile of the therapeutic agent. The size and number of the plurality of channels  150 SC and thickness of the porous structure can be configured so as to provide the release rate profile. 
         [0124]    The porous structure  150  may comprise the control release mechanism having one or more straight channels  150 SC through which material (e.g., fluid that contains therapeutic agent) can pass. There can be at least 3, for example at least 6 and even more typically at least 10 channels. There may be fewer than 1000 channels, for example no more than 200 and in many embodiments no greater than 50 of the channels  150 SC. 
         [0125]    Material, particularly ophthalmic pharmaceutical composition and aqueous humor fluid, is typically allowed to freely flow and/or diffuse into and out of the reservoir chamber  140  ( FIG. 3A ) with the size of the openings of channels  150 SC assisting in controlling the rate of flow and/or diffusion into and out of the reservoir chamber  140 . The openings of the plurality of channels  150 SC, particularly for a passive system, have a cross-sectional area that controls the rate at which material, particularly therapeutic agent, flows out of the reservoir and into the eye. That cross-sectional area can be at least 8 μm 2 , more typically at least 15 μm 2  and even more typically at least 50 μm 2 . That same cross-sectional area can also be no greater than 4000 μm 2 , for example no greater than 2000 μm 2  and in many embodiments no greater than 500 μm 2 . The cross-sectional area of the opening may comprise any sectional area of the opening wherein the outer perimeter of the opening is fully defined by the material of the control release mechanism and wherein, for fluid to pass through the opening into or out of the reservoir chamber  140 , it also passes through the cross-sectional area. 
         [0126]    In the illustrated embodiments, as shown in  FIG. 3B , the porous structure  150  comprising the control release mechanism can be a plate  150 PL. The plurality of channels  150 SC extends through the plate  150 PL. The plate  150 PL may have opposing substantially parallel surfaces through with the channels extend to the opening on each surface. In the embodiments shown, the channels  150 SC are cylindrical shape although they may be shaped otherwise as well. The channels  150 SC may have a diameter of at least about 0.2 microns, for example at least about 2 microns and in many embodiments at least about 8 microns. The diameter of the openings may be no greater than about 100 microns, for example no greater than 40 microns and in many embodiments no greater than about 25 microns. While it is understood that a generally uniform distribution of the openings over the surface of the plate  150 PL is desirable, other non-uniform distribution of opening the openings are also possible. A suitable thickness for the plate will typically be at least about 0.05 mm, more typically at least about 0.08 mm and will typically no greater than 0.5 mm and more typically no greater than 0.3 mm. 
         [0127]    The porous structure  150  comprising the control release mechanism may comprise a plate  150 PL. The plate  150 PL may be formed of a variety of materials such as metals or polymeric materials. In many embodiments, the plate  150 PL is formed of an etchable material such as silicon, which allows the channels  150 SC to be etched into the material. 
         [0128]    The number and size of each of the openings provides a combined cross-sectional surface area for the plate  150 PL. The combined cross-sectional surface area of the channels  150 SC may be no more than about 100,000 μm 2 , so as to provide sustained release of the therapeutic agent for an extended time. While the combined cross-sectional surface area can be within a range from about 1000 μm 2  to about 100,000 μm 2 , in many embodiments the combined cross-sectional area is within a range from about 2,000 μm 2  to about 30,000 μm 2 , for example about 2,000 to about 10,000 μm 2 . The combined cross-sectional area can be determined based on one or more of the thickness of the plate  150 PL, the diffusion coefficient of the therapeutic agent, the volume of the reservoir chamber, the concentration of the therapeutic agent placed in the reservoir chamber, or the targeted release rate profile of the therapeutic agent above a minimum inhibitory concentration for a predetermined amount of time, or combinations thereof, for example. 
         [0129]      FIG. 4  shows an exemplary apparatus  200  to exchange fluid of a device implanted in an eye. The apparatus  200  may comprise or be coupled to a syringe  300  to inject a therapeutic fluid comprising a therapeutic agent in to the device implanted in the eye. The apparatus  200  comprise an elongate structure  201  comprising a distal portion  210 , and intermediate portion  220  and a proximal portion  230 . The elongate structure  201  extends along an axis  202  from a stop  240  to position the distal portion  210 , the intermediate portion  220 , and the proximal portion  230  corresponding locations of the reservoir chamber. The distal portion  210  comprises a distal tip  212  to penetrate tissue and the penetrable barrier of the implantable device and an opening  214  to inject therapeutic fluid into the implantable device. The intermediate portion  220  comprises a tapered section  224  to gradually increase a size of the channel formed in the penetrable barrier when the needle is advanced through the penetrable barrier, so as to maintain integrity of the penetrable barrier and inhibit damage to the penetrable barrier. In many embodiments, the tapered portion  224  may extend along axis  202  without holes so as to decrease pressure to the penetrable barrier that may otherwise occur near the edge of a hole. The proximal portion  230  may comprise a plurality of openings  236  to receive the fluid from the reservoir chamber of the implantable device. The proximal portion  230  may comprise an extension  238  extending from the stop  240 . The extension  238  may extend from the stop  240  without holes to inhibit leakage when the fluid is exchanged and the stop  240  engages the conjunctiva. 
         [0130]      FIG. 5  shows the apparatus  200  coupled to an implantable device  100 . The stop  240  is positioned to engage the conjunctiva  16 , and the elongate structure  201  extends through the conjunctiva  16  and penetrable barrier  184  into the reservoir chamber  140  of the implantable device  100  when the apparatus  200  is coupled thereto. The elongate structure  201  can be sized so as to place distal tip  212  at a location within the reservoir chamber of the implantable device when the surface of the stop contacts the conjunctiva, for example. The distal tip  212  can be located on elongate structure  201  so as to place the distal tip  212  at a location from the penetrable barrier within implantable device  100  that is no more than a desired length, such as about ¾ of the length  136  of the implantable device, and in some embodiments no more than about half of the distance  136 C of the reservoir chamber. The plurality of openings  236  is located near the penetrable barrier  184  so as to receive fluid contacting the reservoir chamber. The extension  238  extends substantially through the penetrable barrier  184 , for example at least about half way through the penetrable barrier so as to position the plurality of openings away from an external surface of the penetrable barrier and to inhibit leakage. 
         [0131]      FIG. 6  shows an enlarged view of the elongate structure  201  of the apparatus  200 . The elongate structure  201  extends along axis  202  between the distal tip  212  and stop  240 . The distal portion  210  may comprise an extension  211  having a substantially constant cross-sectional size extending between the tip  212  to penetrate tissue and the intermediate portion  220 . In many embodiments, the extension  211  comprises a portion of a needle  270  extending between the stop  240  and the tip  212  to penetrate tissue, which tip may comprise the tip of the needle to penetrate conjunctival tissue. 
         [0132]    The tip to penetrate tissue  212  and the opening  214  can be located a distance  204  from the stop and the plurality of opens to provide efficient exchange of the fluid within the reservoir chamber of the implanted device. In many embodiments, the opening  214  is placed within the reservoir chamber at a distance from the stop  240  greater than the plurality of openings  236  to inhibit mixing of the injected therapeutic fluid with the fluid within the reservoir chamber of the implanted device. The opening  214  can be separated from the plurality of openings with a distance  208 , such that the opening  214  can be located below the plurality of openings when the therapeutic fluid is injected. 
         [0133]    The therapeutic fluid may comprise a density greater than the fluid of the implanted device and opening  214  can be placed below the plurality of openings  236  when the therapeutic fluid is injected to inhibit mixing. The axis  100 A (see  FIG. 3A ) of the implantable device and the corresponding axis of the reservoir chamber can be oriented away from horizontal, such that porous structure  150  may be located below the penetrable barrier  184  when the therapeutic fluid is injected. The axis  202  can oriented away from horizontal such that opening  214  can be placed below the plurality of openings  236 . The therapeutic fluid comprising the greater density can flow toward the distal end of the therapeutic device and the displaced fluid of the implantable device having the lesser density can be received by the plurality of openings  236  located above the opening  214 . 
         [0134]    Examples of therapeutic agents and corresponding formulations and fluids that may have a density greater than the density of the fluid within the chamber of the implanted device are listed in Table 1A. For example, one or more of the therapeutic agent or a stabilizer can increase the density of the therapeutic fluid. In many embodiments the therapeutic fluid having the greater density comprises a stabilizer, such as trehalose, and the therapeutic agent such as a protein comprising an antibody fragment. Alternatively or in combination, the therapeutic formulation may comprise an amount of therapeutic agent sufficient to provide a density greater than the fluid of the implanted device. The difference in density can be within a range from about 1% to about 10% and can depend on the density of the fluid within the reservoir chamber of the therapeutic device and density of the therapeutic fluid placed in the reservoir chamber with the exchange apparatus. The density of the therapeutic fluid may correspond to a density of the therapeutic agent and a density of the stabilizer (when present). In many embodiments, the density of the fluid of the reservoir chamber may correspond to a density of phosphate buffered saline, or plasma, or an amount of therapeutic fluid remaining in the reservoir from a prior exchange, or combinations thereof, for example. 
         [0135]    When injected into a device implanted within the patient, the distance  204  may correspond to no more than approximately the distance of the reservoir chamber of device  140 . The distance  204  may correspond substantially to the length of the reservoir chamber so as to place the distal tip near the porous structure, and the elongate structure of the exchange apparatus can be aligned with an elongate axis of the implantable device. In many embodiments, the distance  204  may correspond to no more than about half the distance of the reservoir chamber, such that the elongate structure  201  can be readily aligned with the implantable device. Work in relation to embodiments suggests than a distance providing a tolerance for angular alignment error of the axis  100 A with the axis  202  can facilitate exchange and improve efficiency of the exchange. The distance  204  from stop  240  to tip  212  comprising no more than about half of the axial distance of the implantable device can facilitate alignment during injection. 
         [0136]    The intermediate portion  220  may comprise an extension  222  extending between tapered portion  224  and the distal portion  210 . The extension  222  may comprise a cross-sectional size that is smaller than the tapered portion  224 . The extension  222  may comprise a smooth outer surface to penetrate tissue. The tapered portion  224  may comprise a smother outer surface to penetrate tissue and the penetrable barrier. The outer surface of the tapered portion can extend at an angle of inclination relative to the axis, and the tapered portion  224  may comprise a conic section having an angle with the axis such that the outer surface extends at the angle of inclination relative the axis. The angle of inclination of the tapered portion  224  can be no more than about 25 degrees, for example. The angle of inclination can be about 1 degree, about 2 degrees, about 5 degrees, about 10 degrees, about 15 degrees, about 20 degrees, or about 25 degrees, for example. The extension portion  216  may comprise a first cross-sectional dimension, and the portion having the plurality of openings may comprise a second cross sectional dimension greater than the first dimension, such that tapered portion having the angle of inclination extends there between to connect the extension portion  216  with the portion having the plurality of openings  236 . 
         [0137]    The proximal portion  230  may comprise the plurality of openings  236  spaced apart along the axis  202  and distributed circumferentially around the proximal portion to receive fluid from a plurality of circumferential and axial locations when the stop  240  engages the conjunctiva to place the plurality of openings within the reservoir chamber. At least one  237  of the plurality of openings can be separated from the stop  240  with a distance  206  corresponding substantially to the thickness of the penetrable barrier  184 , such that the at least one  237  of the plurality of openings  236  can be placed near the inner surface of the penetrable barrier to receive fluid contacting the inner surface of the penetrable barrier. In many embodiments, the thickness of the penetrable barrier is within a range from about 0.25 to about 2 mm, for example within a range from about 0.5 to about 1.5 mm, such that the thickness of the penetrable barrier is substantially greater than a thickness of the conjunctiva which can be approximately 100 μm. The distance  206  corresponding substantially to the thickness of the penetrable barrier may correspond substantially to the thickness of the penetrable barrier and the epithelium of the patient. 
         [0138]    A sheath  280  can be configured to extend over at least a portion of needle  270 . The sheath  280  may extend along the intermediate portion  220  and the proximal portion  230 , and the needle  270  can extend through the sheath. The sheath  280  may comprise the plurality of openings  236  and provide one or more channels extending along needle  270  to pass the fluid of the implantable device through the septum. 
         [0139]    The sheath  280  may comprise portions corresponding to the intermediate and proximal portions of the elongate structure  201 . The extension  222  may comprise a distal portion sheath  280  having an inner surface sized to engage an outer surface of the needle, and the diameter of the portion to engage the needle may comprise an inner cross sectional diameter less than the needle to engage the needle with at least one or of pressure or friction. The tapered portion  224  may comprise an intermediate portion of sheath  280 , in which the sheath  280  comprises tapered surface to penetrate the tissue and penetrable barrier  184 . The proximal portion  230  may comprise a proximal portion of the sheath  280  comprising the plurality of openings  236  and the extension  238 . A channel  239  can extend along an outer surface of the needle to the plurality of openings  236 . The channel  239  can extend proximally along extension portion  238  toward a container  250  (see  FIG. 8A ) to receive the fluid of the implantable device. The channel  239  may couple the plurality of openings to the container to receive the fluid of the implantable device. 
         [0140]      FIG. 7  shows a cross-sectional view of an elongate structure of the apparatus exchange fluid comprising the sheath  280  over the needle  270 . The needle may comprise channel  219 , for example a lumen, extending distally to the opening  214  (see  FIG. 6 ) and proximally to a connector to couple the channel  219  to a syringe, for example. A wall  252  of container  250  comprises sufficient strength to resist deformation when the stop  240  engages the tissue, and the stop  240  may comprise a deformable stop to couple to the tissue (see  FIG. 8A ). An outlet channel  254  extends from container  250  to at least one vent opening  258  to atmospheric pressure (see  FIG. 8A ). 
         [0141]      FIG. 7A  shows an exchange apparatus comprising a locking connector to couple to a syringe. The connector  290  may comprise a locking connector having an extension  292  sized to fit in a channel of connector  320  of syringe  300 , for example (see  FIG. 8B ). The exchange apparatus  200  may comprise components of a standard locking needle assembly, for example a standard locking needle such as a Luer-Lok™ fitting. The wall  252  that defines container  250  and sheath  280  can fit over the needle  270  which may comprise a standard needle assembly. The wall  252  can extend a substantial distance from stop  240  to opening  258 , for example, so as to define container  250  and channel  254  extending between the locking needle assembly and the wall. 
         [0142]      FIG. 7B  shows the elongate structure  201  and receiver container  250  of the exchange apparatus  200  of  FIG. 7A . The wall  252  can extend around a distal portion of receiver container  250 . The needle  270  and sheath  280  may extend through the wall  250 . The stop  240  can be located on a distal portion of wall  252  and may comprise a soft material, for example a soft elastomeric material such as silicone elastomer. The stop  240  may fit within a recess formed on the surface of wall  252 , and the needle  270  and the sheath  280  may extend through the soft elastomer stop  240 , for example. The sheath  280  may comprise the tapered portion  224  proximal to the plurality of openings  236 . The needle  270  can extend from tip  212  through chamber  250  to the connector  290  (see  FIG. 7A ), for example. The sheath  280  can extend from a first end  281  distal of the tapered portion  224  to a second end  283 . The second end  283  may comprise an opening  285  into chamber  250 . The outflow path of the displaced fluid from the implantable device may extend through the plurality of openings  236  to channel  239 , along channel  239  to opening  285 , and through opening  285  and into receiver container  250 . 
         [0143]      FIG. 7C  shows sheaths suitable for combination with the exchange apparatus of  FIGS. 7A and 7B . The sheath  280  can be configured in many ways (see  280 A through  280 K), and may comprise a wall thickness from about 0.0001 inches to about 0.01 inches, for example about 0.001 inches ( 1/1000 inch, 25 μm). The sheath  280  may comprise an inside diameter sized larger than the outside diameter of needle  270  so as to provide an annular channel extending axially between the needle and the sheath from the plurality of openings  236  to the opening  285 . The diameter of each of the holes can be within a range from about 0.0001 inches to about 0.1 inches, for example within a range from about 0.001 inches to about 0.01 inches. 
         [0144]    The plurality of openings  236  may comprise one or more of many shapes and can be arranged in many ways. Each row may comprise from about 2 to about 20 holes, for example, and may comprise circular, oval, elliptical or other shapes, for example. The sheath  280  may comprise a sheath  280 A having four rows of circular holes. Each of the holes may have a diameter of no more than about one half of the thickness of the outside diameter of the sheath  280 , for example, and may be located circumferentially at 90 degrees to each other, for example. Each of the four rows may extend axially along the sheath  280 . The rows can be spaced angularly at 90 degrees to each other, for example. 
         [0145]    The sheath  280  may comprise sheath  280 B having about two rows, each row comprising about four holes, each hole having a diameter of no more than about one eighth of the diameter of the outside diameter of the sheath  280 . The two rows may be spaced apart circumferentially at 180 degrees, and the holes may comprise holes cross-drilled through both sides of the sheath, such that each hole has a corresponding hole on the other row on an opposite side of the sheath. 
         [0146]    The sheath  280  may comprise sheath  280 C comprising about four cross drilled holes, each hole having a diameter of no more than about three quarters of the diameter of the outside diameter of the sheath  280 , for example. The holes may comprise pairs of holes, in which the holes of each pair have corresponding axial locations. The holes can be arranged in two rows spaced circumferentially at 180 degrees. 
         [0147]    The sheath  280  may comprise sheath  280 D comprising at least about three rows of at least about 3 holes, each hole having a diameter of no more than about one quarter of the diameter of the outside diameter of the sheath  280 . The rows can be spaced apart circumferentially at about 120 degrees, for example. 
         [0148]    The sheath  280  may comprise sheath  280 E comprising at least about 40 holes, each hole having a diameter of no more than about one tenth of the diameter of the outside diameter of the sheath  280 . 
         [0149]    The sheath  280  may comprise sheath  280 F comprising slots. Each of the slots may comprise a narrow dimension across and a long dimension across. The long dimension can extend axially along the sheath  280  and may extend a distance greater than the narrow dimension across. The long dimension can extend a distance greater than the outside diameter of the sheath  280  where the slots are located, for example. The narrow dimension across each slot may comprise no more than about half of the outside diameter of the sheath, for example. 
         [0150]    The sheath  280  may comprise sheath  280 G comprising staggered rows of holes. The plurality of openings  236  may comprise a first row and a second row of cross drilled holes  236 A, in which the holes of the first row are paired with the holes of the second row at a common axial location for each pair. A third row of holes and a fourth row of holes may comprise cross drilled holes  236 B located at 180 degrees to each other and 90 degrees to the first row and the second row. The axial locations of the third and fourth rows of holes can be staggered from the first and second rows of holes, such that the axial locations of the holes  236 A of the first row and second row correspond to axial locations away from the holes  236 B of the first row and the second row, for example. 
         [0151]    The sheath  280  may comprise sheath  280 H comprising oval holes having a long dimension and a short dimension, with the long dimension extending transverse to the axis of the sheath  280  and the short dimension extending along the axis of the sheath  280 . The oval holes can be spaced apart and located in rows extending along the axis of the sheath as described herein, for example. 
         [0152]    The sheath  280  may comprise sheath  280 I comprising elongate oval holes having the long axis of the oval extending along the axis of the sheath and the narrow dimension of the oval extending transverse to the long axis of the sheath, for example. 
         [0153]    The sheath  280  may comprise sheath  280 J comprising at least about three rows of at least about 3 oval holes, each oval hole having a maximum dimension across of no more than about one quarter of the diameter of the outside diameter of the sheath  280 . The rows can be spaced apart circumferentially at about 120 degrees as described herein, for example. 
         [0154]    The sheath  280  may comprise sheath  280 K comprising at least about 40 holes, each hole having a diameter of no more than about one tenth of the diameter of the outside diameter of the sheath  280 . The holes can be located on opposite sides of the sheath  280 , and may comprise cross drilled holes, for example. 
         [0155]      FIG. 7D  shows one of the sheath openings  236  having a beveled channel surface  284  to inhibit degradation of the penetrable barrier. The thickness  286  of the sheath wall may be within a range from about 0.0001 to about 0.01 inches, for example. The corner of  282  of the beveled channel surface of the opening may comprise an angle to inhibit degradation of the penetrable barrier, such as tearing with repeated injections. 
         [0156]      FIG. 7E  shows one of the sheath openings  236  having a rounded channel surface of the opening and edge to inhibit degradation such as tearing of the penetrable barrier with repeated injections, in accordance with embodiments of the present disclosure; 
         [0157]      FIG. 7F  shows a schematic illustration of the parallel outflow paths from the reservoir chamber  140 . The first outflow path  140 P 1  extends from the reservoir chamber  140  to the receiver container  250 , and the second outflow path  140 P 2  extends from the reservoir chamber  140  across the porous structure  150  to the vitreous humor  30  of the eye. As the intraocular pressure of the eye may be substantially less than the pressure of the implantable device during exchange, the intraocular pressure of the eye approximates atmospheric pressure. The second outflow path  140 P 2  extends comprises a pressure drop DP across the porous structure  150 . The first outflow path  140 P 1  comprises the pressure drop DP across the plurality of openings  236 , along the one or more channels  239  extending from the plurality of openings to the opening  285 , and through the one or more openings  285  into the receiver container  250 . In many embodiments, the channel  254  and the opening  258  each comprise air, such that the resistance to flow  254 R of the channel  254  and the resistance to flow  258 R of the opening such that the pressure drop across channel  254  and the opening  258  can be substantially less than the pressure drop DP, for example negligible. 
         [0158]    In many embodiments, a valve  256 V can be provided, so as to vary the resistance to flow of the outflow path to provide a bolus. The valve  256 V may comprise a porous structure  256 , for example, or a stop, plunger or other mechanism so as to increase pressure and provide the bolus when the exchange apparatus  200  has received a predetermined amount of displaced liquid from the reservoir container  140 . The porous structure  256  may comprise a gas such as air initially, and be configured to contact the liquid from the reservoir chamber when the predetermined amount of fluid has been received and provide a substantial increase in the resistance to flow  156 R, such that the bolus is passed through porous structure  150 . Examples of valves and mechanisms to provide the bolus injection are described in U.S. PCT Pat. App. No. PCT/US2011/046812, filed Aug. 5, 2011, entitled “Injector Apparatus and Method for Drug Delivery”, the entire disclosure of which has been previously incorporated herein by reference. 
         [0159]    The pressure drops can be configured in many ways so as to inhibit a bolus release into the eye when the therapeutic fluid is exchanged with the implantable device fluid, or so as to release a bolus of therapeutic fluid through the porous structure of the implantable device, for example. The therapeutic fluid  260  comprising therapeutic agent  110  is injected through needle  270  into the reservoir chamber  140  of the implantable device, so as to pressurize the implantable device chamber with a force sufficient to pass a substantial portion of the implantable device fluid  262  into the receiver container  250 . A pressure drop DP extends from the reservoir chamber of the implantable device through the plurality of openings  236 , along channel  239  extending to opening  285 , and through opening  285 , such that the implantable device fluid  262  is received in receiver container  250 . The outflow path from the reservoir chamber of the implantable device to the receiver container  250  comprises a resistance to flow corresponding to a resistance to flow  236 R of the plurality of openings  236 , the resistance to flow  239 R of the channel  239 , and the resistance to flow  285 R of opening  285 , for example. The resistance  150 R to flow of the porous structure corresponds to an amount of therapeutic fluid  260  passed from the reservoir chamber of the implantable device to the chamber of the eye containing vitreous humor, for example. The amount of fluid into the receiver container such as the chamber  250  relative to the amount of fluid through the porous structure is related to the resistances based on parallel flow. The amounts of flow to the receiver container  250  and through the porous structure  150  correspond substantially to the following equations: 
         [0000]      (Amount through porous structure)/(Amount through receiver)=(Resistance 236 R +Resistance 239 R )/(Resistance 150 R ) 
         [0000]      (Amount through porous structure)=(Amount through receiver)*(Resistance 236 R +Resistance 239 R )/(Resistance 150 R ) 
         [0000]      (Amount to receiver container)=(Amount through porous structure)*(Resistance 150 R )/(Resistance 236 R +Resistance 239 R ) 
         [0160]    The resistance  150 R corresponding to extended release of the therapeutic agent can be substantially greater than the resistance of the outflow path to the receiver container  250  comprising resistance  236 R and resistance  239 R, such that the amount of bolus of therapeutic fluid  260  and implantable device fluid  262  through the porous structure  150  can be less than about 1 μL combined, for example. Alternatively, the resistance to flow of the outflow path can be sufficient such that a substantial amount of therapeutic agent  110  is released through porous structure  150  with a bolus during exchange. The resistance to flow along the outflow path may comprise one or more of the resistance to flow  236 R of the plurality of openings  236 , the resistance to flow  239 R of the channel  239  extending from the plurality of openings to the opening  285 , or the resistance to flow  285 R of the opening  285 , for example, or combinations thereof. The size and number of the plurality of openings  236  and the thickness  286  of the sheath can determine substantially the resistance  236 R of the plurality of openings. The length of the channel  239  extending from the plurality of openings  236  to the opening  285 , and the transverse dimensions of the channel can determine substantially the resistance to flow  239 R. For example the channel  239  may comprise a plurality of channels extending from the plurality of openings opening  236  to the reservoir container  250 . 
         [0161]    The resistance to flow  150 R can vary with the RRI of the porous structure  150 . In many embodiments, the resistance to flow  150 R of porous structure  150  is inversely related to the RRI of the porous structure. For example, experimental testing with syringes and test therapeutic devices has shown that a bolus can be achieved through a porous structure  150  having an RRI of about 0.06 when the resistance to flow of outflow path is sufficiently large and device  100  is constructed such that chamber  140  can be pressurized to at least about one atmosphere, for example. However, porous structures having lower RRIs can provide a substantial resistance to flow so as to inhibit release of a substantial bolus. For example a porous structure  150  having an RRI of about 0.02 has a resistance to flow  150 R such that an attempt to pass a substantial bolus amount through the porous structure  150  with a clinically acceptable injection time of 30 seconds or less may result in substantial pressure, for example greater than about four atmospheres. 
         [0162]    The resistance to flow  150 R of the porous structure  150  comprising the plurality of straight channels  150 SC varies with one or more of the combined cross-sectional surface area of the channels  150 SC, the number of openings, the size of each of the openings, or the thickness  150 T, and combinations thereof. The combined cross-sectional surface area of the channels  150 SC may be no more than about 100,000 μm 2 , so as to provide a resistance to flow  150 R of the porous structure  150  sufficient decrease flow through the porous structure and provide exchange as described herein. The combined cross-sectional surface area can be within a range from about 1000 μm 2  to about 100,000 μm 2 , for example, so as to provide a resistance to flow  150 R greater than the resistance to flow of the outflow path  140 P 1 . For example, the combined cross-sectional area within a range from about 1,000 μm 2  to about 30,000 μm 2  may provide a substantial resistance to flow  150 R, which may be substantially greater than the resistance to flow of the outflow path. In many embodiments, the combined surface area is within a range from about 1,000 μm 2  to about 10,000 μm 2 , and the resistance to flow  150 R is substantially greater than the resistance to flow of the outflow path so as to inhibit bolus release through the porous structure (see also  FIGS. 3A and 3B ). 
         [0163]    The resistance to flow of the outflow path comprising resistance  236 R and  239 R may comprise about 5 per cent of the resistance  150 R to flow of the porous structure  150 , such that about 5 μL of fluid flows through the porous structure and about 95 μL flows through the plurality of openings  236  and channel  239 . The size and number of the plurality of openings and dimensions of channel  239  can be determined by a person of ordinary skill in the art based on the teachings described herein so as to provide a target amount of bolus for a target amount of injected therapeutic fluid. 
         [0164]    As the therapeutic fluid  260  can be denser than the implantable device fluid  262 , a substantial portion of the fluid through the porous structure  150  may comprise the therapeutic fluid  260 , for example. 
         [0165]      FIG. 8A  shows a cross-sectional view of the apparatus to exchange fluid as in  FIGS. 5 and 6  coupled to a syringe. The channel  239  extends from the plurality of openings  236  to a container  250  to receive the fluid of the implantable device. The distal portion  210  comprising tip  212  and opening  214  comprise a distal portion of needle  270 . The channel  219  extends along an axis  202  from the opening  214  to a connector  290 . The connector  290  is configured to couple to a connector  320  of an injector. The injector may comprise a syringe  300  (not to scale). The injector may comprise a container  310  comprising a therapeutic fluid for injection, and the container  310  can be fluidically coupled to the opening  214  on distal tip  212  when the connector  320  engages the connector  290 . 
         [0166]    The sheath may comprise an annular configuration shaped for placement over the substantially annular needle, such that the sheath and needle comprise a substantially concentric configuration extending along axis  202 . 
         [0167]    The connector  290  of the exchange apparatus and the connector  320  of the injector can be configured in many ways. For example, the connector  290  and the connector  320  may comprise a standard connector such as a Luer connector or a pressure fit connector. Alternatively, the connector  290  may comprise a non-standard connector to limit access to the exchange apparatus  200 . For example the connector  290  may comprise a star connector or other connector, and connector  290  may comprise a lock and key mechanism. The lock and key mechanism may comprise a lock on the exchange apparatus configured to receive a key of the injector, such that the lock of connector  290  can receive the key of connector  320  to couple the injector to the exchange apparatus and permit injection from chamber  310  through opening  214 . Alternatively, the syringe  300  may be affixed to exchange apparatus  200 , and syringe  300  provided with a single dose of therapeutic agent. 
         [0168]    The container  250  of the exchange apparatus may have a volume to limit and amount of fluid received from the implantable device and to limit use of the apparatus to a single use. For example, the volume of the container may comprise no more than about 100 μL, for example no more than about 50 μL, so as to limit and amount of fluid exchanged with the implantable device and inhibit reuse of the exchange apparatus from patient to patient. The implantable device can be provided to a health care provider with an amount of gas, such as air within the receiver container  250 , and the receiver container may comprise a structure along a vent path to limit the amount of fluid that can be received by the container  250 . 
         [0169]    The exchange apparatus  200  may comprise a porous structure  256  to inhibit passage of the fluid of the implantable device and limit the amount of fluid exchanged. The porous structure  256  may comprise a material to pass a gas, such as air and inhibit flow of a liquid, such as the fluid of the implantable device. The material may comprise one or more of a fabric, a porous fabric, a semipermeable membrane, an air permeable material, a moisture vapor transfer waterproof fabric, a hydrophilic porous material, or a porous sintered material, for example. The channels extending through the porous structure  256  may comprise a gas, such as air and a lower resistance to flow of the gas and a substantially greater resistance to flow of a liquid, such as the therapeutic fluid, such that the exchange is substantially inhibited when receiver container  250  is substantially filled with fluid of implanted device and the fluid exchanged with the implanted device contacts the porous structure  256 . The porous structure  256  may comprise one or more of a fabric, a porous fabric, a semipermeable membrane, an air permeable material, a moisture vapor transfer waterproof fabric, a hydrophilic porous material, or a porous material or a porous sintered material, for example. 
         [0170]    The exchange apparatus may comprise a structure  259  composed of a material penetrable with a needle to draw a sample from the receiver container. The structure  259  may comprise one or more materials suitable for penetration with a needle such as one or more of rubber or silicone elastomer, for example. The structure  259  may comprise the porous structure  256 , for example, and the material penetrable with the needle may comprise one or more of a fabric, a porous fabric, a semipermeable membrane, an air permeable material, a moisture vapor transfer waterproof fabric, a hydrophilic porous material, or a porous material or a porous sintered material, for example. 
         [0171]      FIG. 8B  shows an embodiment of an implantable therapeutic device  100  comprising a lock and key mechanism  850  to place a therapeutic agent in the implantable device. The lock and key mechanism  350  comprises a lock  360  and a key  370 . The lock  360  can be located on the implantable device to inhibit access to the reservoir chamber of the implantable device. The exchange apparatus  200  comprises the key  370  to access the reservoir chamber to place the therapeutic agent  110  as described herein. The lock can be configured in many ways and may comprise one or more of a deflected channel, a curved channel, a helical channel, a serpentine channel, engagement structures, a magnet, a door, a movable door, a tumbler, a cylinder, pins or a shear line, for example. The key can be configured in many ways so as to correspond to the lock and may comprise one or more of a deflectable elongate structure, a curved elongate structure, a helical elongate structure, a serpentine elongate structure, engagement structures sized to engage engagement structures of the lock, for example. 
         [0172]    In many embodiments, the lock  360  inhibits access with a straight rigid needle, so as to inhibit placement of the therapeutic agent which may be ineffective or inappropriate when placed in the therapeutic device. For example, the exchange apparatus  200  can be delivered to the physician with a predetermined therapeutic agent formulation and key, and the implantable device has the lock configured to receive the key to place the therapeutic agent, such that access to the implantable device can be limited substantially. 
         [0173]    In many embodiments, the lock  360  comprises the deflected channel  364 , which may comprise one or more of a bent channel, a curved channel, a helical channel, or a serpentine channel, for example. The lock  360  may comprise a stiff substantially non-penetrable biocompatible material, for example one or more of rigid plastic, polymethylmethacrylate (hereinafter “PMMA”), polycarbonate, metal, or titanium, for example. The key  370  may comprise one or more of many components and structures of elongate structure  201  as described herein. The key  370  may comprise one or more of a deflectable key or a deflected key configured to extend along the deflected channel  364  to deliver the therapeutic fluid  260  and receive the implantable device fluid  262 . The lock comprises an engagement structure  362  to engage an engagement structure  372  of the key. The engagement structure  362  may comprise an inner surface of the channel  364 , and the outer surface of the deflectable key engages the inner surface of the channel so as to deflect the elongate structure  201  to advance along channel  364 . 
         [0174]    FIG.  8 B 1  shows an embodiment of a deflectable elongate structure  201  in an unloaded configuration prior to insertion in the lock  360  of  FIG. 8B . The elongate structure comprises an axis  202 , and the elongate structure may extend substantially along the axis  202  so as to provide column strength to the elongate structure  201  to penetrate the penetrable barrier  184  of access port  180 . The elongate structure  201  may comprise a resistance to deflection sufficiently low so as to advance along channel  364  and a column strength sufficient to penetrate tissue and the penetrable barrier. The deflectable elongate structure  201  can be deflected substantially away from axis  202  when advanced into the lock  360 . 
         [0175]    The lock  360  may comprise a rigidity sufficient to inhibit penetration with a straight needle, and the channel  364  can be extend internally with lock  360 . 
         [0176]    The key  370  comprising the elongate structure  201  can extend through tissue such as the conjunctiva and epithelium to reach the lock  360 , and the key can be configured to penetrate the tissue. The penetration of the tissue and penetrable barrier  184  inhibits contamination of the reservoir chamber as the barrier function of the conjunctiva  16  and Tenon&#39;s capsule  17  can be substantially maintained. The deflectable elongate structure  201  can be made of one or more of many components and may comprise sheath  280  and needle  270 . The needle and sheath can be configured to deflect together when advanced along channel  364 . The deflectable needle may comprise a metal, for example Nitinol, and the sheath may comprise a polymer such as polyimide, for example. 
         [0177]    FIG.  8 B 2  shows an embodiment of a deflected elongate structure  201  in an unloaded configuration prior to insertion in the lock of  FIG. 8B . The key  370  comprising deflected elongate structure may comprise one or more of many materials providing a stiffness sufficient to retain the deflected shape in the unloaded configuration. In the unloaded configuration, the deflected elongate structure  201  of key  370  extends away from axis  202 . The deflected elongate structure  201  may comprise a preformed deflection profile corresponding to the path of channel  364  extending through the lock  360  from a first side of the lock toward the conjunctiva to a second side of the lock toward the reservoir chamber  140 . 
         [0178]    FIG.  8 C 1  shows an embodiment of an implantable therapeutic device  100  comprising a lock  360  and an exchange apparatus  200  comprising a rotatable key  370  to the lock  360 . The exchange apparatus  200  can be advanced toward the implantable device  100  and rotated as shown with arrows  374 . The engagement structures  372  of the key couple to the engagement structures  362  of the lock, such that the lock  360  opens to allow access of the elongate structure  201 . The engagement structures may comprise one or more of many structures, for example magnets, teeth, or notches, and the engagement structures can be spaced apart at appropriate distances such that the engagement structures of the lock are keyed to the engagement structures of the key to allow access. For example the engagement structures  372  of the key may comprise magnets, and the engagement structure of the lock may comprise a magnetic material such that the key can be opened with the lock and the magnetic field extending through the conjunctiva  16  and the Tenon&#39;s capsule  17 , for example. Alternatively, the conjunctiva and/or Tenon&#39;s capsule can be displaced and the engagement structures  372  of the key can contact the engagement structures  362  of the lock to allow access to the reservoir chamber. 
         [0179]    FIG.  8 C 2  shows an embodiment of the implantable therapeutic device  100  of FIG.  8 C 1  in a unlocked configuration in which the elongate structure  201  extends through the open lock and penetrable barrier  184  to access the reservoir chamber  140  of the implantable device  100 . The exchange apparatus can place the therapeutic fluid  260  in the implantable device  100  and receive the implantable device fluid  262  in the receiver container  250  as described herein. 
         [0180]    FIG.  8 D 1  shows an embodiment of an implantable therapeutic device comprising  100  a slide lock  360  and exchange apparatus  200  comprising a slidable key to engage the slide lock. The exchange apparatus  200  can be advanced toward the implantable device  100  and slid as shown with arrows  374 . The engagement structures  372  of the key couple to the engagement structures  362  of the lock, such that the lock  360  opens to allow access of the elongate structure  201 . The engagement structures of the slide lock  360  and slide key  370  may comprise structures similar to the rotatable key and lock described with reference to FIG.  8 C 1 . 
         [0181]    FIG.  8 D 2  shows an embodiment of an implantable therapeutic device  100  in an unlocked configuration in which the elongate structure  201  extends through the open lock  360  and penetrable barrier  184  to access the reservoir chamber  140  of the implantable device. The exchange apparatus can place the therapeutic fluid  260  in the implantable device  100  and receive the implantable device fluid  262  in the receiver container  250  as described herein. 
         [0182]      FIG. 8E  shows an embodiment of an implantable therapeutic device  100  comprising a lock  360  and the elongate structure  201  of the exchange apparatus  200  comprising the key  370 . The elongate structure  201  can be configured in many ways so as to comprise the key  370 . The engagement structures  372  of the key  370  can be located near a distal end  212  of the elongate structure  201 , for example. The engagement structures  272  can be affixed to the needle  270  and may comprise annular structures extending around the needle. Alternatively or in combination, the sheath  280  of the elongate structure may comprise the engagement structures. For example, the one or more openings  289  of the sheath  280  can be sized and located so as to comprise the engagement structures  372  of the key  370 . 
         [0183]    The lock can be configured in many ways to receive the key, and the engagement structures  362  of the lock may comprise pins aligned to a shear plane  368  when the key is inserted, for example. 
         [0184]      FIG. 9  shows a container  400  to receive and store the exchange apparatus  200 . The container  400  may comprise a barrier material  410  to inhibit evaporation from within the container to the outside environment, a cap  430  and a base supporting a soft penetrable material  420 . The cap  430  may comprise a protrusion such as an annular protrusion  432  to seal around an outer portion of the wall of the container. The cap  430  may comprise a retention structure to hold the injector apparatus, for example a second protrusion, such as an annular protrusion  434  to receive and hold the exchange apparatus  200 . The cap  430  may comprise a soft barrier material, such as an elastomer, for example. 
         [0185]      FIG. 10  shows an exchange apparatus  200  having the implantable device fluid  262  comprising a fluid sample  264  within the receiver container  250 . The receiver container  250  can be coupled to the elongate structure  201 . The channel  254  can extend from the container to  250  to opening  258 . The receiver container  250  may comprise a combination of one or more of the therapeutic fluid  260 , the implantable device fluid  262  comprising sample fluid  264 . Depending on the exchange apparatus and orientation, the implantable device fluid  262  comprising sample fluid  264  may comprise a substantial majority of the fluid of the receiver container  250 . 
         [0186]      FIG. 11  shows the exchange apparatus  200  having the fluid sample  264  placed partially within the storage container  400 . The cap  430  is shown over but not yet covering the vent channel  254  extending from the receiver container  250  to the opening  258 . 
         [0187]      FIG. 12  shows a cap  430  of the storage container placed over the outlet channel opening  258  of channel  254  coupled to the receiver container  250  of the exchange apparatus, so as to inhibit one or more of leakage or evaporation from container  250 . 
         [0188]      FIG. 13  shows an elongate structure  201  of the exchange apparatus placed within a soft penetrable material  420  near the bottom of the storage container and the cap placed over the container so as to seal the exchange apparatus container. The soft penetrable material  420  may comprise a soft material capable of sealing, for example a soft elastomeric material such as silicone elastomer. 
         [0189]      FIG. 14  shows an apparatus  500  to remove the sample fluid from the receiver container  250  of the exchange apparatus  200 . The apparatus  500  comprises a sample container  400 , a plug  520 , a syringe  540  to pressurize the receiver container  250 , and a coupling  530  to couple the syringe to the receiver container of the exchange apparatus  200 . The coupling  530  may comprise a receptacle  536  to receive the proximal end portion of the exchange apparatus  200 . The receptacle  536  may comprise a structure  532  to couple the syringe to the coupling, for example a Luer connector, a Luer-Lok™ connector, or other known connector, for example. The retention structure  532  to retain the exchange apparatus  200  and a contact structure  534  to contact the outer wall of the exchange apparatus and fluidly couple the syringe to the opening  528  when the exchange apparatus  200  is retained with the coupling  530 . The contact structure  534  may inhibit flow of injection fluid from syringe  540 , such as air, between the retention structure  532  and wall  252  of the exchange apparatus, for example with a seal between the retention structure  532  and the wall  252  of the exchange apparatus  200 . 
         [0190]      FIG. 15  shows a cap  520  placed on the connector  290  to couple the syringe to the exchange apparatus, so as to inhibit fluidic flow from syringe  540  through the needle of the elongate structure  201 . 
         [0191]      FIG. 16  shows the exchange apparatus placed within receptacle  536  of the coupling  530  so as to couple the receiver container  250  with the syringe  540 . The syringe  540  can pressurize the channel  254  so as to displace the implantable device fluid comprising the sample fluid  264  from the receiver container  250  into a sample container  400  for analysis. The annular protrusion  534  can engage the outer wall  252  of the exchange apparatus  200  form a seal and pressurize chamber  250  when the plunger of syringe  540  is depressed. The pressurization of chamber  250  urges the implantable device fluid  262   
         [0192]      FIG. 17  shows an exchange apparatus  200  coupled to a removable receiver container  250 . The removable container  250  may comprise a penetrable barrier, for example a septum. The exchange apparatus  200  can be coupled to a syringe  300 . The exchange apparatus can be coupled to a device  100  implanted in an eye with the elongate structure  201  configured to extend through the conjunctiva  16  and the penetrable barrier  184 . The exchange apparatus may comprise a first channel coupled to the plurality of openings to receive the fluid from the implantable device, and a second channel coupled to a vent. The first channel  239  may extend to a first needle  710  to puncture container  250  and the second channel may extend to a second needle  720  to puncture the container  250 . The first needle may have a first opening  712 , and the second needle may have a second opening  722 . The first opening can be located below the second opening, such that the second opening allows air to pass when liquid passes through the first opening. 
         [0193]      FIG. 18  shows the exchange apparatus  200  coupled to the implanted device  100  so as to exchange fluid and receive sample fluid  264  from the implanted device. The container  250  can be coupled to the exchange apparatus during exchange. 
         [0194]      FIG. 19  shows the exchange apparatus  200  removed from the implanted device  100  and the receiver container  250  detached from the exchange apparatus  200 . The sample fluid  264  from the implantable device can be contained within the container  250 . 
         [0195]      FIG. 20A  shows components of a container  400  to remove a sample fluid  264  from exchange apparatus  200 . The container  400  may comprise a sealable container having a wall composed of a barrier material  410  to inhibit evaporation, a cap  430  and an annular protrusion  432 . A support  450  can be placed within container to receive and hold the exchange apparatus  200  within the container. The support  450  may comprise a piece of soft elastomeric tubing such as silicone tubing, for example. 
         [0196]      FIG. 20B  shows an exchange apparatus  200  placed in the container  400  having components as in  FIG. 20A . The exchange apparatus is placed such that the wall  252  of container  250  rests on the support  450 . The elongate structure  201  extends below the support  450 . The container  400  comprises an axis  400 A, which axis may be aligned with the axis of exchange apparatus  200 . The opening  258  coupled to container  250  with channel  254  is exposed to air. 
         [0197]      FIGS. 20C and 20D  show removal of implantable device fluid  262  comprising sample fluid  264  from exchange apparatus. The sample fluid  264  may be drawn into the container  400  with aspiration. A syringe  300  can be coupled to the exchange apparatus  200  with a connector  320  such as a locking connector, for example. The syringe  300  may comprise a piston  302  connected to a plunger  304  which allows the piston to be advanced and pulled back. The syringe  300  comprises a chamber  310  having a volume defined with the location of piston  302 . 
         [0198]    The piston of the syringe can be drawn outward to draw air from chamber  440 , which chamber draws sample fluid  264  into chamber  440 . 
         [0199]      FIG. 21  shows a method  1800  of removal from an exchange apparatus with a removal container as in  FIGS. 20A to 20D . A step  1810  removes the exchange apparatus  200  from the syringe after injection of the therapeutic fluid. The implantable device fluid comprising the sample fluid is contained in the receiver container  250 . 
         [0200]    A step  1810  removes therapeutic fluid  260  from the needle of the elongate structure  201  with injection of a gas comprising air from a syringe  300 . 
         [0201]    A step  1820  depresses the plunger towards the needle. 
         [0202]    A step  1830  places the exchange apparatus  200  on the support  450  of container  400  with the exchange apparatus coupled to syringe  300 . The support  450  coupled to exchange apparatus  200  may define a chamber  440 . The support  450  can be shaped to inhibit air flow between and outer surface of the exchange apparatus and an inner surface of the support  450 , for example with a seal formed between the outer surface of the exchange apparatus  200  and the inner surface of the support  450 . The support may comprise a soft material, such as a soft elastomeric material, for example. 
         [0203]    A step  1840  draws air from chamber  440  with syringe  300  through the injection needle of the elongate structure extending into chamber  440 . The implantable device fluid  262  comprising sample fluid  264  is displaced from the receiver container with air drawn into the receiver container  250  through opening  258  of channel  254 . The implantable device fluid  262  comprising sample fluid  264  falls to the lower end of chamber  440  and is contained on an inner surface of container  400 . 
         [0204]    A step  1850  removes the exchange apparatus  200  and syringe  300  from the sample container  400 . The cap  430  is placed on the container  400 , so as to inhibit evaporation of the implantable device fluid  260  comprising sample fluid  264 . 
         [0205]      FIG. 22  shows an exchange apparatus  200  having a receiver container  250  comprising a penetrable barrier structure  259  on a side port to remove a sample from the receiver container with a needle and syringe. The syringe can draw implantable device fluid  262  comprising sample fluid  264  from the receiver container  250  through a needle  330  passing through the penetrable barrier structure  259  on the side port. 
         [0206]      FIG. 23A  shows an exchange apparatus  200  having a receiver container  250  coupled to a sample container  400  and a syringe  300  to displace fluid from the receiver container  250 . The sample container  400  is placed over the plurality of openings  236  and a needle  330  of a syringe  300  extends into a chamber  440  the sample container. The syringe  300  can draw fluid from chamber  440  so as to displace fluid from the receiver container  250 . The channel  254  extends from container  250  to opening  258 . Fluid drawn through needle  330  into syringe  300  urges the implantable device fluid  262  comprising sample fluid  264  through the one or more openings comprising the plurality of openings  236 , and air can move inward through opening  258  and along channel  254  to displace the implantable device fluid  262  comprising sample fluid  264 . The needle  270  extends through the sample container  400  such that the distal end of the needle extends beyond sample container  400 . The plurality of openings  236  may comprise a plurality of openings of sheath  280 . 
         [0207]      FIG. 23B  shows the sample container  400  of  FIG. 23A  placed over the plurality of openings  236  of the exchange apparatus. The sample container  400  may comprise a first penetrable barrier comprising penetrable barrier material  420  and a second penetrable barrier comprising penetrable barrier material  420 . A first septum  422  can be located opposite a second septum  422 , for example. The elongate structure  201  can extend through the first penetrable barrier and the second penetrable barrier so as to position the one or more openings between the first penetrable barrier and the second penetrable barrier. The sample container  400  may comprise a wall composed of a barrier material  410 , and the wall may comprise an amount of rigidity sufficient to resist deflection when the sample is drawing with needle  330 . The wall may comprise an annular shape, for example a tubular geometry. The needle  270  may extend through the second penetrable barrier so as to inhibit fluidic coupling of the syringe  300  and needle  330  with the opening on the distal end of needle  270 . The sample container  400  can be shaped in many ways, for example with a spherical ball or other shape having a walls composed of penetrable barrier material  410  such that the needle tip can extend through both side of the container  400 . 
         [0208]      FIGS. 24A and 24B  show an exchange apparatus having a receiver container  250  coupled to a syringe  300  with a sample container  400  placed over openings  236  of the exchange apparatus  200  so as to remove a sample fluid  264  from the receiver container  250 . The sample container  400  comprises a chamber  440  enclosed with a wall comprising a barrier material  410  and a penetrable barrier material  420 , in which the penetrable barrier material may comprise a septum, for example. The wall of the container  400  may comprise one or more of many shapes such as annular, spherical, cubic, ellipsoidal or oval, for example. The elongate structure  201  comprising needle  270  and sheath  280  can be advanced into the container  400  so as to place at least one opening of the plurality of openings  236  within the chamber  440  and the distal needle tip comprising the opening to place therapeutic fluid within the chamber  440 . The needle can be coupled to syringe  300 , and fluid drawn from chamber  440  with syringe  300  through an opening in the distal tip of needle  270 . The fluid drawn through the needle  270  is replaced with the fluid passed through the plurality of openings  236 . 
         [0209]    The receiver container  250  comprising the implantable device fluid  262  comprising sample fluid  264  is fluidically coupled to the plurality of openings as described herein such that the implantable device fluid  262  comprising the therapeutic fluid  264  is passed through the plurality of openings. The channel  254  extends from the receiver container  250  to the opening  258  such that air may be drawn into the receiver container  250  to replace the volume of the displaced implantable device fluid  262  comprising sample fluid  264 . In many embodiments, the implantable device fluid  262  comprising the sample fluid  264  comprises a liquid comprising water as described herein. 
         [0210]      FIG. 25A  shows an exchange apparatus  200  comprising a removable receiver container  250  comprising a removable sheath  280  placed over a needle  270 . The receiver container  250  may comprise the sample container  400 . The wall  252  of container  250  and needle  270  can be configured for removal and separation from the needle  270  so as to provide the sample container  400 . The sheath  280  may be supported on a distal end of the wall  252  of container  250 , such that the sheath  280  can be supported with the wall  252  of container  400  when removed. A plug  960  comprising penetrable barrier material  420  can be placed over the sheath  280  needle  270  prior to removal of the needle to inhibit leakage of the implantable device fluid  262  comprising sample fluid  264 . 
         [0211]      FIG. 25B  shows the removable container  400  of  FIG. 25A  with a plug  960  comprising penetrable barrier material  420  placed over the sheath  280  and the needle  270  removed, such that the sheath  280  is supported with the container  400 . The implantable device fluid  262  comprising sample fluid  264  remain in the receiver container  250  comprising sample container  400  subsequent to removal of the needle  200 . 
         [0212]      FIG. 25C  shows the removable container of  FIGS. 25A and 25B  with plug  960  placed over the sheath  280  and a cap  430  over the removable receiver container. The cap  430  can inhibit one or more of evaporation or leakage of the implantable device fluid  262  comprising sample fluid  264 . 
         [0213]      FIGS. 26A to 26E  show a centrifuge used to remove the fluid sample from the receiver container of the exchange apparatus. 
         [0214]      FIG. 26A  shows the exchange apparatus  200  comprising the receiver container  250  having the implantable device fluid  262  comprising the sample fluid  264  contained therein, in which the exchange apparatus is configured for placement within the sample container  400 . The sample container  400  may comprise a centrifuge tube having a support  450  as described herein. The exchange apparatus  200  may comprise a channel  254  extending from receiver container  450  to opening  258 , so as to couple the opening  258  to the plurality of openings  236 . As the implantable device fluid  262  comprising sample fluid  264  contained within receiver container  250  comprises a density greater than air, the fluid within the receiver container can be displaced through the plurality of openings  236  of the exchange apparatus  200 . Air can pass through opening  258  and channel  254  into the receiver container  250  to replace the volume of implantable device fluid  262  comprising sample fluid  264  displaced from receiver container  250  and through the plurality of openings  236 . 
         [0215]      FIG. 26B  shows the exchange apparatus  200  placed in the sample container  400 . 
         [0216]      FIG. 26C  shows the exchange apparatus  200  in the sample container  400  configured for placement in a centrifuge  500 . 
         [0217]      FIG. 26D  shows the exchange apparatus  200  in the sample container  400  placed in a centrifuge  500 . 
         [0218]      FIG. 26E  shows the exchange apparatus  200  within the sample container  400  subjected to force within the centrifuge  500 , such that the force of the centrifuge  500  is sufficient to displace the implantable device fluid  262  comprising sample fluid  264  from the receiver container  400  through the plurality of openings  236  as described herein. The implantable device fluid  262  comprising sample fluid  264  is deposited on the lower end portion of an inner surface the sample container  400 . 
         [0219]      FIG. 26F  shows an embodiment comprising exchange apparatus  200  placed in a sample container  400  comprising a centrifuge tube. The container  400  may comprise a barrier material  410  to inhibit evaporation from within the container to the outside environment, a cap  430  and a base supporting a soft penetrable material as described herein. The cap  430  may comprise a protrusion such as an annular protrusion  432  to seal around an outer portion of the wall of the container, for example. When the cap  430  is placed on the top of the tube, the chamber  440  can be sealed so as to inhibit evaporation, for example. The barrier  410  may comprise sufficient strength so as to inhibit penetration with the needle of the elongate structure  201  when placed in a centrifuge, for example. 
         [0220]      FIG. 26G  shows an embodiment comprising an exchange apparatus  200  placed in a sample container  400  comprising a centrifuge tube, in which the centrifuge tube comprises a support  450  comprising an annular shoulder  450 S of the tube to engage and hold the exchange apparatus. The support  450  can engage the exchange apparatus  200  to support the exchange apparatus in a centrifuge, for example, with a gap extending between the lower surface of the tube and the distal tip of the needle of the exchange apparatus so as to inhibit penetration of the sample container with the needle. The container  400  may comprise additional structures as described herein. 
         [0221]      FIG. 26H  shows an embodiment of an exchange apparatus  200  placed in a sample container  400  comprising a centrifuge tube, in which the centrifuge tube comprises a support  450  comprising restricted portion to hold the exchange apparatus. The support  450  may comprise a rib to engage the exchange apparatus  400 , for example. The rib  450 R can be formed with a recess in the outer surface of the container  400 . The support comprising the rib can engage and support the exchange apparatus such that a gap extends between the distal end of elongate structure  201  and the lower surface of the tube 
         [0222]      FIG. 27A  shows an embodiment of a collapsible fluid separator  510  for use with a therapeutic device. The collapsible fluid separator  510  may comprise a plunger and can be penetrable with a needle and configured to form a seal around the outer perimeter. The fluid separator  510  may comprise a distal shape profile corresponding to the distal portion of the reservoir chamber so as to displace fluid from the distal portion near the porous structure  150  as described herein. The fluid separator  510  may be penetrated with a needle and may comprise a septum, for example. The penetrable fluid separator can be penetrated with a needle for fluid removal and refill. In many embodiments, the fluid separator  510  is configured to expand and contract so as to contact the inner wall of the reservoir chamber  140  and form a seal with wall of the reservoir chamber. The fluid separator  510  can be configured to expand and contract to maintain contact with a wall having a varying cross-sectional dimension such as a varying diameter. In many embodiments, the fluid separator  510  is configured to contract so as to decrease the volume of the fluid separator such that the volume of the reservoir chamber available to receiver therapeutic fluid  260  can be substantially maintained. 
         [0223]      FIG. 27B  shows an embodiment of plunging structure  520  comprising an exchange needle  522  and an engagement structure comprising shoulder  524  suitable for use with the collapsible fluid separator as in  FIG. 27A  and a therapeutic device. The needle  522  comprises an internal channel to receiver fluid to remove the implantable device fluid and place the therapeutic fluid in the reservoir chamber. The plunging structure may comprise an engagement structure, for example shoulder  524 , so as to engage the collapsible separator and advance the fluid separator  510  distally toward the porous structure with a thrusting movement. 
         [0224]      FIG. 27C  shows an embodiment of the collapsible fluid separator as in  FIG. 27B  placed within a reservoir chamber  140  of a therapeutic device  100 . The collapsible separator  510  is shown near the proximal end of the implantable therapeutic device  100 , which comprises the access port  180  and retention structure  120 . The access port  180  may comprise a penetrable barrier  184  capable of penetration with the needle of the plunging structure, or a removable structure such as a cap, plug or the like which can be removed to introduce the plunging structure. 
         [0225]      FIG. 27D  shows an embodiment of the plunger  520  comprising the exchange needle and shoulder as in  FIG. 27B  advanced into the access port  180  of the therapeutic device having the collapsible fluid separator  510  placed within the reservoir chamber  140  of the therapeutic device as in  FIG. 27C . 
         [0226]      FIG. 27E  shows an embodiment of the plunging structure  520  and collapsible fluid separator  510  advanced within the reservoir chamber  140  of the therapeutic device as in  FIG. 27D  so as to displace the implantable device fluid  562  from the reservoir chamber through the needle. The collapsible fluid separator  510  has expanded from a first cross-sectional dimension across, for example a first diameter, to a second cross-sectional dimension across, for example a second cross-sectional diameter larger than the first. The expandable and collapsible fluid separator  510  can expand or collapse so as to contact the side wall of the reservoir chamber  140  and inhibit flow between a lower side and an upper side of the expandable and collapsible fluid separator  510 . The inhibited flow around the outer perimeter of the fluid separator can provide pressurization of the implantable device fluid near the tip of exchange needle  522  so as to drive implantable device fluid into the exchange needle. Alternatively or in combination, suction can be applied to the exchange needle so as to draw implantable fluid from the exchange needle  522  and advance the separator  510  toward the porous structure  150 . In many embodiments, the porous structure  150  comprises a resistance to flow sufficient to inhibit flow of one or more of the implantable device fluid or the therapeutic fluid through the porous structure during the exchange as described herein. 
         [0227]      FIG. 27F  shows an embodiment of the collapsible fluid separator  510  advanced within the reservoir chamber to a location near the distal end of the reservoir chamber so as to displace most of the implantable device fluid from the reservoir chamber through the needle  522 . The needle  522  may contact porous structure  150 , which may comprise a rigid porous structure as described herein. 
         [0228]      FIG. 27G  shows an embodiment of the collapsible fluid separator  510  moved from the distal end of the reservoir chamber comprising porous structure  150 . The collapsible fluid separator  510  can be moved in one or more of many ways to place the therapeutic fluid in the distal portion of the reservoir container. The therapeutic fluid can be injected through the needle  522 , or another needle for example, so as to place the therapeutic fluid  260  in the distal portion of the container. Alternatively or in combination, the expandable and collapsible fluid separator can be pulled toward the proximal end of the reservoir chamber so as to draw therapeutic device fluid through the needle and into the reservoir chamber from an external container of the exchange apparatus as described herein. 
         [0229]      FIG. 27H  shows an embodiment of the collapsible fluid separator  510  moved from the distal end of the reservoir chamber to the proximal end of the reservoir chamber so as to fill substantially the reservoir chamber with therapeutic fluid  260 . The collapsible fluid separator  510  comprises a substantially decreased size and volume so as to fit substantially within the neck of the reservoir chamber such that a substantial amount of the volume of the reservoir is filled with therapeutic fluid  260 . 
         [0230]      FIG. 27I  shows an embodiment of a substantially non-collapsible fluid separator  510  placed within the reservoir chamber  140  of therapeutic device  100  having a substantially fixed cross sectional size. The container  130  comprising reservoir chamber  140  may comprise a substantially cylindrical tubular barrier  160 . The fluid separator may comprise a piston slidable within the tubular barrier  160 , for example. 
         [0231]      FIG. 28A  shows an embodiment of an exchange apparatus  550  comprising a balloon  560  supported on a elongate tubular member  580  capable of introduction into an implantable therapeutic device  100  as to exchange the implantable device fluid  262  with a therapeutic fluid  260 . 
         [0232]    The exchange apparatus  550  may comprise an elongate tubular structure  570  shaped to penetrate tissue, for example a needle. The elongate tubular structure  570  shaped to penetrate tissue can be advanced into access port  180  through penetrable barrier  184 , followed by balloon  560  and the distal end of elongate tubular member  580 , such that balloon  560  is placed in the reservoir chamber. 
         [0233]    The balloon  560  may comprise a highly compliant balloon. As the balloon  560  is inflated, implantable device fluid is displaced out of the reservoir chamber. The balloon  560  may comprise Pebax™ or another highly elastic material such as silicone, for example, or a non-elastic material capable of being one or more of folded, rolled or compressed, for example. The balloon  560  may comprise a tubular structure and supported on the outside diameter of the needle or a sheath over the needle prior to inflation. The balloon may be designed to inflate proximally to distally, e.g. top down, to contact the inner wall of the reservoir chamber and displace fluid toward the vent needle opening. The balloon may be inflated with therapeutic fluid  260 . The balloon may be retractable within a sheath, for example. A sheath may be provided to deliver the balloon through the penetrable barrier, for example with the sheath penetrating the penetrable barrier to protect and place the balloon in the reservoir chamber without substantial contact of the balloon to the penetrable barrier when the balloon is placed. 
         [0234]    The exchange apparatus  550  comprises components and structure to inflate balloon  560  and remove implantable device fluid  262  from the reservoir chamber  140 . The elongate tubular structure  570  shaped to penetrate tissue may comprise a channel  572  to fluidically couple the reservoir chamber  140  with an external container, for example. The elongate tubular member  580  may comprise a first lumen  582  and a second lumen  584 , for example. The elongate tubular member  580  can be connected to one or more containers, syringes, or pumps, for example. The elongate tubular member  580  may comprise a first connector  588  fluidically coupled to first lumen  582 , and a second connector  586  fluidically coupled to the second lumen  584 , for example. The first lumen  582  of the elongate tubular member  580  can fluidically couple to channel  572  and external connector  588 , for example, such that the implantable device fluid  262  can be received in a receiver container as described herein. The second lumen  584  can fluidically couple the connector  586  to balloon  560 , so as to allow inflation of the balloon, for example with a syringe. The connector  586  and the connector  588  may each comprise standard known connectors as described herein, for example. The exchange apparatus  550  may comprise one or more catheter components known to a person of ordinary skill in the art in the field of catheter design and suitable for combination in accordance with the teachings described herein, for example. 
         [0235]      FIG. 28B  shows an embodiment of the balloon  260  as in  FIG. 28A  inflated within the therapeutic device to displace the implantable device fluid  262 . The balloon  560  may be inflated with the therapeutic fluid  260  as described herein, for example. The therapeutic fluid  260 , or another fluid, can be injected into the balloon with a syringe coupled to connector  586  such that the injected fluid travels along lumen  584  to inflate the balloon  560 . The implantable device fluid  262  can be displaced with the balloon so as to urge the implantable device fluid  262  into channel  572  of the elongate structure  260  shaped to penetrate tissue. The porous structure  150  may comprise a substantial resistance to flow to inhibit flow of implantable device fluid  262  through the porous structure. 
         [0236]      FIG. 28C  shows an embodiment of the balloon  560  deflated within the therapeutic device  100  to provide space for the therapeutic fluid  260 . In many embodiments, the receiver container as described herein, for example a bag, can be disconnected from connector  588 , and a syringe comprising therapeutic fluid  560  coupled to connector  580 . The syringe or other fluid source used to fill balloon  560  can be decoupled from lumen  582 , and the therapeutic fluid  560  can be injected into elongate structure  570  to place therapeutic fluid  260  in reservoir chamber  140  such that the fluid within balloon  560  is displaced and the size of balloon  560  decreased. When the size of balloon  560  has decreased sufficiently, the balloon  560  and elongate structure  570  can be removed from the implantable device  100  by passing through the penetrable barrier  184 . The balloon  560  and elongate structure  570  can be removed in many ways, for example by one or more of pulling on elongate tubular member  580  or injecting therapeutic fluid  560  into reservoir chamber  140 , so as to displace balloon  560  and elongate structure  570  from the reservoir chamber  140 . In many embodiments, reservoir chamber  140  can be pressurized with injection of therapeutic fluid  260  so as to displace the balloon  560  and elongate structure  570  through the penetrable barrier  184  with pressure. 
         [0237]      FIG. 28D  shows an embodiment of the balloon  560  punctured within the therapeutic device  100  so as to release the therapeutic fluid  260  from the balloon to the reservoir chamber  140  of the therapeutic device  100 . The therapeutic  100  may comprise internal structures  590  to puncture the balloon and release the therapeutic agent. The internal structure  290  may comprise a sharp tip, for example a needle tip to penetrate the balloon  560  and release the therapeutic agent. The internal structure  590  can be supported on the wall of the reservoir chamber, for example. 
         [0238]      FIG. 29A  shows an embodiment of a deflectable fluid separator  600  placed within an implantable therapeutic device  100 . The deflectable fluid separator  600  inhibits mixing of the implantable device fluid  262  with the therapeutic fluid  260 . The deflectable fluid separator  600  can separate portions of the reservoir chamber so as to define a first portion  141  on a first side of the chamber and a second portion  143  on a second side of the reservoir chamber. The first portion  141  of the reservoir chamber  140  may be coupled to a first porous structure  151  to provide sustained release from the first portion and the second portion  143  of the reservoir chamber  140  may be coupled to a second porous structure  153  to provide sustained release from the second portion. The porous structures can be substantially similar to porous structure  150  as described herein. The deflectable fluid separator  600  may comprise a barrier material to inhibit flow of the therapeutic agent, and may comprise one or more of a bladder, diaphragm, a membrane, or a sheet of distensible material, for example. The deflectable fluid separator may comprise an expandable bladder capable of deflection to either side of the reservoir chamber, for example. The deflectable fluid separator may be used with exchange apparatus  200  as described herein. The elongate structure  201  of the exchange apparatus may comprise a bi-needle design as described herein, for example with a first needle to advance fluid into a first side of the bladder and a second needle to receiver fluid from a second side of the bladder, in no particular order, or simultaneously, for example. 
         [0239]      FIG. 29B  shows an embodiment of the deflectable fluid separator as in  FIG. 29A  displaced to the second side of the reservoir chamber to remove fluid from the second portion  143  of the reservoir chamber. The removal of fluid from portion  143  can be achieved in many ways. For example, the deflectable fluid separator can be displaced with injection into first portion  141  so as to displace implantable device fluid  262  from second portion  143 . A first needle  611  and a second needle  613  can be advanced so as to extend through penetrable barrier  184  into first portion  141  and into second portion  143 , respectively. The first needle can inject fluid into first portion  141  to displace fluid from second portion  143 . Alternatively or in combination, the second needle  613  can be aspirated to draw fluid from second portion  143  with suction, and a fluid may be drawn into first portion  141  through first needle  611 . 
         [0240]      FIG. 29C  shows an embodiment of the deflectable fluid separator  600  as in  FIG. 29B  displaced to the first side of the reservoir chamber with a therapeutic fluid  260  placed in the second portion  143  of the reservoir chamber  140 . The therapeutic agent  110  contained within second portion  143  can be released through porous structure  153  in a manner similar to porous structure  150  as described herein. When a sufficient amount of therapeutic agent has been released from second chamber  143  for an extended time through porous structure  153 , the fluid can be removed from second portion  143  as described herein and a second amount of therapeutic fluid  260  placed in first portion  141  for sustained release for another extended time through porous structure  151 . The removal and placement of fluid with the deflectable separator can be repeated as many times as is helpful to treat the patient. 
         [0241]      FIG. 30A  shows an embodiment of an exchange apparatus  200  comprising a valve  700  to direct flow toward a second receiver container  704  when a sample  264  of the implantable device fluid  262  has been placed in a first receiver container  702 . The valve  700  can inhibit mixing of the implantable device fluid  262  with the therapeutic fluid  260 , such that sample fluid  264  may comprise no substantially amount of therapeutic fluid  260 . The sample fluid  264  can be removed used for one or more assays as described herein. The valve  700  may comprise one or more of a porous structure, a float valve, an annular float valve, a ball float valve, a flap valve, a flap valve with a float, a duckbill valve, or a stopcock. The valve  700  may comprise a manual valve, or may comprise one or more structures to automatically close or open when a sufficient amount of fluid has been placed in the first receiver container. The receiver container  250  may comprise the first receiver container  702  and the second receiver container  704 . The exchange apparatus  200  may comprise one or more of the elongate structure  201 , needle  270 , sheath  280 , receiver container  250 , at least one opening  258 , connector  290 , syringe  300 , piston  302 , plunger  304 , chamber  310 , or connector  320  as described herein, for example. 
         [0242]    The valve  700  may be configured in many ways to provide sample  264  of implantable device fluid  262 . With elongate structure  301  introduced into therapeutic device  100 , an initial amount of implantable device fluid  262  can be placed in first receiver container  702  with valve  700  comprising a first configuration. The first configuration of valve  700  can fluidically couple one or more openings  236  of elongate structure  201  with the first receiver container  702  and inhibit fluidic coupling of the one or more openings of elongate structure  201  with second receiver container  702 . When a sufficient amount of implantable device fluid  262  has been placed in the first receiver container  702 , the configuration valve  700  can change from the first configuration to the second configuration. The second configuration of valve  700  can fluidically couple the one or more openings  236  with the second receiver container  704  and inhibit flow to the first receiver container  702 , such that a majority of the therapeutic fluid  260  mixed with implantable device fluid  262  is placed in second receiver container  704 . 
         [0243]    The valve  700  may comprise a manual valve  710  operable by a user, and may comprise one or more of many valves known to a person of ordinary skill in the art, for example a stopcock or other manual or automatic valve, for example. 
         [0244]    The sample  264  within first container  702  can be removed for analysis with one or more of many methods or structures as described herein. 
         [0245]      FIG. 30B  shows an embodiment of an exchange apparatus  200  having a valve  700  comprising a porous structure  720  to direct flow toward a second receiver container  704  when sample  264  of the implantable device fluid  262  has been placed in first receiver container  702 . The valve  720  may comprise a substantially dry porous structure in an initial open configuration and a gas such as air can be situated within first receiver container  702 . Implantable device fluid  262  accumulates in the first receiver container  702  and rises inside the first container  702  from a distal end near the elongate structure to a proximal end of the first container. When a sufficient amount of implantable device fluid  262  is placed on first container  702 , the valve  720  contacts the implantable device fluid  262  comprising liquid and the resistance to flow of the valve  720  increases substantially. The wetted valve  720  comprises a substantially closed configuration such that the implantable device fluid  262  passes through a flow resistance structure  722 . The flow resistance structure  722  comprises a resistance to flow when wet that is greater than the resistance to flow of valve  720  in the dry configuration and substantially less than the resistance to flow of valve  720  in the wet configuration, such that the dry valve  720  corresponds to a substantially open configuration and the wet valve  720  corresponds to a substantially closed configuration. The valve  720  and the flow resistance structure  722  may each comprise a porous structure similar to the porous structure for sustained release of the therapeutic agent as described herein, for example. 
         [0246]    The valve  720  and flow resistance structure  722  can be configured in many ways to provide sample  264  of implantable device fluid  262  with no substantial portion of therapeutic fluid  260 . The relative resistance to flow of the porous structure  720  when we can be substantially greater than the resistance to flow of the resistance structure  722  when wet, for example at least about twice, and in many embodiments at least about five times the resistance to flow of the flow resistance structure. The flow resistance structure  722  may comprise a valve that opens under pressure such as a duckbill valve or flap with a spring, for example. A baffle  728 , a channel, or other internal structure can be provided to inhibit mixing of the therapeutic fluid  260  and implantable device fluid  262  with the sample fluid  264  when valve  720  is wet and comprises the closed configuration. 
         [0247]      FIG. 30C  shows an embodiment of an exchange apparatus  200  in which valve  700  comprises a float valve  730 . The float valve  730  comprises a float ball  732  to direct flow toward a second receiver container  704  when a sample  264  of the implantable device fluid  262  has been placed in a first receiver container  702 . The valve  732  can slide along first container  702 . A valve  736  such as a flap valve or duckbill valve, for example, can be provided to provide a resistance to flow and drive fluid into the first receiver container  702 . When the implantable device fluid  262  advances into container  702 , float ball  732  rises in the first container  702  until the float ball contacts a seat  734  and inhibits flow into the first container. When float ball  732  contacts seat  734  additional flow into first container  702  is inhibited and valve  736  opens to allow implantable device fluid  262  into the second receiver container  704 . The received implantable device fluid  262  mixed with therapeutic fluid  260  may displace a gas such as air through opening  258 . A flow resistance structure  738  such as a second duck bill valve or baffle can be provided near the opening to the first container to inhibit mixing of sample  264  of the first receiver container  702 , for example. 
         [0248]      FIG. 30D  shows an embodiment of an exchange apparatus  200  having a valve  700  comprising a float valve  740 . The float valve  740  comprises a sliding annular structure  744  to direct flow toward a second receiver container  704  when a sample  264  of the implantable device fluid  262  has been placed in first receiver container  702 . The sliding annular structure  744  may comprise an annular float ring  742  coupled to a tube having an opening  745  to pass fluid when the valve  740  is open. The sheath  280  can extend over needle  270  upward from the first receiver container  702  to the second receiver container  704 . The sheath  280  may comprise one or more openings  236  to pass the implantable device fluid  262  into the first receiver container  702  through opening  745 . As the first receiver container  702  receives implantable device fluid  262 , valve  740  rises and slides axially along sheath  280  such that a portion  747  of annular structure  744  slides over one or more openings  236  to inhibit flow to the first receiver container  702 . 
         [0249]    In the closed configuration, valve  740  directs flow of the implantable device fluid  262  and therapeutic fluid  260  into second receiver container  704  through holes  748  in sheath  280 . The exchange apparatus may comprise connector  290  to couple to a syringe as described herein. 
         [0250]      FIG. 30E  shows an embodiment of an exchange apparatus  200  in which valve  700  comprises a float valve  750  to direct flow toward a second receiver container when a sample of the implantable device fluid has been placed in a first receiver container. Float valve  750  comprises a flap  752 . The flap  750  allows sample fluid  262  to enter the first receiver container  702  through openings  757  of sheath  280 , and when a sufficient amount of sample fluid has been received with sample container  702 , float valve  750  closes to inhibit flow through openings  757 . The implantable device fluid  262  is passed through opening  758  into second receiver container  704  when the float valve  750  is closed. 
         [0251]    FIG.  31 A 1  shows an embodiment of an exchange apparatus  200  having a receiver container  250  comprising a fluid separator  800  comprising an internal channel  822  sized to support the implantable device fluid  262  with a pocket of air. The fluid separator  800  may comprise a tubular structure  820 , for example a column, having an internal dimension such as a diameter sized to support the implantable device fluid with an immiscible separator fluid. The immiscible separator fluid may comprise one or more of an oil, a hydrophobic liquid, a gas, or air, for example. The exchange apparatus may comprise one or more of many structures as described herein such as connectors to couple to a syringe and an elongate structure comprising a sheath and needle. The internal channel  822  of fluid separator  800  can be fluidly coupled to openings  236  to receive implantable device fluid  262  as described herein. The fluid received from the implantable device can be received in receiver container so as to separate the implantable device fluid  262  from the therapeutic fluid  260 . The internal channel  822  may initially comprise a gas such as air which can be displaced through opening  258  of receiver container  250 . 
         [0252]    While the exchange apparatus can be used in many ways with an immiscible separator fluid such as a gas comprising air, in many embodiments the therapeutic fluid  260  is first drawn into a syringe  300 , and then the immiscible separator fluid such as air drawn into syringe  300 . The syringe  300  can be coupled to the exchange apparatus  200  with the therapeutic fluid supported with the immiscible separator fluid such as air within the container, for example. In many embodiments, the barrel of the syringe comprises an inner diameter sized such that the therapeutic fluid  260  can remain free standing within the barrel of the syringe and may be supported with air, such that the air can be injected into the implantable device before the air is injected. The implantable device may comprise a maximum cross-sectional dimension, for example a maximum diameter, such the implantable device fluid can be supported and displaced with the immiscible separator fluid  810  placed in the lower portion of the reservoir chamber  140  near porous structure  150 . Injection of the immiscible separator fluid  810  displaces implantable device fluid  262  through one or more openings  236  of sheath  280  and upward into channel  822 . When a substantial portion of the implantable device fluid has been displaced from the reservoir chamber, for example with air, the therapeutic fluid  260  can enter the reservoir chamber such that the implantable device fluid  262  remains substantially separated from the therapeutic fluid  260  introduced into the reservoir chamber  140 . 
         [0253]    The separator fluid  810  may comprise a miscible separator fluid, for example saline or other liquid capable of mixing with the therapeutic fluid  260  and the implantable device fluid  262 , and the separator fluid  810  may comprise a sufficient volume so as to inhibit mixing of the therapeutic fluid  260  with the implantable device fluid  262 . In many embodiments, the separator fluid  810  comprises a fluid not miscible with the therapeutic fluid  260  and implantable device fluid  262 , each of which may comprise substantial amounts of water. The immiscible separator fluid  810  can inhibit mixing of the implantable device fluid  262  and the therapeutic fluid  260  with the separator fluid  810 , such that the separator fluid  810  may comprise a barrier and inhibit mixing of the components of the implantable device fluid  262  with components of the therapeutic fluid  260 . 
         [0254]    FIG.  31 A 2  shows an embodiment of the exchange apparatus  200  of FIG.  31 A 1  having the implantable device fluid  262  supported with a pocket of immiscible separator fluid  810  such as air  812 , so as to separate the implantable device fluid  262  from the therapeutic fluid  260 . An interface  818  extends between the immiscible separator fluid  810  and the implantable device fluid  262 . An interface  814  extends between the immiscible separator fluid  810  and the therapeutic fluid  260 . In many embodiments, immiscible separator fluid  810  comprises a gas, and implantable device fluid  262  and therapeutic fluid  260  each comprise liquid such that interface  814  comprises a meniscus and interface  818  comprise a meniscus. 
         [0255]    FIG.  31 B 1  shows an embodiment of an exchange apparatus  200  having a fluid separator  800  comprising an internal channel having a first portion  852  sized to support the implantable device fluid with a pocket of an immiscible separator fluid air and a second portion  854  sized to pass an immiscible separator fluid such as air through the implantable device fluid. The first portion may comprise a volume approximating the volume of the reservoir chamber, for example. The exchange apparatus may comprise one or more of the structures of the exchange apparatus  200  as described herein, for example receiver container  200  and container wall  252  may have dimensions so as to define the first portion  852  and the second portion  854 . 
         [0256]    FIG.  31 B 2  shows an embodiment of the exchange apparatus of FIG.  31 B 1  having the first portion  852  supporting the implantable device fluid  262  with the immiscible separator fluid  810  such as air  812 . The tip  212  of needle  270  may extend to the distal end of the reservoir chamber  140  such that the bubble forms at the distal end of the reservoir to increase exchange efficiency, for example. The reservoir chamber  140  and the first portion  852  may comprise immiscible separator fluid  810  such as air  812 . 
         [0257]    FIG.  31 B 3  shows an embodiment of the exchange apparatus of FIGS.  31 B 1  and  31 B 2  having the first portion  852  supporting the implantable device fluid  262  with the pocket of immiscible separator fluid  810  and therapeutic fluid  260 , and the second portion containing the implantable device fluid. As additional gas such as air moves upward from the first portion  852  to the second portion  854 , the immiscible separator fluid comprising a gas such as air forms bubbles in second portion  854  having the increased inner dimensions and the bubble can travel upward to escape through opening  258 . The first portion  852  and the second portion  854  may each comprise an annular channel having an inner dimension determined by the outside diameter of needle  270 , for example. The increased outer dimension of the annular channel of the second portion  854  allows bubbles to form in the implantable device fluid  262  contained in the second portion such that the bubbles can rise and escape through valve  258 . 
         [0258]      FIG. 31C  shows an embodiment of exchange apparatus  200  coupled to a syringe  300  comprising a separator structure  860  to inject a separation fluid  810  and a therapeutic fluid into therapeutic device  100  to collect a sample  264  of implantable device fluid  262 . The separator structure  860  may comprise one or more of a piston  862 , a plunger, a disk or a plug having one or more holes  862 . The holes  864  may comprise a sufficient resistance to flow such that the piston  864  moves downward toward the elongate structure  201  when the piston  302  is advanced. 
         [0259]    The piston  864  can displace the immiscible separator fluid  810  comprising air, such that the immiscible separator fluid  810  is displaced into reservoir chamber  140  and forms an interfacial boundary  816 . The interfacial boundary  816  moves toward sheath  280  as the implantable device fluid is displaced with the immiscible separator fluid  810 . When the piston  810  has advanced a sufficient distance, movement of piston  864  along the cylinder barrel is inhibited, and the therapeutic fluid  260  is displaced through the one or more holes  862  with piston  302 . The displaced therapeutic fluid  260  is placed in reservoir chamber  140 , for example with injection through needle  270 . The immiscible separator fluid  810  is displaced with therapeutic fluid  260  such that the immiscible separator fluid  810  enters receiver container  250 . 
         [0260]    In many embodiments the receiver container  250  comprises a volume that is at least the volume of the injected material comprising therapeutic fluid  260  and immiscible separator fluid  810 , such that the volume of the receiver container  250  is sufficient to retain the implantable device fluid  262  and the immiscible separator fluid  810 . The volume of immiscible separator fluid  810  injected with the therapeutic fluid can be less than, approximately the same as, or greater than the volume of the therapeutic agent injected. In many embodiments, the immiscible separator fluid  810  comprises a volume sufficient to separate the therapeutic fluid from the implantable device fluid and which is substantially less than the volume of the reservoir chamber. For example, the amount of immiscible separator fluid  810  may comprise a volume that is sufficient to form a bubble within the reservoir chamber  140  and that is substantially less than the volume of the volume of reservoir chamber  140 . 
         [0261]    The receiver container  250  can be configured in many ways to receive the implantable device fluid  262  and the immiscible separator fluid  810 . For example, the receiver container  250  may comprise the inside dimension sufficient to support the implantable device fluid with the immiscible separator fluid along a majority of the length of the receiver container  250 . Alternatively, the first portion  852  of the receiver container may comprise the inside dimension sufficient to support the implantable device fluid  262  and the second portion  854  of the receiver container may comprise the inside dimension sufficiently large so as to pass the immiscible separator fluid  810  through the implantable device fluid. A person or ordinary skill in the art can determine the internal dimensions of the first portion and the second portion based on the teachings of the present disclosure. 
         [0262]      FIG. 32  shows an embodiment of an exchange apparatus coupled to syringe  300  to draw therapeutic fluid into the implantable device from the container  250 . The implantable device fluid  262  can be drawn from the reservoir chamber in one or more of many ways, for example with syringe so to provide aspirating suction of the implantable device fluid from the implantable device into the syringe. As the needle  272  extends through penetrable barrier  184  so as to provide a seal and the porous structure  150  comprises a resistance to flow of components of the eye, the movement of the implantable device fluid  262  into the chamber of syringe  300  results in therapeutic fluid  260  moving from chamber  250  through the one or more openings  289  in sheath  280 . Air at approximately atmospheric pressure can move into container  250  to urge and displace the therapeutic fluid  260  into the reservoir chamber when the implantable device fluid  262  is drawn with the syringe. 
         [0263]      FIG. 33  shows an embodiment of a curved needle  270  of an exchange apparatus to direct therapeutic fluid  260  toward a wall  260  of a container  230  of the reservoir chamber  240 . The curved needle can be placed near the porous structure  150  and may result in a reproducible flow pattern of the therapeutic fluid  260  placed in the container. The reproducible flow pattern provided by the curved needle  270  can provide a consistent flow pattern over porous structure  150  and may provide a more uniform amount of bolus through porous structure  150 . 
         [0264]      FIG. 34  shows an embodiment of a covering  870  on a porous structure of a therapeutic device to inhibit bolus release when the therapeutic fluid is introduced. The covering  870  can inhibit bolus release when the needle is oriented toward the porous structure  150  and the covering  870 , for example. 
         [0265]      FIG. 35  shows an embodiment of a first exchange apparatus  200 A coupled to a double barrel syringe  300  to exchange a first exchange fluid  900  with the implantable device fluid  262 , and a second exchange apparatus  200 B to exchange the first exchange fluid placed in the therapeutic device with therapeutic fluid  260 . The first exchange fluid  900  may comprise the separator fluid  810  as described herein. The first exchange fluid  900  may comprise water, for example phosphate buffered saline (hereinafter “PBS”). Alternatively, the first exchange fluid may comprise an immiscible separator fluid as described herein. 
         [0266]    The first exchange apparatus  200 A and the second exchange apparatus  200 B may each comprise many of the structures of exchange apparatus  200  as described herein. For example, the first exchange apparatus  200 A and the second exchange apparatus  200 B may each comprise the elongate structure  201  and receiver container  250  as described herein. The double barrel syringe  300  may comprise the therapeutic fluid and the first exchange fluid  900 . The double barrel syringe  300  may comprise a first chamber  910  containing the first exchange fluid  900  and a second chamber  920  containing the therapeutic fluid  260 . The first chamber  910  may be coupled to a first piston  912  and plunger  914  having a first length. The second chamber  920  may be coupled to a second piston  922  and plunger  924  having a second length. The first length can be longer than the second length to that the contents of the first chamber are injected before the second chamber. The first exchange apparatus  200 A can be connected to the syringe  300  and the elongate structure  201  inserted into the implantable device as described herein, and the first plunger advanced so as to displaced the implantable device fluid  262  from the reservoir chamber  140  with the first exchange fluid  900 . The first exchange apparatus  200 A can be removed from therapeutic device implanted in the eye. The first exchange apparatus  200 A can be disconnected from the syringe  300 , and the second exchange apparatus  200 B connected to the syringe  300  and advanced into the therapeutic device  100 . The second plunger  924  can be advanced to displace the first exchange fluid  900  from the reservoir chamber  140  of the implantable device with the therapeutic fluid  260  as described herein. 
         [0267]    In many embodiments, one or more of the components of the first exchange apparatus  200 A and the second exchange apparatus  200 B can be combined for use with the double barrel syringe so that the first exchange fluid and the therapeutic fluid can each be exchanged sequentially when the exchange apparatus  200  is placed in the implantable device and without removing the exchange apparatus from the implanted device. For example, the exchange apparatus  200  may comprise the first receiver  702  container to receive the implantable device fluid and the second receiver container  704  as described herein to receive the first exchange fluid, and the first receiver container and the second receiver container can be coupled to one or more valves as described herein such that the implantable device fluid  262  is directed to the first receiver container when the valve comprises a first configuration and the first exchange fluid is directed to the second receiver container when the valve comprises a second configuration as described herein. 
       EXPERIMENTAL 
       [0268]      FIG. 36  shows an experimental test apparatus. The test apparatus comprised an injector coupled to a bi-needle exchange apparatus  200  to inject a therapeutic fluid comprising a therapeutic agent into a test implantable device  100 . The therapeutic fluid comprised a 100 mg/mL formulation of ranibizumab prepared in accordance with U.S. Pat. Pub. No. 2010/0015157, entitled “Antibody Formulations”, the full disclosure of which is incorporated by reference. The injected formulation comprised a density at least about 1% greater than the fluid of the implantable device, which comprised saline. 
         [0269]    The therapeutic fluid was injected through the penetrable barrier comprising a septum of silicone elastomer. The injector needle was approximately 33 gauge and coupled to a syringe and positioned below the receiver needle. The receiver needle received liquid from the implantable device and extended upward to a receiver container. Axis of the injector needle  202  and the axis of the implantable device  100 A were oriented to obtain samples. The reservoir chamber of the implantable device comprised about 25 μL, and about 50 μL were injected. The orientation of the axes varied from 0 degrees (horizontal) 45 degrees away from horizontal. At the −45 degree orientation the penetrable barrier was located above the reservoir chamber and the opening to the receiver needle located above the opening to the injector needle. 
         [0270]      FIG. 37  shows experimental results obtained with the test apparatus of  FIG. 36 . The refill efficiency corresponded to the amount of therapeutic fluid placed in the reservoir chamber of the implantable device when the 50 uL had been injected. For 0 degrees, the efficiency was about 80%. The efficiency increased with the angle to about 95% at −45 degrees. 
         [0271]    Table 2 shows device angles and fill efficiencies corresponding to the values in the graph of  FIG. 37 . 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Device Angle (+/−sign arbitrary) 
                 Refill Efficiency 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 0 
                 77.5 
               
               
                   
                 15 
                 88.3 
               
               
                   
                 25 
                 88.9 
               
               
                   
                 35 
                 94 
               
               
                   
                 45 
                 94 
               
               
                   
                   
               
             
          
         
       
     
         [0272]    A concentric needle device was also tested and provided similar results. 
         [0273]    Pressure studies have been conducted with the injector apparatus having the plurality of openings. The sheath comprised polyimide placed over a 33 Gauge needle. A first pressure gauge was coupled to a syringe on the input side of the needle, and a second pressure gauge was coupled to the implantable device reservoir chamber where the porous structure is shown above. The input pressure to the syringe of 12 N produced a pressure of 85 pounds per square inch (hereinafter “psi”) into the needle and implantable device chamber had a pressure of about 45 psi. This amount of input pressure corresponds to a clinically acceptable exchange time of about 5 seconds, for example. 
         [0274]    Additional experiments can be conducted by a person of ordinary skill in the art based on the teachings described herein, for example experiments with an exchange apparatus comprising a polyimide sheath comprising a plurality of openings over a needle as described herein. 
         [0275]    Additional experiments can be conducted with one or more of many release control mechanisms to determine the resistance to flow of the release control mechanism suitable for use in accordance with embodiments described herein. For example, studies can be conducted with porous structures of varying dimensions, release rates, and manufacturing processes, in order to measure the flow through the frits with pressure so as to determine the resistance to flow. 
         [0276]    While the exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of skill in the art will recognize that a variety of modifications, adaptations, and changes may be employed. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1A 
               
             
             
               
                   
               
               
                 Therapeutic Agent List 
               
             
          
           
               
                   
                   
                   
                   
                 Molecular 
               
               
                 Generic Name 
                 Brands (Companies) 
                 Category 
                 Indication 
                 Weight 
               
               
                   
               
             
          
           
               
                 2-Methoxyestradiol 
                 (Paloma 
                 Angiogenesis inhibitors 
                 AMD 
                   
               
               
                 analogs 
                 Pharmaceuticals) 
               
               
                 3-aminothalidomide 
               
               
                 13-cis retinoic acid 
                 Accutane TM (Roche 
               
               
                   
                 Pharmaceuticals) 
               
               
                 A0003 
                 (Aqumen 
                 A0003 
                 AMD 
               
               
                   
                 BioPharmaceuticals) 
               
               
                 A5b1 integrin inhibitor 
                 (Jerini Ophthalmic); 
                 Inhibitors of a5b1 integrin 
                 AMD 
               
               
                   
                 (Ophthotech) 
               
               
                 Abarelix 
                 Plenaxis ™ (Praecis 
                 Anti-Testosterone Agents; 
                 For palliative treatment of 
                 37731 
               
               
                   
                 Pharmaceuticals) 
                 Antineoplastic Agents 
                 advanced prostate cancer. 
               
               
                 Abatacept 
                 Orencia ™ (Bristol- 
                 Antirheumatic Agents 
                 For the second line reduction of 
                 37697 
               
               
                   
                 Myers Squibb) 
                   
                 the signs and symptoms of 
               
               
                   
                   
                   
                 moderate-to-severe active 
               
               
                   
                   
                   
                 rheumatoid arthritis, inducing 
               
               
                   
                   
                   
                 major clinical response, slowing 
               
               
                   
                   
                   
                 the progression of structural 
               
               
                   
                   
                   
                 damage, and improving physical 
               
               
                   
                   
                   
                 function in adult patients who 
               
               
                   
                   
                   
                 have 
               
               
                 Abciximab 
                 ReoPro ™; ReoPro ™ 
                 Anticoagulants; 
                 For treatment of myocardial 
                 42632 
               
               
                   
                 (Centocor) 
                 Antiplatelet Agents 
                 infarction, adjunct to 
               
               
                   
                   
                   
                 percutaneous 73oronary 
               
               
                   
                   
                   
                 intervention, unstable angina 
               
               
                 ABT-578 
                 (Abbott Laboratories) 
                 Limus Immunophilin 
               
               
                   
                   
                 Binding Compounds 
               
               
                 Acetonide 
               
               
                 Adalimumab 
                 Humira ™ (Abbott 
                 Antirheumatic Agents; 
                 Uveitis, AMD 
                 25645 
               
               
                   
                 Laboratories) 
                 Immunomodulatory Agents 
               
               
                 Aldesleukin 
                 Proleukin ™; 
                 Antineoplastic Agents 
                 For treatment of adults with 
                 61118 
               
               
                   
                 Proleukin ™ (Chiron 
                   
                 metastatic renal cell carcinoma 
               
               
                   
                 Corp) 
               
               
                 Alefacept 
                 Amevive ™ 
                 Immunomodulatory 
                 For treatment of moderate to 
                 42632 
               
               
                   
                   
                 Agents; 
                 severe chronic plaque psoriasis 
               
               
                   
                   
                 Immunosuppressive 
               
               
                   
                   
                 Agents 
               
               
                 Alemtuzumab 
                 Campath ™; Campath ™ 
                 Antineoplastic Agents 
                 For treatment of B-cell chronic 
                 6614 
               
               
                   
                 (ILEX Pharmaceuticals 
                   
                 lymphocytic leukemia 
               
               
                   
                 LP); MabCampath ™ 
               
               
                 Alpha-1-proteinase 
                 Aralast ™ (Baxter); 
                 Enzyme Replacement 
                 For treatment of panacinar 
                 28518 
               
               
                 inhibitor 
                 Prolastin ™ (Talecris 
                 Agents 
                 emphysema 
               
               
                   
                 Biotherapeutics C 
               
               
                   
                 formerly Bayer) 
               
               
                 Alteplase 
                 Activase ™ (Genentech 
                 Thrombolytic Agents 
                 For management of acute 
                 54732 
               
               
                   
                 Inc) 
                   
                 myocardial infarction, acute 
               
               
                   
                   
                   
                 ischemic strok and for lysis of 
               
               
                   
                   
                   
                 acute pulmonary emboli 
               
               
                 AMG-1470 
               
               
                 Anakinra 
                 Kineret ™ (Amgen Inc) 
                 Anti-Inflammatory Agents, 
                 For the treatment of adult 
                 65403 
               
               
                   
                   
                 Non-Steroidal; 
                 rheumatoid arthritis. 
               
               
                   
                   
                 Antirheumatic Agents; 
               
               
                   
                   
                 Immunomodulatory Agents 
               
               
                 Anecortave acetate 
               
               
                 Angiostatin 
               
               
                 Anistreplase 
                 Eminase ™ (Wulfing 
                 Thrombolytic Agents 
                 For lysis of acute pulmonary 
                 54732 
               
               
                   
                 Pharma GmbH) 
                   
                 emboli, intracoronary emboli and 
               
               
                   
                   
                   
                 management of myocardial 
               
               
                   
                   
                   
                 infarction 
               
               
                 Anti-angiogenesis 
                 (Eyecopharm) 
                 Anti-angiogenesis peptides 
                 AMD 
               
               
                 peptides 
               
               
                 Anti-angiogenesis 
                 (TRACON Pharma) 
                 Anti-angiogenesis 
                 AMD 
               
               
                 antibodies, TRC093, 
                   
                 antibodies 
               
               
                 TRC105 
               
               
                 Anti-angiogeric 
                 Icon-1 ™ (Iconic 
                 Anti-angiogeric bifunctional 
                 AMD 
               
               
                 bifunctional protein 
                 Therapeutics) 
                 protein, Icon-1 
               
               
                 Anti-endothelial growth 
               
               
                 factor 
               
               
                 Antihemophilic Factor 
                 Advate ™; Alphanate ™; 
                 Coagulants; Thrombotic 
                 For the treatment of hemophilia 
                 70037 
               
               
                   
                 Bioclate ™; Helixate ™; 
                 Agents 
                 A, von Willebrand diseae and 
               
               
                   
                 Helixate FS ™; Hemofil 
                   
                 Factor XIII deficiency 
               
               
                   
                 M ™; Humate-P ™; 
               
               
                   
                 Hyate:C ™; Koate- 
               
               
                   
                 HP ™; Kogenate ™; 
               
               
                   
                 Kogenate FS ™; 
               
               
                   
                 Monarc-M ™; 
               
               
                   
                 Monoclate-P ™; 
               
               
                   
                 ReFacto ™; Xyntha ™ 
               
               
                 Antithymocyte globulin 
                 Genzyme); 
                 Immunomodulatory Agents 
                 For prevention of renal 
                 37173 
               
               
                   
                 Thymoglobulin ™ 
                   
                 transplant rejection 
               
               
                   
                 (SangStat Medical 
               
               
                 Anti-hypertensive 
                 (MacuCLEAR) 
                 Anti-hypertensive MC1101 
                 AMD 
               
               
                 MC1101 
               
               
                 Anti-platelet devired 
               
               
                 growth factor 
               
               
                 Anti-VEGF 
                 (Neurotech); Avastin ™ 
                 Anti-VEGF 
                 AMD 
               
               
                   
                   
                 (NeoVista) 
               
               
                 AP23841 
                 (Ariad) 
                 Limus Immunophilin 
               
               
                   
                   
                 Binding Compounds 
               
               
                 ARC1905 
                 Ophthotech 
                 Complement Cascade 
               
               
                   
                   
                 Inhibitor (Factor C5) 
               
               
                 Aprotinin 
                 Trasylol ™ 
                 Antifibrinolytic Agents 
                 For prophylactic use to reduce 
                 90569 
               
               
                   
                   
                   
                 perioperative blood loss and the 
               
               
                   
                   
                   
                 need for blood transfusion in 
               
               
                   
                   
                   
                 patients undergoing 
               
               
                   
                   
                   
                 cardiopulmonary bypass in the 
               
               
                   
                   
                   
                 course of coronary artery bypass 
               
               
                   
                   
                   
                 graft surgery who are at an 
               
               
                   
                   
                   
                 increased risk for blood loss and 
               
               
                   
                   
                   
                 blood transfusio 
               
               
                 Arcitumomab 
                 CEA-Scan ™ 
                 Diagnostic Agents; 
                 For imaging colorectal tumors 
                 57561 
               
               
                   
                   
                 Imaging Agents 
               
               
                 Asparaginase 
                 Elspar ™ (Merck &amp; Co. 
                 Antineoplastic Agents 
                 For treatment of acute 
                 132.118 
               
               
                   
                 Inc) 
                   
                 lympocytic leukemia and non- 
               
               
                   
                   
                   
                 Hodgkins lymphoma 
               
               
                 Axitinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 386 
               
               
                 Basiliximab 
                 Simulect ™ (Novartis 
                 Immunomodulatory 
                 For prophylactic treatment of 
                 61118 
               
               
                   
                 Pharmaceuticals) 
                 Agents; 
                 kidney transplant rejection 
               
               
                   
                   
                 Immunosuppressive 
               
               
                   
                   
                 Agents 
               
               
                 Becaplermin 
                 Regranex ™; 
                 Anti-Ulcer Agents; Topical 
                 For topical treatment of skin 
                 123969 
               
               
                   
                 Regranex ™(OMJ 
                   
                 ulcers (from diabetes) 
               
               
                   
                 Pharmaceuticals) 
               
               
                 Bevacizumab 
                 Avastin ™; Avastin ™ 
                 Antiangiogenesis Agents; 
                 For treatment of metastatic 
                 27043 
               
               
                   
                 (Genentech Inc) 
                 Antineoplastic Agents 
                 colorectal cancer 
               
               
                 Bivalirudin 
                 Angiomax ™; 
                 Anticoagulants; 
                 For treatment of heparin-induced 
                 70037 
               
               
                   
                 Angiomax ™ (Medicines 
                 Antithrombotic Agents 
                 thrombocytopenia 
               
               
                   
                 Co or MDCO); 
               
               
                   
                 Angiox ™ 
               
               
                 Bortezomib 
                   
                 Proteosome Inhibitors 
               
               
                 Bosutinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 530 
               
               
                 Botulinum Toxin Type A 
                 BOTOX ™ (Allegran 
                 Anti-Wrinkle Agents; 
                 For the treatment of cervical 
                 23315 
               
               
                   
                 Inc); BOTOX 
                 Antidystonic Agents; 
                 dystonia in adults to decrease 
               
               
                   
                 Cosmetic ™ (Allegran 
                 Neuromuscular Blocking 
                 the severity of abnormal head 
               
               
                   
                 Inc); Botox ™; 
                 Agents 
                 position and neck pain 
               
               
                   
                 Dysport ™ 
                   
                 associated with cervical 
               
               
                   
                   
                   
                 dystonia. Also for the treatment 
               
               
                   
                   
                   
                 of severe primary axillary 
               
               
                   
                   
                   
                 hyperhidrosis that is 
               
               
                   
                   
                   
                 inadequately managed with 
               
               
                   
                   
                   
                 topical 
               
               
                 Botulinum Toxin Type B 
                 Myobloc ™ (Solstice 
                 Antidystonic Agents 
                 For the treatment of patients with 
                 12902 
               
               
                   
                 Neurosciences); 
                   
                 cervical dystonia to reduce the 
               
               
                   
                 Neurobloc ™ (Solstice 
                   
                 severity of abnormal head 
               
               
                   
                 Neurosciences) 
                   
                 position and neck pain 
               
               
                   
                   
                   
                 associated with cervical 
               
               
                   
                   
                   
                 dystonia. 
               
               
                 C5 inhibitor 
                 (Jerini Ophthalmic); 
                 Inhibitors of C5 
                 AMD 
               
               
                   
                 (Ophthotech) 
               
               
                 Cal101 
                 Calistoga 
                 PI3Kdelta Inhibitor 
                 AMD, DME 
               
               
                 Canstatin 
               
               
                 Capromab 
                 ProstaScint ™ (Cytogen 
                 Imaging Agents 
                 For diagnosis of prostate cancer 
                 84331 
               
               
                   
                 Corp) 
                   
                 and detection of intra-pelvic 
               
               
                   
                   
                   
                 metastases 
               
               
                 Captopril 
                   
                 ACE Inhibitors 
               
               
                 CCI-779 
                 (Wyeth) 
                 Limus Immunophilin 
               
               
                   
                   
                 Binding Compounds 
               
               
                 Cediranib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 450 
               
               
                 Celecoxib 
                   
                 Cyclooxygenase Inhibitors 
               
               
                 Cetrorelix 
                 Cetrotide ™ 
                 Hormone Antagonists; 
                 For the inhibition of premature 
                 78617 
               
               
                   
                   
                 Infertility Agents 
                 LH surges in women undergoing 
               
               
                   
                   
                   
                 controlled ovarian stimulation 
               
               
                 Cetuximab 
                 Erbitux ™; Erbitux ™ 
                 Antineoplastic Agents 
                 For treatment of metastatic 
                 42632 
               
               
                   
                 (ImClone Systems Inc) 
                   
                 colorectal cancer. 
               
               
                 Choriogonadotropin alfa 
                 Novarel ™; Ovidrel ™; 
                 Fertility Agents; 
                 For the treatment of female 
                 78617 
               
               
                   
                 Pregnyl ™; Profasi ™ 
                 Gonadotropins 
                 infertility 
               
               
                 Cilary neurotrophic factor 
                 (Neurotech) 
                 Cilary neurotrophic factor 
                 AMD 
               
               
                 Coagulation Factor IX 
                 Benefix ™ (Genetics 
                 Coagulants; Thrombotic 
                 For treatment of hemophilia 
                 267012 
               
               
                   
                 Institute) 
                 Agents 
                 (Christmas disease). 
               
               
                 Coagulation factor VIIa 
                 NovoSeven ™ (Novo 
                 Coagulants; Thrombotic 
                 For treatment of hemorrhagic 
                 54732 
               
               
                   
                 Nordisk) 
                 Agents 
                 complications in hemophilia A 
               
               
                   
                   
                   
                 and B 
               
               
                 Colchicines 
               
               
                 Collagenase 
                 Cordase ™; Santyl ™ 
                 Anti-Ulcer Agents; Topical 
                 For treatment of chronic dermal 
                 138885 
               
               
                   
                 (Advance Biofactures 
                   
                 ulcers and severe skin burns 
               
               
                   
                 Corp); Xiaflextm ™ 
               
               
                 Complement factor H 
                 (Optherion); (Taligen 
                 Complement factor H 
                 AMD, Geographic Atrophy 
               
               
                 recombinant 
                 Therapeutics) 
                 recombinant 
               
               
                 Compstatin derivative 
                 (Potentia 
                 Complement Factor C3 
                 AMD 
               
               
                 peptide, POT-4 
                 Pharmaceuticals) 
                 Inhibitors; Compstatin 
               
               
                   
                   
                 Derivative Peptides 
               
               
                 Corticotropin 
                 ACTH ™; Acethropan ™; 
                 Diagnostic Agents 
                 For use as a diagnostic agent in 
                 33927 
               
               
                   
                 Acortan ™; Acthar ™; 
                   
                 the screening of patients 
               
               
                   
                 Exacthin ™; H.P. Acthar 
                   
                 presumed to have adrenocortical 
               
               
                   
                 Gel ™; Isactid ™; 
                   
                 insufficiency. 
               
               
                   
                 Purified cortrophin 
               
               
                   
                 gel ™; Reacthin ™; 
               
               
                   
                 Solacthyl ™; Tubex 
               
               
                 Cosyntropin 
                 Cortrosyn ™; Synacthen 
                 Diagnostic Agents 
                 For use as a diagnostic agent in 
                 33927 
               
               
                   
                 depot ™ 
                   
                 the screening of patients 
               
               
                   
                   
                   
                 presumed to have adrenocortical 
               
               
                   
                   
                   
                 insufficiency. 
               
               
                 Cyclophilins 
                   
                 Limus Immunophilin 
               
               
                   
                   
                 Binding Compounds 
               
               
                 Cyclosporine 
                 Gengraf ™ (Abbott 
                 Antifungal Agents; 
                 For treatment of transplant 
                 32953 
               
               
                   
                 labs); Neoral ™ 
                 Antirheumatic Agents; 
                 rejection, rheumatoid arthritis, 
               
               
                   
                 (Novartis); Restasis ™; 
                 Dermatologic Agents; 
                 severe psoriasis 
               
               
                   
                 Restasis ™ (Allergan 
                 Enzyme Inhibitors; 
               
               
                   
                 Inc); Sandimmune ™ 
                 Immunomodulatory 
               
               
                   
                 (Novartis); Sangcya ™ 
                 Agents; 
               
               
                   
                   
                 Immunosuppressive 
               
               
                   
                   
                 Agents 
               
               
                 Daclizumab 
                 Zenapax ™ (Hoffmann- 
                 Immunomodulatory 
                 For prevention of renal 
                 61118 
               
               
                   
                 La Roche Inc) 
                 Agents; 
                 transplant rejection; Uveitis 
               
               
                   
                   
                 Immunosuppressive 
               
               
                   
                   
                 Agents 
               
               
                 Darbepoetin alfa 
                 Aranesp ™ (Amgen 
                 Antianemic Agents 
                 For the treatment of anemia 
                 55066 
               
               
                   
                 Inc.) 
                   
                 (from renal transplants or certain 
               
               
                   
                   
                   
                 HIV treatment) 
               
               
                 Dasatinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 488 
               
               
                 Defibrotide 
                 Dasovas ™; Noravid ™; 
                 Antithrombotic Agents 
                 Defibrotide is used to treat or 
                 36512 
               
               
                   
                 Prociclide ™ 
                   
                 prevent a failure of normal blood 
               
               
                   
                   
                   
                 flow (occlusive venous disease, 
               
               
                   
                   
                   
                 OVD) in the liver of patients who 
               
               
                   
                   
                   
                 have had bone marrow 
               
               
                   
                   
                   
                 transplants or received certain 
               
               
                   
                   
                   
                 drugs such as oral estrogens, 
               
               
                   
                   
                   
                 mercaptopurine, and many 
               
               
                   
                   
                   
                 others. 
               
               
                 Denileukin diftitox 
                 Ontak ™ 
                 Antineoplastic Agents 
                 For treatment of cutaneous T- 
                 61118 
               
               
                   
                   
                   
                 cell lymphoma 
               
               
                 Desmopressin 
                 Adiuretin ™; 
                 Antidiuretic Agents; 
                 For the management of primary 
                 46800 
               
               
                   
                 Concentraid ™; 
                 Hemostatics; Renal 
                 nocturnal enuresis and indicated 
               
               
                   
                 Stimate ™ 
                 Agents 
                 as antidiuretic replacement 
               
               
                   
                   
                   
                 therapy in the management of 
               
               
                   
                   
                   
                 central diabetes insipidus and for 
               
               
                   
                   
                   
                 the management of the 
               
               
                   
                   
                   
                 temporary polyuria and 
               
               
                   
                   
                   
                 polydipsia following head trauma 
               
               
                   
                   
                   
                 or surgery in the pitu 
               
               
                 Dexamethasone 
                 Ozurdex ™ (Allergan) 
                 Glucocorticoid 
                 DME, inflammation, macular 
                 392 
               
               
                   
                   
                   
                 edema following branch retinal 
               
               
                   
                   
                   
                 vein occlusion (BRVO) or central 
               
               
                   
                   
                   
                 retinal vein occlusion (CRVO) 
               
               
                 Diclofenac 
                   
                 Cyclooxygenase Inhibitors 
               
               
                 Dithiocarbamate 
                   
                 NFκB Inhibitor 
               
               
                 Dornase Alfa 
                 Dilor ™; Dilor-400 ™; 
                 Enzyme Replacement 
                 For the treatment of cystic 
                 7656 
               
               
                   
                 Lufyllin ™; Lufyllin- 
                 Agents 
                 fibrosis. 
                 (double 
               
               
                   
                 400 ™; Neothylline ™; 
                   
                   
                 strand) 
               
               
                   
                 Pulmozyme ™ 
               
               
                   
                 (Genentech Inc). 
               
               
                 Drotrecogin alfa 
                 Xigris ™; Xigris ™ (Eli 
                 Antisepsis Agents 
                 For treatment of severe sepsis 
                 267012 
               
               
                   
                 Lilly &amp; Co) 
               
               
                 Eculizumab 
                 Solids ™; Solids ™ 
                 Complement Cascade 
                 AMD 
                 188333 
               
               
                   
                 (Alexion 
                 Inhibitor (Factor C5) 
               
               
                   
                 Pharmaceuticals) 
               
               
                 Efalizumab 
                 Raptiva ™; Raptiva ™ 
                 Immunomodulatory 
                 For the treatment of adult 
                 128771 
               
               
                   
                 (Genentech Inc) 
                 Agents; 
                 patients with moderate to severe 
               
               
                   
                   
                 Immunosuppressive 
                 chronic plaque psoriasis, who 
               
               
                   
                   
                 Agents 
                 are candidates for phototherapy 
               
               
                   
                   
                   
                 or systemic therapy. 
               
               
                 Endostatin 
               
               
                 Enfuvirtide 
                 Fuzeon ™; Fuzeon ™ 
                 Anti-HIV Agents; HIV 
                 For treatment of HIV AIDS 
                 16768 
               
               
                   
                 (Roche 
                 Fusion Inhibitors 
               
               
                   
                 Pharmaceuticals) 
               
               
                 Epoetin alfa 
                 Epogen ™ (Amgen 
                 Antianemic Agents 
                 For treatment of anemia (from 
                 55066 
               
               
                   
                 Inc.); Epogin ™ 
                   
                 renal transplants or certain HIV 
               
               
                   
                 (Chugai); Epomax ™ 
                   
                 treatment) 
               
               
                   
                 (Elanex); Eprex ™ 
               
               
                   
                 (Janssen-Cilag. Ortho 
               
               
                   
                 Biologics LLC); 
               
               
                   
                 NeoRecormon ™ 
               
               
                   
                 (Roche); Procrit ™ 
               
               
                   
                 (Ortho Biotech); 
               
               
                   
                 Recormon ™ (Roche) 
               
               
                 Eptifibatide 
                 Integrilin ™; Integrilin ™ 
                 Anticoagulants; 
                 For treatment of myocardial 
                 7128 
               
               
                   
                 (Millennium Pharm) 
                 Antiplatelet Agents; 
                 infarction and acute coronary 
               
               
                   
                   
                 Platelet Aggregation 
                 syndrome. 
               
               
                   
                   
                 Inhibitors 
               
               
                 Erlotinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 393 
               
               
                 Etanercept 
                 Enbrel ™; Enbrel ™ 
                 Antirheumatic Agents; 
                 Uveitis, AMD 
                 25645 
               
               
                   
                 (Immunex Corp) 
                 Immunomodulatory Agents 
               
               
                 Everolimus 
                 Novartis 
                 Limus Immunophilin 
                 AMD 
               
               
                   
                   
                 Binding Compounds, 
               
               
                   
                   
                 mTOR 
               
               
                 Exenatide 
                 Byetta ™; Byetta ™ 
                   
                 Indicated as adjunctive therapy 
                 53060 
               
               
                   
                 (Amylin/Eli Lilly) 
                   
                 to improve glycemic control in 
               
               
                   
                   
                   
                 patients with Type 2 diabetes 
               
               
                   
                   
                   
                 mellitus who are taking 
               
               
                   
                   
                   
                 metformin, a sulfonylurea, or a 
               
               
                   
                   
                   
                 combination of both, but have 
               
               
                   
                   
                   
                 not achieved adequate glycemic 
               
               
                   
                   
                   
                 control. 
               
               
                 FCFD4514S 
                 Genentech/Roche 
                 Complement Cascade 
                 AMD, Geographic Atrophy 
               
               
                   
                   
                 Inhibitor (Factor D) 
               
               
                 Felypressin 
                 Felipresina ™ [INN- 
                 Renal Agents; 
                 For use as an alternative to 
                 46800 
               
               
                   
                 Spanish]; 
                 Vasoconstrictor Agents 
                 adrenaline as a 79ocalizing 
               
               
                   
                 Felipressina ™ [DCIT]; 
                   
                 agent, provided that local 
               
               
                   
                 Felypressin ™ 
                   
                 ischaemia is not essential. 
               
               
                   
                 [USAN:BAN:INN]; 
               
               
                   
                 Felypressine ™ [INN- 
               
               
                   
                 French]; 
               
               
                   
                 Felypressinum ™ [INN- 
               
               
                   
                 Latin]; Octapressin ™ 
               
               
                 Fenretinide 
                 Sirion/reVision 
                 Binding Protein Antagonist 
                 AMD, Geographic Atrophy 
               
               
                   
                 Therapeutics 
                 for Oral Vitamin A 
               
               
                 Filgrastim 
                 Neupogen ™ (Amgen 
                 Anti-Infective Agents; 
                 Increases leukocyte production, 
                 28518 
               
               
                   
                 Inc.) 
                 Antineutropenic Agents; 
                 for treatment in non-myeloid 
               
               
                   
                   
                 Immunomodulatory Agents 
                 cancer,neutropenia and bone 
               
               
                   
                   
                   
                 marrow transplant 
               
               
                 FK605-binding proteins, 
                   
                 Limus Immunophilin 
               
               
                 FKBPs 
                   
                 Binding Compounds 
               
               
                 Fluocinolone Acetonide 
                 Retisert ™ (Bausch &amp; 
                 Glucocorticoid 
                 Retinal inflammation, diabetic 
                 453 
               
               
                   
                 Lomb); Iluvien ™ 
                   
                 macular edema 
               
               
                   
                 (Alimera Sciences, Inc.) 
               
               
                 Follitropin beta 
                 Follistim ™ (Organon); 
                 Fertility Agents 
                 For treatment of female infertility 
                 78296 
               
               
                   
                 Gonal F ™; Gonal-F ™ 
               
               
                 Fumagillin 
               
               
                 Galsulfase 
                 Naglazyme ™; 
                 Enzyme Replacement 
                 For the treatment of adults and 
                 47047 
               
               
                   
                 Naglazyme ™ (BioMarin 
                 Agents 
                 children with 
               
               
                   
                 Pharmaceuticals) 
                   
                 Mucopolysaccharidosis VI. 
               
               
                 Gefitinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 447 
               
               
                 Gemtuzumab ozogamicin 
                 Mylotarg ™; Mylotarg ™ 
                 Antineoplastic Agents 
                 For treatment of acute myeloid 
                 39826 
               
               
                   
                 (Wyeth) 
                   
                 leukemia 
               
               
                 Glatiramer Acetate 
                 Copaxone ™ 
                 Adjuvants, Immunologic; 
                 For reduction of the frequency of 
                 29914 
               
               
                   
                   
                 Immunosuppressive 
                 relapses in patients with 
               
               
                   
                   
                 Agents 
                 Relapsing-Remitting Multiple 
               
               
                   
                   
                   
                 Sclerosis. 
               
               
                 Glucagon recombinant 
                 GlucaGen ™ (Novo 
                 Antihypoglycemic Agents 
                 For treatment of severe 
                 54009 
               
               
                   
                 Nordisk); Glucagon ™ 
                   
                 hypoglycemia, also used in 
               
               
                   
                 (Eli Lilly) 
                   
                 gastrointestinal imaging 
               
               
                 Goserelin 
                 Zoladex ™ 
                 Antineoplastic Agents; 
                 Breast cancer; Prostate 
                 78617 
               
               
                   
                   
                 Antineoplastic Agents, 
                 carcinoma; Endometriosis 
               
               
                   
                   
                 Hormonal 
               
               
                 Human Serum Albumin 
                 Albutein ™ (Alpha 
                 Serum substitutes 
                 For treatment of severe blood 
                 39000 
               
               
                   
                 Therapeutic Corp) 
                   
                 loss, hypervolemia, 
               
               
                   
                   
                   
                 hypoproteinemia 
               
               
                 Hyaluronidase 
                 Vitragan ™; Vitrase ™; 
                 Anesthetic Adjuvants; 
                 For increase of absorption and 
                 69367 
               
               
                   
                 Vitrase ™ (Ista Pharma) 
                 Permeabilizing Agents 
                 distribution of other injected 
               
               
                   
                   
                   
                 drugs and for rehydration 
               
               
                 Ibritumomab 
                 Zevalin ™ (IDEC 
                 Antineoplastic Agents 
                 For treatment of non-Hodgkin&#39;s 
                 33078 
               
               
                   
                 Pharmaceuticals) 
                   
                 lymphoma 
               
               
                 Idursulfase 
                 Elaprase ™ (Shire 
                 Enzyme Replacement 
                 For the treatment of Hunter 
                 47047 
               
               
                   
                 Pharmaceuticals) 
                 Agents 
                 syndrome in adults and children 
               
               
                   
                   
                   
                 ages 5 and older. 
               
               
                 Imatinib 
                   
                 Tyrosine Kinase Inhibitors 
                 AMD, DME 
                 494 
               
               
                 Immune globulin 
                 Civacir ™; 
                 Anti-Infectives; 
                 For treatment of 
                 42632 
               
               
                   
                 Flebogamma ™ 
                 Immunomodulatory Agents 
                 immunodeficiencies, 
               
               
                   
                 (Instituto Grifols SA); 
                   
                 thrombocytopenic purpura, 
               
               
                   
                 Gamunex ™ (Talecris 
                   
                 Kawasaki disease, 
               
               
                   
                 Biotherapeutics) 
                   
                 gammablobulinemia, leukemia, 
               
               
                   
                   
                   
                 bone transplant 
               
               
                 Infliximab 
                 Remicade ™ (Centocor 
                 Immunomodulatory 
                 Uveitis, AMD 
                 25645 
               
               
                   
                 Inc) 
                 Agents; 
               
               
                   
                   
                 Immunosuppressive 
               
               
                   
                   
                 Agents 
               
               
                 Insulin Glargine 
                 Lantus ™ 
                 Hypoglycemic Agents 
                 For treatment of diabetes (type I 
                 156308 
               
               
                 recombinant 
                   
                   
                 and II) 
               
               
                 Insulin Lyspro 
                 Humalog ™ (Eli Lily); 
                 Hypoglycemic Agents 
                 For treatment of diabetes (type I 
                 154795 
               
               
                 recombinant 
                 Insulin Lispro (Eli Lily) 
                   
                 and II) 
               
               
                 Insulin recombinant 
                 Novolin R ™ (Novo 
                 Hypoglycemic Agents 
                 For treatment of diabetes (type I 
                 156308 
               
               
                   
                 Nordisk) 
                   
                 and II) 
               
               
                 Insulin, porcine 
                 Iletin II ™ 
                 Hypoglycemic Agents 
                 For the treatment of diabetes 
                 156308 
               
               
                   
                   
                   
                 (type I and II) 
               
               
                 Interferon 
               
               
                 Interferon Alfa-2a, 
                 Roferon A ™ 
                 Antineoplastic Agents; 
                 For treatment of chronic hepatitis 
                 57759 
               
               
                 Recombinant 
                 (Hoffmann-La Roche 
                 Antiviral Agents 
                 C, hairy cell leukemia, AIDS- 
               
               
                   
                 Inc); Veldona ™ 
                   
                 related Kaposi&#39;s sarcoma, and 
               
               
                   
                 (Amarillo Biosciences) 
                   
                 chronic myelogenous leukemia. 
               
               
                   
                   
                   
                 Also for the treatment of oral 
               
               
                   
                   
                   
                 warts arising from HIV infection. 
               
               
                 Interferon Alfa-2b, 
                 Intron A ™ (Schering 
                 Antineoplastic Agents; 
                 For the treatment of hairy cell 
                 57759 
               
               
                 Recombinant 
                 Corp) 
                 Antiviral Agents; 
                 leukemia, malignant melanoma, 
               
               
                   
                   
                 Immunomodulatory Agents 
                 and AIDS-related Kaposi&#39;s 
               
               
                   
                   
                   
                 sarcoma. 
               
               
                 Interferon alfacon-1 
                 Advaferon ™; 
                 Antineoplastic Agents; 
                 For treatment of hairy cell 
                 57759 
               
               
                   
                 Infergen ™ (InterMune 
                 Antiviral Agents; 
                 leukemia, malignant melanoma, 
               
               
                   
                 Inc) 
                 Immunomodulatory Agents 
                 and AIDS-related Kaposi&#39;s 
               
               
                   
                   
                   
                 sarcoma 
               
               
                 Interferon alfa-n1 
                 Wellferon ™ 
                 Antiviral Agents; 
                 For treatment of venereal or 
                 57759 
               
               
                   
                 (GlaxoSmithKline) 
                 Immunomodulatory Agents 
                 genital warts caused by the 
               
               
                   
                   
                   
                 Human Papiloma Virus 
               
               
                 Interferon alfa-n3 
                 Alferon ™ (Interferon 
                 Antineoplastic Agents; 
                 For the intralesional treatment of 
                 57759 
               
               
                   
                 Sciences Inc.); Alferon 
                 Antiviral Agents; 
                 refractory or recurring external 
               
               
                   
                 LDO ™; Alferon N 
                 Immunomodulatory Agents 
                 condylomata 81 cuminate. 
               
               
                   
                 Injection ™ 
               
               
                 Interferon beta-1b 
                 Betaseron ™ (Chiron 
                 Antiviral Agents; 
                 For treatment of 
                 57759 
               
               
                   
                 Corp) 
                 Immunomodulatory Agents 
                 relapsing/remitting multiple 
               
               
                   
                   
                   
                 sclerosis 
               
               
                 Interferon gamma-1b 
                 Actimmune ™; 
                 Antiviral Agents; 
                 For treatment of Chronic 
                 37835 
               
               
                   
                 Actimmune ™ 
                 Immunomodulatory Agents 
                 granulomatous disease, 
               
               
                   
                 (InterMune Inc) 
                   
                 Osteopetrosis 
               
               
                 Lapatinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 581 
               
               
                 Lepirudin 
                 Refludan ™ 
                 Anticoagulants; 
                 For the treatment of heparin- 
                 70037 
               
               
                   
                   
                 Antithrombotic Agents; 
                 induced thrombocytopenia 
               
               
                   
                   
                 Fibrinolytic Agents 
               
               
                 Lestaurtinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 439 
               
               
                 Leuprolide 
                 Eligard ™ (Atrix 
                 Anti-Estrogen Agents; 
                 For treatment of prostate cancer, 
                 37731 
               
               
                   
                 Labs/QLT Inc) 
                 Antineoplastic Agents 
                 endometriosis, uterine fibroids 
               
               
                   
                   
                   
                 and premature puberty 
               
               
                 Lutropin alfa 
                 Luveris ™ (Serono) 
                 Fertility Agents 
                 For treatment of female infertility 
                 78617 
               
               
                 Mecasermin 
                 Increlex ™; Increlex ™ 
                   
                 For the long-term treatment of 
                 154795 
               
               
                   
                 (Tercica); Iplex 
                   
                 growth failure in pediatric 
               
               
                   
                   
                   
                 patients with Primary IGFD or 
               
               
                   
                   
                   
                 with GH gene deletion who have 
               
               
                   
                   
                   
                 developed neutralizing 
               
               
                   
                   
                   
                 antibodies to GH. It is not 
               
               
                   
                   
                   
                 indicated to treat Secondary 
               
               
                   
                   
                   
                 IGFD resulting from GH 
               
               
                   
                   
                   
                 deficiency, malnutrition, hypoth 
               
               
                 Menotropins 
                 Repronex ™ 
                 Fertility Agents 
                 For treatment of female infertility 
                 78617 
               
               
                 Methotrexate 
                   
                 Immunomodulatory 
                 Uveitis, DME 
               
               
                 mTOR inhibitors 
               
               
                 Muromonab 
                 Orthoclone OKT3 ™ 
                 Immunomodulatory 
                 For treatment of organ transplant 
                 23148 
               
               
                   
                 (Ortho Biotech) 
                 Agents; 
                 recipients, prevention of organ 
               
               
                   
                   
                 Immunosuppressive 
                 rejection 
               
               
                   
                   
                 Agents 
               
               
                 Natalizumab 
                 Tysabri ™ 
                 Immunomodulatory Agents 
                 For treatment of multiple 
                 115334 
               
               
                   
                   
                   
                 sclerosis. 
               
               
                 Nepafenac 
                   
                 Cyclooxygenase Inhibitors 
               
               
                 Nesiritide 
                 Natrecor ™ 
                 Cardiac drugs 
                 For the intravenous treatment of 
                 118921 
               
               
                   
                   
                   
                 patients with acutely 
               
               
                   
                   
                   
                 decompensated congestive 
               
               
                   
                   
                   
                 heart failure who have dyspnea 
               
               
                   
                   
                   
                 at rest or with minimal activity. 
               
               
                 Nilotinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 530 
               
               
                 NS398 
                   
                 Cyclooxygenase Inhibitors 
               
               
                 Octreotide 
                 Atrigel ™; 
                 Anabolic Agents; 
                 For treatment of acromegaly and 
                 42687 
               
               
                   
                 Longastatin ™; 
                 Antineoplastic Agents, 
                 reduction of side effects from 
               
               
                   
                 Sandostatin ™; 
                 Hormonal; Gastrointestinal 
                 cancer chemotherapy 
               
               
                   
                 Sandostatin LAR ™; 
                 Agents; Hormone 
               
               
                   
                 Sandostatin LAR ™ 
                 Replacement Agents 
               
               
                   
                 (Novartis) 
               
               
                 Omalizumab 
                 Xolair ™ (Genentech 
                 Anti-Asthmatic Agents; 
                 For treatment of asthma caused 
                 29596 
               
               
                   
                 Inc) 
                 Immunomodulatory Agents 
                 by allergies 
               
               
                 Oprelvekin 
                 Neumega ™; 
                 Coagulants; Thrombotics 
                 Increases reduced platelet levels 
                 45223 
               
               
                   
                 Neumega ™ (Genetics 
                   
                 due to chemotherapy 
               
               
                   
                 Institute Inc) 
               
               
                 OspA lipoprotein 
                 LYMErix ™ (SmithKline 
                 Vaccines 
                 For prophylactic treatment of 
                 95348 
               
               
                   
                 Beecham) 
                   
                 Lyme Disease 
               
               
                 OT-551 
                 (Othera) 
                 Anti-oxidant eyedrop 
                 AMD 
               
               
                 Oxytocin 
                 Oxytocin ™ (BAM 
                 Anti-tocolytic Agents; 
                 To assist in labor, elective labor 
                 12722 
               
               
                   
                 Biotech); Pitocin ™ 
                 Labor Induction Agents; 
                 induction, uterine contraction 
               
               
                   
                 (Parke-Davis); 
                 Oxytocics 
                 induction 
               
               
                   
                 Syntocinon ™ (Sandoz) 
               
               
                 Palifermin 
                 Kepivance ™ (Amgen 
                 Antimucositis Agents 
                 For treatment of mucositis 
                 138885 
               
               
                   
                 Inc) 
                   
                 (mouth sores) 
               
               
                 Palivizumab 
                 Synagis ™ 
                 Antiviral Agents 
                 For treatment of respiratory 
                 63689 
               
               
                   
                   
                   
                 diseases casued by respiratory 
               
               
                   
                   
                   
                 syncytial virus 
               
               
                 Panitumumab 
                 Vectibix ™; Vectibix ™ 
                 Antineoplastic Agents 
                 For the treatment of EGFR- 
                 134279 
               
               
                   
                 (Amgen) 
                   
                 expressing, metastatic colorectal 
               
               
                   
                   
                   
                 carcinoma with disease 
               
               
                   
                   
                   
                 progression on or following 
               
               
                   
                   
                   
                 fluoropyrimidine-, oxaliplatin-, 
               
               
                   
                   
                   
                 and irinotecan-containing 
               
               
                   
                   
                   
                 chemotherapy regimens. 
               
               
                 PDGF inhibitor 
                 (Jerini Ophthalmic); 
                 Inhibitors of PDGF 
                 AMD 
               
               
                   
                 (Ophthotech) 
               
               
                 PEDF (pigment 
               
               
                 epithelium derived factor) 
               
               
                 Pegademase bovine 
                 Adagen ™ (Enzon Inc.) 
                 Enzyme Replacement 
                 For treatment of adenosine 
                 36512 
               
               
                   
                   
                 Agents 
                 deaminase deficiency 
               
               
                 Pegaptanib 
                 Macugen ™ 
                 Oligonucleotide 
                 For the treatment of neovascular 
                 103121 
               
               
                   
                   
                   
                 (wet) age-related macular 
               
               
                   
                   
                   
                 degeneration. 
               
               
                 Pegaspargase 
                 Oncaspar ™ (Enzon 
                 Antineoplastic Agents 
                 For treatment of acute 
                 132.118 
               
               
                   
                 Inc) 
                   
                 lymphoblastic leukemia 
               
               
                 Pegfilgrastim 
                 Neulasta ™ (Amgen 
                 Anti-Infective Agents; 
                 Increases leukocyte production, 
                 28518 
               
               
                   
                 Inc.) 
                 Antineutropenic Agents; 
                 for treatment in non-myeloid 
               
               
                   
                   
                 Immunomodulatory Agents 
                 cancer, neutropenia and bone 
               
               
                   
                   
                   
                 marrow transplant 
               
               
                 Peginterferon alfa-2a 
                 Pegasys ™ (Hoffman- 
                 Antineoplastic Agents; 
                 For treatment of hairy cell 
                 57759 
               
               
                   
                 La Roche Inc) 
                 Antiviral Agents; 
                 leukemia, malignant melanoma, 
               
               
                   
                   
                 Immunomodulatory Agents 
                 and AIDS-related Kaposi&#39;s 
               
               
                   
                   
                   
                 sarcoma. 
               
               
                 Peginterferon alfa-2b 
                 PEG-Intron (Schering 
                 Antineoplastic Agents; 
                 For the treatment of chronic 
                 57759 
               
               
                   
                 Corp); Unitron PEG ™ 
                 Antiviral Agents; 
                 hepatitis C in patients not 
               
               
                   
                   
                 Immunomodulatory Agents 
                 previously treated with interferon 
               
               
                   
                   
                   
                 alpha who have compensated 
               
               
                   
                   
                   
                 liver disease and are at least 18 
               
               
                   
                   
                   
                 years of age. 
               
               
                 Pegvisomant 
                 Somavert ™ (Pfizer Inc) 
                 Anabolic Agents; Hormone 
                 For treatment of acromegaly 
                 71500 
               
               
                   
                   
                 Replacement Agents 
               
               
                 Pentoxifylline 
               
               
                 Perindozril 
                   
                 ACE Inhibitors 
               
               
                 Pimecrolimus 
                   
                 Limus Immunophilin 
               
               
                   
                   
                 Binding Compounds 
               
               
                 PKC (protein kinase C) 
               
               
                 inhibitors 
               
               
                 POT-4 
                 Potentia/Alcon 
                 Complement Cascade 
                 AMD 
               
               
                   
                   
                 Inhibitor (Factor C3) 
               
               
                 Pramlintide 
                 Symlin ™; Symlin ™ 
                   
                 For the mealtime treatment of 
                 16988 
               
               
                   
                 (Amylin 
                   
                 Type I and Type II diabetes in 
               
               
                   
                 Pharmaceuticals) 
                   
                 combination with standard 
               
               
                   
                   
                   
                 insulin therapy, in patients who 
               
               
                   
                   
                   
                 have failed to achieve adequate 
               
               
                   
                   
                   
                 glucose control on insulin 
               
               
                   
                   
                   
                 monotherapy. 
               
               
                 Proteosome inhibitors 
                 Velcade ™ 
                   
                 Proteosome inhibitors 
               
               
                 Pyrrolidine 
               
               
                 Quinopril 
                   
                 ACE Inhibitors 
               
               
                 Ranibizumab 
                 Lucentis ™ 
                   
                 For the treatment of patients with 
                 27043 
               
               
                   
                   
                   
                 neovascular (wet) age-related 
               
               
                   
                   
                   
                 macular degeneration. 
               
               
                 Rapamycin (siroliums) 
                 (MacuSight) 
                 Limus Immunophilin 
                 AMD 
               
               
                   
                   
                 Binding Compounds 
               
               
                 Rasburicase 
                 Elitek ™; Elitek ™ 
                 Antihyperuricemic Agents 
                 For treatment of hyperuricemia, 
                 168.11 
               
               
                   
                 (Sanofi-Synthelabo 
                   
                 reduces elevated plasma uric 
               
               
                   
                 Inc); Fasturtec ™ 
                   
                 acid levels (from chemotherapy) 
               
               
                 Reteplase 
                 Retavase ™ (Centocor); 
                 Thrombolytic Agents 
                 For lysis of acute pulmonary 
                 54732 
               
               
                   
                 Retavase ™ (Roche) 
                   
                 emboli, intracoronary emboli and 
               
               
                   
                   
                   
                 management of myocardial 
               
               
                   
                   
                   
                 infarction 
               
               
                 Retinal stimulant 
                 Neurosolve ™ 
                 Retinal stimulants 
                 AMD 
               
               
                   
                 (Vitreoretinal 
               
               
                   
                 Technologies) 
               
               
                 Retinoid(s) 
               
               
                 Rituximab 
                 MabThera ™; Rituxan ™ 
                 Antineoplastic Agents 
                 For treatment of B-cell non- 
                 33078 
               
               
                   
                   
                   
                 Hodgkins lymphoma (CD20 
               
               
                   
                   
                   
                 positive) 
               
               
                 RNAI (RNA interference 
               
               
                 of angiogenic factors) 
               
               
                 Rofecoxib 
                 Vioxx ™; Ceoxx ™; 
                 Cyclooxygenase Inhibitors 
               
               
                   
                 Ceeoxx ™ (Merck &amp; 
               
               
                   
                 Co.) 
               
               
                 Rosiglitazone 
                   
                 Thiazolidinediones 
               
               
                 Ruboxistaurin 
                 Eli Lilly 
                 Protein Kinase C (PKC)-b 
                 DME, diabetic peripheral 
                 469 
               
               
                   
                   
                 Inhibitor 
                 retinopathy 
               
               
                 Salmon Calcitonin 
                 Calcimar ™; Miacalcin ™ 
                 Antihypocalcemic Agents; 
                 For the treatment of post- 
                 57304 
               
               
                   
                 (Novartis) 
                 Antiosteporotic Agents; 
                 menopausal osteoporosis 
               
               
                   
                   
                 Bone Density 
               
               
                   
                   
                 Conservation Agents 
               
               
                 Sargramostim 
                 Immunex ™. 
                 Anti-Infective Agents; 
                 For the treatment of cancer and 
                 46207 
               
               
                   
                 Leucomax ™ (Novartis); 
                 Antineoplastic Agents; 
                 bone marrow transplant 
               
               
                   
                 Leukine ™; Leukine ™ 
                 Immunomodulatory Agents 
               
               
                   
                 (Berlex Laboratories 
               
               
                   
                 Inc) 
               
               
                 SAR 1118 
                 SARCode 
                 Immunomodulatory Agent 
                 Dry eye, DME, conjunctivitis 
               
               
                 SDZ-RAD 
                   
                 Limus Immunophilin 
               
               
                   
                   
                 Binding Compounds 
               
               
                 Secretin 
                 SecreFlo ™; 
                 Diagnostic Agents 
                 For diagnosis of pancreatic 
                 50207 
               
               
                   
                 Secremax ™, 
                   
                 exocrine dysfunction and 
               
               
                   
                 SecreFlo ™ (Repligen 
                   
                 gastrinoma 
               
               
                   
                 Corp) 
               
               
                 Selective inhibitor of the 
               
               
                 factor 3 complement 
               
               
                 cascade 
               
               
                 Selective inhibitor of the 
               
               
                 factor 5 complement 
               
               
                 cascade 
               
               
                 Semaxanib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 238 
               
               
                 Sermorelin 
                 Geref ™ (Serono 
                 Anabolic Agents; Hormone 
                 For the treatment of dwarfism, 
                 47402 
               
               
                   
                 Pharma) 
                 Replacement Agents 
                 prevention of HIV-induced 
               
               
                   
                   
                   
                 weight loss 
               
               
                 Serum albumin iodinated 
                 Megatope ™ (IsoTex 
                 Imaging Agents 
                 For determination of total blood 
                 39000 
               
               
                   
                 Diagnostics) 
                   
                 and plasma volumes 
               
               
                 SF1126 
                 Semafore 
                 Pl3k/mTOR Inhibition 
                 AMD, DME 
               
               
                 Sirolimus reformulation 
                 (MacuSight) 
                 Limus Immunophilin 
                 AMD 
               
               
                 (rapamycin) 
                   
                 Binding Compounds 
               
               
                 siRNA molecule 
                 (Quark 
                 siRNA molecule synthetic 
                 AMD 
               
               
                 synthetic, FTP-801i-14 
                 Pharmaceuticals) 
               
               
                 Somatropin recombinant 
                 BioTropin ™ (Biotech 
                 Anabolic Agents; Hormone 
                 For treatment of dwarfism, 
                 71500 
               
               
                   
                 General); Genotropin ™ 
                 Replacement Agents 
                 acromegaly and prevention of 
               
               
                   
                 (Pfizer); Humatrope ™ 
                   
                 HIV-induced weight loss 
               
               
                   
                 (Eli Lilly); Norditropin ™ 
               
               
                   
                 (Novo Nordisk); 
               
               
                   
                 Nutropin ™ (Genentech 
               
               
                   
                 Inc.); NutropinAQ ™ 
               
               
                   
                 (Genentech Inc.); 
               
               
                   
                 Protropin ™ (Genentech 
               
               
                   
                 Inc.); Saizen ™ (Serono 
               
               
                   
                 SA); Serostim ™; 
               
               
                   
                 Serostim ™ (Serono 
               
               
                   
                 SA); Tev-Tropin ™ 
               
               
                   
                 (GATE) 
               
               
                 Squalamine 
               
               
                 Streptokinase 
                 Streptase ™ (Aventis 
                 Thrombolytic Agents 
                 For the treatment of acute 
                 90569 
               
               
                   
                 Behringer GmbH) 
                   
                 evolving transmural myocardial 
               
               
                   
                   
                   
                 infarction, pulmonary embolism, 
               
               
                   
                   
                   
                 deep vein thrombosis, arterial 
               
               
                   
                   
                   
                 thrombosis or embolism and 
               
               
                   
                   
                   
                 occlusion of arteriovenous 
               
               
                   
                   
                   
                 cannulae 
               
               
                 Sunitinib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 398 
               
               
                 TA106 
                 Taligen 
                 Complement Cascade 
                 AMD 
               
               
                   
                   
                 Inhibitor (Factor B) 
               
               
                 Tacrolimus 
                   
                 Limus Immunophilin 
               
               
                   
                   
                 Binding Compounds 
               
               
                 Tenecteplase 
                 TNKase ™ (Genentech 
                 Thrombolytic Agents 
                 For treatment of myocardial 
                 54732 
               
               
                   
                 Inc) 
                   
                 infarction and lysis of 
               
               
                   
                   
                   
                 intracoronary emboli 
               
               
                 Teriparatide 
                 Apthela ™; Forsteo ™; 
                 Bone Density 
                 For the treatment of 
                 66361 
               
               
                   
                 Forteo ™; Fortessa ™; 
                 Conservation Agents 
                 osteoporosis in men and 
               
               
                   
                 Opthia ™; Optia ™; 
                   
                 postmenopausal women who 
               
               
                   
                 Optiah ™; Zalectra ™; 
                   
                 are at high risk for having a 
               
               
                   
                 Zelletra ™ 
                   
                 fracture. Also used to increase 
               
               
                   
                   
                   
                 bone mass in men with primary 
               
               
                   
                   
                   
                 or hypogonadal osteoporosis 
               
               
                   
                   
                   
                 who are at high risk for fracture. 
               
               
                 Tetrathiomolybdate 
               
               
                 Thalidomide 
                 Celgene 
                 Anti-inflammatory, Anti- 
                 Uveitis 
               
               
                   
                   
                 proliferative 
               
               
                 Thyrotropin Alfa 
                 Thyrogen ™ (Genzyme 
                 Diagnostic Agents 
                 For detection of residueal or 
                 86831 
               
               
                   
                 Inc) 
                   
                 recurrent thyroid cancer 
               
               
                 Tie-1 and Tie-2 kinase 
               
               
                 inhibitors 
               
               
                 Toceranib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 396 
               
               
                 Tositumomab 
                 Bexxar ™ (Corixa Corp) 
                 Antineoplastic Agents 
                 For treatment of non-Hodgkin&#39;s 
                 33078 
               
               
                   
                   
                   
                 lymphoma (CD20 positive, 
               
               
                   
                   
                   
                 follicular) 
               
               
                 TPN 470 analogue 
               
               
                 Trastuzumab 
                 Herceptin ™ 
                 Antineoplastic Agents 
                 For treatment of HER2-positive 
                 137912 
               
               
                   
                 (Genentech) 
                   
                 pulmonary breast cancer 
               
               
                 Triamcinolone acetonide 
                 Triesence ™ 
                 Glucocorticoid 
                 DME, For treatment of 
                 435 
               
               
                   
                   
                   
                 inflammation of the retina 
               
               
                 Troglitazone 
                   
                 Thiazolidinediones 
               
               
                 Tumistatin 
               
               
                 Urofollitropin 
                 Fertinex ™ (Serono S.A.) 
                 Fertility Agents 
                 For treatment of female infertility 
                 78296 
               
               
                 Urokinase 
                 Abbokinase ™; 
                 Thrombolytic Agents 
                 For the treatment of 88ulmonary 
                 90569 
               
               
                   
                 Abbokinase ™ (Abbott 
                   
                 embolism, coronary artery 
               
               
                   
                 Laboratories) 
                   
                 thrombosis and IV catheter 
               
               
                   
                   
                   
                 clearance 
               
               
                 Vandetanib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 475 
               
               
                 Vasopressin 
                 Pitressin ™; Pressyn ™ 
                 Antidiuretics; Oxytocics; 
                 For the treatment of enuresis, 
                 46800 
               
               
                   
                   
                 Vasoconstrictor Agents 
                 polyuria, diabetes insipidus, 
               
               
                   
                   
                   
                 polydipsia and oesophageal 
               
               
                   
                   
                   
                 varices with bleeding 
               
               
                 Vatalanib 
                   
                 Tyrosine Kinase Inhibitors 
                   
                 347 
               
               
                 VEGF receptor kinase 
               
               
                 inhibitor 
               
               
                 VEGF Trap 
                 Aflibercept ™ 
                 Genetically Engineered 
                 DME, cancer, retinal vein 
                 96600 
               
               
                   
                 (Regneron 
                 Antibodies 
                 occlusion, choroidal 
               
               
                   
                 Pharmaceuticals, Bayer 
                   
                 neovascularization, delay wound 
               
               
                   
                 HealthCare AG) 
                   
                 healing, cancer treatment 
               
               
                 Visual Cycle Modulator 
                 (Acucela) 
                 Visual Cycle Modulator 
                 AMD 
               
               
                 ACU-4229 
               
               
                 Vitamin(s) 
               
               
                 Vitronectin receptor 
               
               
                 antagonists 
               
               
                 Volociximab 
                 Ophthotech 
                 alpha5beta1 Integrin 
                 AMD 
               
               
                   
                   
                 Inhibitor 
               
               
                 XL765 
                 Exelixis/Sanofi-Aventis 
                 Pl3k/mTOR Inhibition 
                 AMD, DME