Source: https://insight.rpxcorp.com/pat/US7781402B2
Timestamp: 2019-10-23 18:18:07
Document Index: 569297859

Matched Legal Cases: ['art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5', 'art 5']

Patent US 7,781,402 B2
1. A method of treating supraventricular arrhythmias (SVA) in a subject in need thereof, the method comprising:
administering to the subject a bolus injection of 0.001-20 mg per KG body weight of acetylcholine or an acetylcholine salt which has the ability to transiently modulate at least one electrical property of at least a portion of atrial cells thereby treating the supraventricular arrhythmia in the subject.
Use of tools, mapping systems, catheters, electrodes or any devices targeting any autonomic nerve(s) structure(s) in the human heart for the diagnostic, treatment and/or prevention of the recurrence of cardiac arrhythmias.
US 20090253974A1
US 6,973,350 B1
US 6,716,196 B2
US 20030032998A1
US 6,537,974 B2
US 6,444,217 B1
N.sup.6 -(epoxynorborn-2-yl) adenosines as A.sub.1 adenosine receptor agonists
US 5,736,528 A
US 5,281,521 A
US 4,866,046 A
AMER MOH. SAMIR
TOP LABORATORIES INC. A CORP. OF DE
US 4,879,219 A
GENERAL HOSPITAL CORPORATION FRUIT ST. BOSTON 02114 A CORP. OF MA
US 4,508,702 A
US 4,098,876 A
US 4,034,074 A
US 3,935,074 A
US 3,984,533 A
US 3,867,517 A
US 3,850,578 A
McConnell Harden M.
US 3,879,262 A
US 3,853,987 A
US 3,901,654 A
Biological Developments Inc. Encino CA
US 3,839,153 A
US 3,791,932 A
FIG. 1a—depicts the structure of the heart. A heart 5, having a right atrium 80, a right ventricle 82, a left atrium 84 and a left ventricle 86. A septum 90, separating between the right and left ventricles, a tricuspid valve 92, enabling a blood flow from the right atrium 80 to the right ventricle 82, a mitral valve 94, enabling a blood flow from the left atrium 84 to the left ventricle 86, a pulmonary valve 96, enabling a blood flow exit the right ventricle 82 towards the lungs (not shown in figure), an aortic valve 98, enabling a blood flow from the LV 86 to an aorta 100, and the superior vena cava 102 and inferior vena cava 101 bringing blood back from a body to the right atrium 80;
FIG. 1b—a schematic illustration depicting the common and different features of atrial fibrillation, atrial flutter and atrial tachycardia, all belong to the family of supraventricular arrhythmias (adapted from Wyse and Gersh, 2004). These arrhythmias are closely interrelated, and the individual forms often coexist in the same patient. Although the present invention focuses primarily on atrial fibrillation, many of the points made with regard to atrial fibrillation apply to these other arrhythmias to varying degrees;
FIGS. 2a-b—are ECG recordings from a rat after the induction of atrial tachycardia and the termination of atrial tachycardia following the injection of acetylcholine, the rapidly hydrolysable cholinergic receptor agonist (RHCA), into the tail vein (FIG. 2a) or the right ventricular cavity (FIG. 2b). FIG. 2a—The three traces (marked I, II and III) represent ECG recording from the three standard leads. Note the effect of RHCA injection through the tail vein in correcting atrial tachycardia following 2.6 seconds. FIG. 2b—The two traces (I and I cont.) represent ECG recording from standard lead I over an extended time period of 10 seconds. Note that following 0.5 second from the administration of the RHCA, the atrial tachycardia was terminated. After short period (1.25 seconds) of cardiac arrest two escape nodal beats appeared and the sinus node activity recovered (appeared P-waves) with high degrees of AV block. Following about 4.5 seconds, the AV conduction completely recovered;
FIGS. 3a-b—are ECG recordings of the three standard leads (I, II, and III) from a rat after the induction of atrial fibrillation and the suppression of atrial fibrillation by RHCA administration via the right ventricular cavity. FIG. 3b represents a continuation over a time scale of the ECG recording of FIG. 3a. Note the variable f-f and R-R intervals characterizing atrial fibrillation prior to RHCA administration. Following 1.5 seconds of a bolus injection of 0.1 ml of 0.2 mg/ml acetylcholine (dosage 0.04 mg/kg body weight), atrial fibrillation was converted into sinus rhythm; transient sinus bradycardia was maximal immediately following the injection and disappeared completely within 20 seconds (not shown);
FIGS. 8a-b—schematically illustrates the placement of the cardiac device in a body and a way of replenishing the medication reservoir with medication, in accordance with a preferred embodiment of the present invention;
FIGS. 9a-d—schematically illustrates an isometric view, and cross sectional views of integrated lead-catheter, in accordance with one embodiment of the present invention;
FIGS. 10a-e—schematically illustrates an isometric view and cross-sectional views at different parts of the integrated lead-catheter, in accordance with another embodiment of the present invention;
FIGS. 12a-b—schematically illustrates the placement of the cardiac device within the body, with the distal end of the catheter in the right hand side of the heart, in accordance with two embodiments of the present invention; and
While reducing the present invention to practice, the present inventors have uncovered that a bolus injection of a relatively low dose of acetylcholine (ACh) can terminate supraventricular arrhythmia. As is shown in FIGS. 2a-b and is described in Example 1 of the Examples section which follows, a bolus injection of 0.02 or 0.2 mg/kg body weight of ACh via the right ventricular cavity or the tail vein of a rat, respectively, terminated atrial tachycardia within 0.5-15 seconds. Moreover, a bolus injection of ACh (0.04-0.2 mg/kg body weight) terminated atrial fibrillation within 0.5-15 seconds and restored normal rhythm within additional 1-5 seconds of ACh administration (FIGS. 3a-b and 5, Example 2 of the Examples section which follows). These results therefore suggest the use of a bolus administration of ACh or any other rapidly hydrolysable cholinergic receptor agonist for treating supraventricular arrhythmias such as atrial fibrillation, atrial flutter and atrial tachycardia.
According to one preferred embodiment, the cholinergic receptor agonist used by the present invention is acetylcholine. The acetylcholine used by the present invention can be the acetylcholine per se [i.e., (CH<sub>3</sub>)<sub>3</sub>N<sup>+</sup>CH<sub>2</sub>CH<sub>2</sub>OCOCH<sub>3</sub>], acetylcholine in a salt formulation (i.e., acetylcholine salt) (available from various suppliers such as Sigma, St Louis, Mo., USA; Merck), a chemical derivative(s) and/or analogue thereof. Acetylcholine derivatives (e.g., dichlorophosphate-acetylcholine) are designed to prolong the stability and/or half life of acetylcholine. It will be appreciated that such a derivative should be rapidly hydrolysable yet exhibiting a longer half-life than acetylcholine itself.
For example, as described in Examples 1 and 2 of the Examples section which follows, administration of acetylcholine resulted in a modulation of the frequency of P (FIGS. 2a-b) and f (FIGS. 3a-b and 5) waves during atrial tachycardia and atrial fibrillation, respectively. Thus, FIGS. 2 and 3 show that administration of acetylcholine rapidly terminates the arrhythmia either by stopping the abnormal focal automaticity or by converting the abnormal spatial pattern of propagation of excitation and refractoriness (e.g., reentry) into the normal one, or by both. The cellular mechanisms of these effects relate to the transient activation of potassium conductance which, by hyperpolarizing and shunting the cellular membrane, prevents focal automaticity and transiently turns atrial cells to less excitable or even inexcitable.
Due to the large gradient in the density of the muscarinic K<sup>+</sup> channel density between atria and ventricles, there is a relatively wide range of a muscarinic agonist concentrations which maximally or almost maximally affect the atrial and nodal tissues but exhibit no effect on excitability or contraction of the ventricular myocardium.
For example, in vitro studies utilizing rat myocardial cells demonstrated that a concentration of 10<sup>−9 </sup>to 3×10<sup>−8 </sup>M acetylcholine causes nearly maximal effects in rat atrial cells but exhibits no effect on the electrical properties and inotropy of ventricular cells (McMorn et al., 1993 Am. J. Physiol. 265:H1393-1400).
Cardiac device 10 includes a sealed housing 11, adapted for implantation in a body 7 (as illustrated hereinbelow, in conjunction with FIG. 8a). Device 10 includes a catheter 22 connected to sealed housing 11, for delivering a medication 13 stored in a medication reservoir 12 that is located within housing 11, to a targeted tissue, in this case heart tissue, preferably into right ventricle 82 or right atrium (as shown in FIGS. 12a-b). Device 10 also includes a sensor 40 which is capable of sensing cardiac activity. Sensor 40 can form a part of housing 11 or be connected thereto. Device 10 preferably also includes a control unit 14, located within housing 11. Control unit 14 is electrically connected to a proximal end 34 of an electrical lead 37 which is in turn connected to sensor 40 at a distal end 36. Control unit 14 functions converting sensor 40 signals into control commands for controlling release of medication 13 from medication reservoir 12.
Medication reservoir 12 has an internal volume of about 1-100 milliliters and is fabricated from a suitable material for containing medication 13 which may include one type of medication or any combination of medicaments suitable for treatment. Medication 13 preferably includes a cholinergic receptor agonist such as acetylcholine and optionally any other type of medication suitable for use with the present invention. Medication reservoir 12 includes a seal 18, formed of a puncturable material (i.e., a material which can be punctured) which will reseal when a needle 19 (shown in FIG. 8b hereinbelow) is withdrawn, for replenishing medication reservoir 12 using e.g., a needle 19, (FIG. 8b). An electrically controlled valve 20, possibly associated with a pump 21, allows the release of medication 13, from reservoir 12. As used herein the phrase “associated with a pump” refers to either a direct or an indirect contact between the electrically controlled valve and the pump. For example, an indirect contact may be via any signaling route (e.g., radio frequency). Valve 20 is responsive to commands of control unit 14. It should be noted that although device 10 is described herein as having a single reservoir 12, multiple reservoir device configurations which are capable of separately providing to heart (or any other) tissue several types of medications are envisaged. For example, a device 10 having 2 reservoirs, one for holding a cholinergic receptor agonist and the other an antagonist thereof can be used to more finely control heart rhythm fluctuations. Another example is of device 10 having one reservoir containing a drug and a second reservoir for holding a dissolving liquid such as 0.9% NaCl solution. Such a multi-reservoir configuration can also be used to provide medication which otherwise cannot be stored in the same reservoir (e.g., different pH requirements and the like).
Sensor 40 can be a plurality of sensors 40 wherein sensor(s) 40 can be any type of sensor capable of sensing electrical, mechanical and hemodynamic activity of the heart, e.g., heart depolarization, heart contraction, blood flow, blood pressure and the like. Sensor(s) 40 is/are preferably connected to control unit 14 through a lead 37 (e.g., an electrical lead) which communicates sensor 40 signal to control unit 14 and optionally also communicates signals from control unit 14 to sensor 40 (which can also function as an electrode for pacing). It is appreciated that sensor 40 may be either a part of lead 37 or connected to distal end 36 of lead 37. Further description of various types of sensors is provided hereinunder (FIGS. 9a-11). Sensor 40 is connected to control unit 14 which receives signal information from sensor 40 and converts such signal information into commands for controlling opening and closing valve 20 of reservoir 12. Furthermore, control unit 14 may also include a pacemaker 15 and thus be capable of single chamber, dual chamber and biventricular pacing i.e., conventional dual chamber pacing or right ventricular pacing combined with left ventricular pacing via distal veins of coronary sinus (CS) for cardiac resynchronization therapy (CRT); McAlister F A, et al. Systematic Review: Cardiac Resynchronization in Patients with Symptomatic Heart Failure. Ann Intern Med. 2004; 141:381-390, and the like, and/or be capable of functioning as a defibrillator or (e.g., function as a universal implantable cardiac device including a pacemaker with all modes of pacing and defibrillator with all kinds of defibrillation) as described hereinbelow, in conjunction with FIGS. 9a-11. Pacemaker 15 component of control unit 14 can be assumed by, for example, a Medtronic AT500 system. Alternatively, pacemaker 15 may be any of the Integrity AFx from St. Jude Medical or Insignia Plus from Guidant, or another pacemaker, as known. Furthermore pacemaker 15 may be part of an ICD such as Medtronic's Marquis or Guidant's Vitality or another ICD, as known.
As is mentioned hereinabove, catheter 22 of device 10 functions in conducting the medication from reservoir 12 to the tissue site targeted. As such, catheter 22 has a proximal end 24 connected to medication reservoir 12, and a distal end 26 that is configured suitable for delivering the medication to a tissue, in this case, a heart 5 tissue (as seen in FIG. 8a). Preferably, the distal end of catheter 22 is positionable in proximity to the tissue. As used herein the term “proximity” refers to being in a cavity defined by the tissue, for example, if the tissue in which the medication is released is a blood vessel (artery or vein) the cavity is a lumen of such a blood vessel. On the other hand, if the tissue in which the medication is released is a heart chamber, then the cavity is an atrium or a ventricle. A length of catheter 22 is selected from a range of 1-70 cm while a width thereof is selected from a range of 2-8 mm. Catheter 22 is preferably integrated with lead 37 of sensor 40. Such an integrated lead-catheter 23 (i.e., a catheter integrated with a lead) that includes electrical lead 37 and defines a lumen 28 that runs substantially the length of integrated lead-catheter 23, is further described in conjunction with FIGS. 9a-11 hereinbelow. It is appreciated that catheter 22 and lead 37 may be separated for administering medication to one location while sensing a different location. For example, lead 37 is connected to the right atria while catheter 22 delivers medication to IVC 101. Catheter 22 or integrated lead-catheter 23 is made of any appropriate bio-compatible material, including, for example, polymers or metals or any combination thereof.
Reference is now made to FIGS. 8a-b which schematically illustrate the placement of cardiac device 10 in a body 7, for treating a heart 5, while also illustrate replenishment of medication reservoir 12 with medication 13, in accordance with a preferred embodiment of the present invention.
FIG. 8a schematically illustrates placement of cardiac device 10 in a body 7 (e.g. subcutaneous in a chest 8), in a manner similar to placement of any permanent pacemaker or implantable cardioverter defibrillator (ICD). Additionally FIG. 8a illustrates establishment of a connection between integrated lead-catheter 23 of cardiac device 10 and heart 5, providing an electrical connection, for transferring electrical signals between heart 5 and cardiac device 10, and providing lumen 28 (see FIGS. 7, 9a-11) within which medication 13 may flow from medication reservoir 12 to heart 5.
FIG. 8b schematically illustrates the use of needle 19 for puncturing seal 18 through skin 17 and replenishing medication reservoir 12 with medication 13.
FIGS. 9a-d schematically illustrates an isometric view, and cross sectional views of integrated lead-catheter 23 described above. Integrated lead-catheter 23 provides both electrical and fluid connections between cardiac device 10 and heart 5 (as shown in FIG. 8a). Integrated lead-catheter 23 includes a cathode 32, an anode 33, and an electrical insulating material 38. Additionally, integrated lead-catheter 23 includes a lumen 28 through which medication 13 are transferred from medication reservoir 12 to heart 5. Furthermore, cathode 32, running substantially the length of integrated lead-catheter 23, has a proximal end 34 and a distal end 36. Proximal end 34 is in electrical contact with control unit 14 (as shown in FIG. 7), and distal end 36 is in contact with heart 5 (as shown in FIGS. 12a-b). Distal end 36 may be formed as an electrode 41, for sensing any heart functions, for example, electrical. Additionally, electrode 41 may be used for electrical stimulation of heart 5, when cardiac device 10 includes pacemaker 15 (as seen in FIG. 7 hereinabove) or ICD. Additionally, anode 33, which is in electrical contact with control unit 14 on one side runs along integrated lead-catheter 23 until a second point 60 which is formed as a ring 61 close to distal end 26 of integrated lead-catheter 23, could be free-floating in the cavity of the heart chamber or in contact with internal wall (endocardium) of heart 5. It is to be noted that cathode 32 and anode 33 used for sensing and pacing as described herein above, together with control and power units, 14 and 16, serve as a bipolar lead. It is also possible to have second point of contact 60, for creating a potential difference with electrode 41, at housing 11 itself, or elsewhere in body 7 for example subcutaneously, in the left side of the subclavicular area (describing a unipolar lead).
As shown in FIGS. 1a, 7, and 9a) additionally or alternatively, sensor 40, (e.g. a piezoelectric sensor) may be placed at or near distal end 36, for example, for sensing heart beat. Cathode 32 and anode 33 are enclosed within an electrical insulating material 38, as is commonly practiced. Opening of valve 20 (shown in FIG. 7) mobilizes medication 13 from medication reservoir 12 (shown in FIG. 7) to heart 5 (shown in FIG. 8a) through lumen 28 and an orifice 42 which is located close to distal end 26 of integrated lead-catheter 23, near sensor 40 and (or) electrode 41, or anywhere else along the length of integrated lead-catheter 23. Orifice 42 located along the length of integrated lead-catheter 23 may be useful in cases where medication 13 in superior vena cava 102 or in the atrial or ventricular cavities is desired and yet placement of sensor 40, or electrode 41, against the heart muscles, for example, of right atrium 80, or right ventricle 82 is preferred (shown in FIGS. 12a and 12b).
FIGS. 10a-e schematically illustrates an isometric view (10a) and cross-sectional views at different parts of integrated lead-catheter 23, in accordance with another embodiment of the present invention. In the embodiment described here, cathode 32 runs substantially the length of integrated lead-catheter 23 and anode 33 has a cylindrical shape. Additionally, integrated lead-catheter 23 comprises a ring shaped lumen 28 confined between anode 33 and cathode 32 for mobilizing medication 13 from medication reservoir 12 to heart 5 (as shown in FIG. 8a). Preferably, cylindrical shaped anode 33 has an electrical insulating layer 38 internally and externally. Furthermore, cathode 32 has sensor 40 and (or) electrode 41 at distal end 26 of integrated lead-catheter 23 for sensing heart 5. For example, sensor 40 may be a transducer 40. Orifice 42 may be located close to distal end 26 of integrated lead-catheter 23, near sensor 40 and (or) electrode 41, or anywhere else along the length of integrated lead-catheter 23.
FIG. 10e illustrates an additional embodiment of catheter 23 of device 10 of the present invention. In this embodiment cathode 32 has a cross section which is shaped as a ring. Additionally, lumen 28 may have a cylindrical shape internal to cathode 32 running substantially the length of integrated lead-catheter 23. Furthermore, orifice 42 from which medication 13 leaves lumen 28 may be located at distal end 26 of integrated lead-catheter 23 (as shown in FIG. 10e) or close to distal end 26 of integrated lead-catheter 23, near sensor 40 and (or) electrode 41, or anywhere else along the length of integrated lead-catheter 23.
FIGS. 12a-b, schematically illustrate the placement of cardiac device 10 in body 7 (as shown in FIG. 8a), with distal end 26 of integrated lead-catheter 23 in the right hand side of heart 5, in accordance with a preferred embodiment of the present invention.
As seen in FIG. 12a, distal end 26 of integrated lead-catheter 23, with sensor 40 and (or) electrode 41 are placed in contact with the internal wall (endocardium) of right atrium 80, while orifice 42 is located in superior vena cava 102, so that medication 13 is released to superior vena cava 102. Alternatively, orifice 42 may be located in right atrium 80 or right ventricle 82, so that medication 13 is released there.
As seen in FIG. 12b, distal end 26 of integrated lead-catheter 23, with sensor 40 and (or) electrode 41 are placed in contact with the internal wall (endocardium) of right ventricle 82, while orifice 42 may be located in superior vena cava 102, right atrium 80, or right ventricle 82, so that medication 13 is released there. It will be appreciated that other combinations and locations are possible.
Bolus injection of acetylcholine into the tail vein terminated atrial tachycardia within 2-15 seconds and restored normal rhythm within additional 1-5 seconds—Atrial tachycardia was induced as described under experimental procedures hereinabove. FIG. 2a illustrates a representative ECG recording from a single rat with induced atrial tachycardia. The analysis of three standard ECG leads recording (I, II and III in FIG. 2a) shows that there exists a well-organized atrial tachycardia with AV conduction 4:1, P-P intervals (i.e., the intervals between two P waves) of 71±2 milliseconds (ms) [844 beats per minute (bpm)] and R-R intervals (i.e., the intervals between two R waves) of 284±3 ms (211 bpm). The episodes of atrial tachycardia in rats lasted, on average, for 7.6±1.8 minutes (n=30) upon induction. Bolus injection of 0.1 ml of 1 mg/ml acetylcholine (dosage 0.2 mg/kg body weight) via the tail vein terminated the arrhythmia with a lag of 2.6 seconds (FIG. 2a). The P-P and R-R intervals immediately following the RHCA administration were moderately prolonged (650±3 ms and 652±3 ms, respectively); the sinus rhythms gradually accelerated and reached its pre-arrhythmic value within about 1 minute following RHCA administration (not shown). All ten rats tested were successfully converted to sinus rhythm within 2-5 seconds following RHCA (0.02-0.2 mg/kg body weigh) injection via the tail vein.
Bolus injection of acetylcholine into the right ventricular cavity terminated atrial tachycardia within 0.5-10.5 seconds and restored normal rhythm within additional 1-5 seconds—FIG. 2b shows an example of termination of a high-frequency, well-organized atrial tachycardia by RHCA injection into the right ventricular cavity. As is shown in FIG. 2b, following 0.5 s from the administration of a bolus injection of 0.1 ml of 0.1 mg/ml acetylcholine (dosage 0.02 mg/kg body weight), the atrial tachycardia was terminated. After short period (1.25 s) of cardiac arrest two escape nodal beats appeared and the sinus node activity recovered (appeared P-waves) with high degrees of AV block. Following about 4.5 sec the AV conduction completely recovered. It should be emphasize that following acetylcholine hydrolysis, the AV node conduction appeared as high degree AV block (2.5 seconds) and completely recovered after a short period (at about 6 seconds following RHCA administration). Thus, RHCA administration resulted in very short periods of cardiac arrest, escape rhythm, high degree AV block, then 1<sup>st </sup>degree AV bock and sinus bradycardia which all disappear within 15 seconds (not shown). All twelve rats tested were successfully converted to sinus rhythm following RHCA (0.02-0.4 mg/kg body weight) injection into the right ventricle.
Bolus injection of acetylcholine into the right ventricular cavity terminated atrial fibrillation within 0.5-10.5 seconds and restored normal rhythm within additional 1-5 seconds—FIGS. 3a-b illustrate ECG recordings of a rat undergoing atrial fibrillation from the three standard leads (I, II, and III) and the suppression of atrial fibrillation by RHCA administration via the right ventricular cavity. Atrial fibrillation was characterized by variable f-f intervals (range 48-62 ms, 970-1250 bpm) and RR intervals (range 100-420 ms, 140-600 bpm). The average duration of such atrial fibrillation episodes without any further treatment (i.e., the time interval since induction till spontaneous termination) was 8.6±2.2 minutes (n=32). Bolus injection of 0.1 ml of 0.2 mg/ml acetylcholine (dosage 0.04 mg/kg body weight) into the right ventricular cavity converted the atrial fibrillation to sinus rhythm within 1.5 seconds; transient sinus bradycardia and AV block were maximal immediately following the injection and disappeared within 20 seconds (not shown).
Gelvan, Dan, Zeldets, Vladimir, Goldberg, Yuri, Fleidervish, Ilya A., Ovsyshcher, Eli
604/20, 607/3
Current Assignee: CLOSED LOOP THERAPIES LTD.
Sponsoring Entity: CLOSED LOOP THERAPIES LTD.