Electrically assisted transdermal method and apparatus for the treatment of erectile dysfunction

A non-invasive method is provided for treating erectile dysfunction using electroporation enhanced with delivery of a vasoactive or androgenic composition applied to the penis which affords an alternative treatment for patients afflicted with erectile dysfunction (ED). Sufficient electric pulses temporarily create new pathways in the penile skin thereby driving a composition, such as a vasoactive or androgenic medication, into the corporal cavernosum.

FIELD OF THE INVENTION
 The present invention relates generally to erectile function, and more
 specifically to methods and an apparatus for treatment of erectile
 dysfunction.
 BACKGROUND OF THE INVENTION
 Penile erection depends on the relaxation of cavernosal smooth muscle.
 Relaxation of the trabecular smooth muscle permits dilation of the lacunar
 spaces, causing engorgement of the penis. Inflow of blood at the systemic
 blood pressure to the lacunar spaces expands the relaxed trabeculae
 against the tunica albuginea. This compresses the subtunical venules,
 reduces venous outflow from the lacunar space, and elevates lacunar space
 pressure, making the penis rigid. Contraction of the cavernosal smooth
 muscle leads to penile detumescence. This results in a reduction of
 arterial inflow and a collapse of the lacunar spaces with decompression of
 subtunical venules and increased venous outflow from the lacunar spaces,
 returning the penis to the flaccid state.
 Penile erectile dysfunction is a common medical disorder. It has been
 estimated that it is prevalent in 2% of men aged 40 years, which an
 increase to over 50% in men over the age of 70 years, affecting some 10 to
 20 million men in the US alone. Intracavernosal injection of vasodilators,
 such as prostaglandin E1 (PGE1, alprostadil; CAVERJECT.TM./Upjohn-for
 intracavernosal use), is a commonly used treatment for erectile
 dysfunction (Porst, J. Urol. 155(1996)802-812). When injected into the
 penis, prostaglandin E1 can induce an erection within a few minutes in up
 to 80% of cases, and acts by relaxing the smooth muscle of the penis.
 Different formulations of prostaglandin E1 are now available and have been
 compared (Vanderschueren et al., J. Urol. 154(1995) 1744-1747). Mechanism
 and side effects have been studied (Granata et al., Psychosom. Med. 57
 (1995) 336-344; Italiano et al., Pharmacol. Res. 31 (1995) 313-317).
 Although effective, the drawbacks of intracavernosal injection therapy
 include the inconvenience of injection, discomfort, stress and pain during
 injection and penile scarring (Gana et al., Curr. Ther. Res. 57 (1996)
 700-710; Chen et al., J. Urol. 155 (1996) 138-140). As prostaglandins
 undergo first pass metabolism and adverse reactions such as diarrhea
 follow oral use, they cannot be administered orally.
 Other methods for treating erectile dysfunction include malleable
 (bendable) or inflatable penile implants or prostheses, which are
 manufactured by several different companies. However, such devices require
 surgery. The use of penile suppositories, in which a drug is delivered
 transurethrally, (alprostadil in MUSE; medicated urethral system for
 erections), can be painful or less effective. Oral corporal
 pharmacotherapy also has been used. Apomorphine treatment, in which a
 pellet is placed under the tongue for absorption into the blood stream,
 works by stimulating receptors in the brain which may then result in an
 erection five to twenty minutes after administration. Sildenafil citrate
 (VIAGRA.TM., Pfizer) has become available more recently and has been shown
 to help about 70% of men with impotency problems. However, in patients
 with preexisting cardiovascular disease, there is a potential for cardiac
 risk of sexual activity associated with VIAGRA use. Further, patients
 taking any medicines that contain nitrates, which are often used as
 treatments for angina (chest pain due to heart disease), cannot take
 VIAGRA. Moreover, not all patients respond to VIAGRA treatment.
 Topical/transdermal delivery of vasodilators that stimulate erectile
 function is another possibility for treating erectile dysfunction (e.g.,
 hydralazine; U.S. Pat. No. 4,801,587). Transdermal delivery of
 prostaglandins has been shown to be feasible (Watkinson et al., Int. J.
 Pharm. 74 (1991) 229-236., Uekama et al., J. Pharm. Pharmacol. 44 (1992)
 119-121), and delivery is facilitated by penetration enhancers. It has
 been shown that PGE1 permeated across hairless mouse skin in-vitro when
 delivered by iontophoresis, but not by passive transport (aqueous solution
 used; Saeki et al., Int. J. Pharm. Therapeutics 36 (1996) 525-529).
 However, the lag time of absorption may be too long for treatment of
 erectile disorders, as a response within 5-20 minutes is desired. When 500
 microgram of PGE1 was applied to the genital area, immediate erection
 could not be obtained (Chiang et al., Ann. Acad. Med. Singapore 24 (1995)
 767-769).
 Thus, in view of the problems associated with current methods for treating
 erectile dysfunction by injectable and systemic pharmacotherapies and
 prostheses, a need exists for the development of alternative methods for
 treating erectile dysfunction. The present invention satisfies this need
 and provides related advantages as well.
 SUMMARY OF THE INVENTION
 The present invention is based on the development of a non-invasive method
 and apparatus for delivery of drugs or genes into the penile erectile
 tissue to induce or enhance penile erection, which affords an alternative
 treatment for patients afflicted with erectile dysfunction (ED).
 Sufficient electric pulses temporarily create new pathways in the penile
 skin thereby driving a composition, such as a vasoactive or androgenic
 medication, into the corporal cavernosum.
 In a first embodiment, the invention provides an electrical apparatus for
 treating erectile dysfunction or inducing or enhancing erectile function
 non-invasively in a subject. The apparatus includes a cuff capable of
 conforming to the shape of a penis; and a pulse applicator connected to
 said cuff capable of applying an electric pulse of sufficient strength and
 duration to the penis for transdermally introducing a composition into the
 penis.
 In another embodiment, the invention includes a method for treating
 erectile dysfunction or for inducing, enhancing or maintaining erectile
 function in a subject, comprising applying an electric pulse to the penis
 substantially contemporaneously with a vasoactive or androgenic
 composition, said electric pulse having sufficient strength and duration
 for transdermally introducing an effective amount of the composition into
 the penis, thereby treating erectile dysfunction or inducing, promoting or
 enhancing erectile function.
 In yet another embodiment, the invention includes a method for preventing
 or inhibiting impotence in a subject including applying an electric pulse
 to the penis substantially contemporaneously with a vasoactive or
 androgenic composition, said electric pulse having sufficient strength and
 duration for transdermally introducing an effective amount of the
 composition into the penis for preventing or inhibiting impotence.
 The invention further includes a method for delivering a composition into
 the penis of a subject including applying an electric pulse to the penis
 substantially contemporaneously with the composition, said electric pulse
 having sufficient strength and duration for transdermally introducing the
 composition into the penis in an amount greater than passive diffusion.
 The invention also includes a kit for treating erectile dysfunction or
 inducing or enhancing erectile function. The kit includes, for example, a
 package having an electrical apparatus for treating erectile dysfunction
 or inducing or enhancing erectile function of a subject; and instructions
 for use.

DETAILED DESCRIPTION OF THE INVENTION
 The present invention is based upon the seminal discovery that applying a
 composition to the penile shaft or glans in conjunction with applying an
 electrical impulse to the penis is effective for introducing compositions
 into the penis. The invention therefore provides an electrical apparatus
 for transdermally introducing compositions into the penis and methods for
 introducing compositions into the penis. A method of the invention
 includes applying an electric pulse of a sufficient strength and duration
 to the penile shaft or glans substantially contemporaneously with a
 vasodilator or androgenic composition, thereby transdermally introducing
 the composition into the penis. A method of the invention in which an
 effective amount of such a composition is transdermally introduced into
 the penis is useful for treating erectile dysfunction or for inducing,
 enhancing or maintaining erectile function.
 The electrical apparatus and the methods of the invention are advantageous
 in several respects. The apparatus and the methods allow for rapid and
 non-invasive delivery of a drug into the penis without the pain and penile
 fibrosis/scarring that results from needle injection. The dose of
 medication needed for local treatment as compared to systemic treatment is
 generally lower thereby minimizing or prevent side effects or other
 problems associated with systemic drug delivery. Thus, the apparatus and
 the methods of the invention are particularly applicable for treating
 erectile dysfunction or for inducing, enhancing or maintaining erectile
 function in subjects having a low pain tolerance, who easily scar or in
 which the use of systemic drugs is not possible or is otherwise
 undesirable. The invention apparatus and methods are additionally
 advantageous when used in combination with other techniques or apparatus
 (e.g., iontophoresis (IPH), vibration, phonophoresis, pharmacotherapeutics
 ( optionally, liposome encapsulated), penile venous flow restriction
 devices,) as the combination can produce an additive or synergistic effect
 so that maximal therapeutical effects for treating erectile dysfunction or
 for inducing or enhancing erectile function are produced. For example,
 successive electropulsing of one vasodilating composition into the penis
 followed by a different composition, or a mixture of different
 vasodilating compositions can produce a greater effect than electropulsing
 a single vasodilating composition alone. Electropulsing the penis with a
 vasoactive composition, followed by iontophoresis, can produce a greater
 therapeutic effect than either applying the pulse or iontophoresis alone.
 Similarly, electropulsing combined with administering a drug for treating
 erectile dysfunction (e.g., VIAGRA.TM.), at doses lower than those
 normally associated with clinical efficacy, can produce an additive or
 synergistic effect greater than that produced by penile transdermal drug
 introduction or VIAGRA.TM. administration alone, while minimizing side
 effects due to the lower dose. Furthermore, electroincorporation (see,
 e.g., U.S. Pat. No. 5,464,386, which is hereby incorporated herein in its
 entirety by reference), or electropulsing in combination with IPH and
 liposomal formulation can enhance delevirey significantly. (see, e.g.,
 Badkar, et al., Drug Delivery 6 (1000) 111-115).
 As used herein, the terms "impulse," "pulse," "electrical impulse,"
 "electrical pulse," "electric pulse," "electropulse" and grammatical
 variations thereof are interchangeable and all refer to an electrical
 stimulus. Although the various terms are frequently used herein in the
 singular, the singular forms of the terms include multiple pulses.
 Preferred electrical impulses are pulsed electric fields applied via
 electroporation. The pulse can be unipolar, bipolar, exponential or square
 wave form.
 The term "erectile dysfunction" is used broadly herein, and refers to
 either an acute or chronic inability to achieve or maintain an erection of
 sufficient rigidity for sexual intercourse. Thus, the term includes severe
 cases of chronic impotence as well as single episodes of impotence in a
 subject not generally characterized as impotent. The term "treating" when
 use in reference to erectile dysfunction further includes "preventing" or
 "inhibiting" erectile dysfunction.
 As used herein, the term "erectile function" refers to either an induction
 of penile tumescence sufficient to achieve sexual intercourse, to an
 increased or enhanced penile tumescence in a penis that already exhibits
 tumescence, or to maintenance of penile tumescence. Generally, erectile
 function "induced, enhanced or maintained" will be that sufficient for
 sexual intercourse.
 As used herein, the term "transdermally introducing" and grammatical
 variations thereof, refers to the delivery of a composition into the skin,
 through/across the skin, or a combination thereof. An electric pulse that
 transdermally introduces a composition into the penis is believed to
 overcome the resistance of the skin barrier or alter the permeability of
 tunica albuginia. Thus, in a method of the invention in which an
 androgenic or vasoactive composition is "transdermally introduced" into
 the penis, the composition is driven into or through/across the penile
 skin. The "transdermally introduced" composition is likely driven into the
 corporal cavernosum, or into the blood supplying the corporal cavernosum
 by the pulse(s), to affect the erectile tissue.
 As used herein, the term "subject" refers to any animal that has a blood
 vessel. It is envisioned that the methods for inducing or increasing
 vasodilation of a vessel and the methods for inducing or increasing the
 flow of fluid through a vessel described herein can be performed on any
 animal. Preferably, the subject is a human.
 The invention provides an electrical apparatus for treating erectile
 function or for inducing, enhancing or maintaining erectile function. The
 apparatus comprises a cuff capable of conforming to the shape of a penis
 and a pulse applicator connected to said cuff capable of applying an
 electric pulse of sufficient strength and duration to the penis for
 transdermally introducing a composition into the penis.
 An exemplary hand-held electrical apparatus, comprising a mini pulse
 generator 100 physically connected to a cuff 102 in association with an
 electrode containing pulse applicator (or sheath) 104, is shown in FIG. 1.
 The cuff shape will preferably be cylindrical, although other shapes can
 be used so long as the shape is ergonomically compatible with the penis
 and can function as described herein. The exemplary pulse applicator
 comprises a sheath, optionally disposable, that conforms to the cuff shape
 (illustrated but not limited to FIGS. 1 and 2); the sheath contains an
 electrode 106 on the inner surface. Depending on the formulation of the
 composition to be transdermally introduced, the electrode can be an
 insulated or porous meander electrode; a meander electrode is an
 interweaving array of metal fingers coated on a thin film, such as
 plastic, which can be placed on skin. The sheath is connected to the mini
 generator via contacts on the outer surface of the sheath. The sheath
 enables one or both sides of the penile midshaft, penile glans or both
 midshaft and glans to be in contact with the electrode, while generally
 avoiding urethra contact with the electrode. Prior to use, the sheath is
 positioned in the cuff so that contacts located on the outer surface are
 made with the mini generator, and the inner surface of the sheath is
 positioned to be in contact with the penis; a desired composition is
 administered, preferably topically, to the penis. In operation, the penis
 is placed longitudinally in the cuff in contact with the electrodes (as
 disposed within the sheath) and the cuff is closed about the penis; the
 exemplary electrical apparatus has an integral snap-closure mechanism 108
 to secure the cuff in the closed position thereby ensuring good contact
 between the electrodes and the penile glans, shaft, or both, as is shown
 in FIG. 1. One or more appropriate electric pulses are then applied,
 preferably a pulsed electric field, by depressing an activator button 110;
 the exemplary electrical apparatus has the activator button positioned on
 the mini-generator.
 The aforementioned invention apparatus shown in FIG. 1 is not meant to be
 limiting. Thus, other apparatus, additional functional components and
 variations thereof are specifically contemplated herein. For example, a
 second exemplary apparatus is shown in FIG. 3 that includes several
 additional components such as a pressure applicator tube 200 (to improve
 contact between penile skin and electrode, or to exert pressure on the
 penis thereby increasing transdermal introduction of a composition into
 the penis), a means for applying pressure (e.g., a bulb 202), a pressure
 sensor tube 204 and a sensor gauge 206 (e.g,. indicating if there is a
 good contact between penile skin and electrode). In the depicted
 embodiment, an infant blood pressure cuff was employed, as it contains a
 pressure tube and sensor. The remaining components of the invention
 assembly are essentially the same as those described and depicted in FIG.
 1. For example, there is a sheath (or pulse applicator) 210, comprising
 electrodes 216, disposed within a meander strip 214, having an elctrode
 side 214a and a back side 214b. As shown in FIG. 3, the pulse generator
 208, although operatively connected to the pulse applicator is not
 physically attached to the sheath 210 or to the cuff, as in the
 mini-apparatus exemplified in FIG. 1. Thus, an invention electrical
 apparatus may or may not be physically attached to the pulse generator,
 but only need be operatively connected.
 Additional functional components that can be added to the invention
 electrical apparatus include, for example, an iontophoresis unit (IPH),
 which can be used in combination with an electrical impulse to
 transdermally introduce a greater amount of the composition into the penis
 than pulsing alone, or that can drive the composition deeper into the
 penis, if desired. A switching unit, such as an automated switch,
 optionally programmable, could be used to control the time between
 applying the impulse and applying IPH, as well as optionally controlling
 the time during which IPH is applied. Each parameter will be determined by
 the composition introduced, the desired effect, the concentration etc. In
 one aspect of this embodiment, electrodes on either side of the penis can
 be operated by an electroporation unit and an IPH unit respectively in a
 sequential manner. More specifically, two electrodes can be disposed on
 either side of the penis (e.g., electrodes 1 and 2 on the left side and
 electrodes 3 and 4 on the right side). In electroporation mode electrode 1
 is pulsed against electrode 2, likewise electrode 3 is pulsed against
 electrode 4. In IPH mode, electrode 1 is connected to electrode 2 (with
 either positive or negative polarity) while electrode 3 is connected to
 electrode 4 with an opposite polarity; then electrodes 1 and 2 will be
 pulsed against electrodes 3 and 4. Of course, these operation parameters
 can be set or programmed into the mini-generator.
 A vibration unit also can optionally be included in the apparatus, which
 can be used in combination with an electrical impulse to transdermally
 introduce a composition into the penis, if desired. A phonophoresis unit,
 which can transdermally introduce a composition into the skin by means of
 ultrasound, also can optionally be included in the apparatus, if desired.
 Thus, by applying vibration or ultrasound before, after or during pulsing
 and/or iontophoresis on the penile glans or midshaft, the composition can
 be driven deeper into the penis or a greater amount of the composition can
 be driven into the penis than pulsing alone. As above, a switching unit,
 such as an automated switch, optionally programmable, could be used to
 control the time between applying the impulse and applying vibration or
 ultrasound, as well as optionally controlling the time during which
 impulse, vibration or ultrasound is applied.
 A means for administering a composition can optionally be included in the
 electrical apparatus, which can be used to administer the composition to
 the penis prior to, substantially contemporaneously with, or after
 applying an electric pulse, iontonophoresis, vibration or ultrasound, in
 their various embodiments. Depending on the specific formulation, a
 composition can be incorporated into a patch reservoir (e.g., as a
 nicotine patch), which is then attached both to the electrode and the
 penis. Formulations employed for IPH are advantageously used in this
 manner.
 As used herein, the term "substantially contemporaneously" means that the
 electric pulse and the composition are applied to the penis reasonably
 close together in time. Preferably, the composition is administered prior
 to or concurrently with electropulsing. When applying multiple electrical
 impulses, the composition can be administered before or after each of the
 pulses, or at any time between the electrical pulses. When applying
 iontophoresis, vibration or ultrasound, the composition can be
 administered before or after each, and at any time between.
 Restricting venous outflow from the penis can induce, enhance or maintain
 erectile function by maintaining the imbalance between arterial inflow and
 venous outflow, or by inhibiting outflow from the penis of a vasodilator
 or an androgenic composition transdermally introduced into the penis as
 set forth herein. Thus, a means for restricting venous flow from the penis
 optionally can be included in an invention apparatus as disclosed herein.
 For example, a mechanical constriction device, band, strap or clamp can be
 physically attached to the apparatus, such as the cuff, to be secured
 around the penis at the base (e.g., as with a tourniquet). Venous outflow
 can be controlled by varying the degree of penile constriction. The band
 or strap can be flexible or elastic (e.g., latex, butyl rubber, synthetic
 or natural elastomers etc.). Optionally, a tubular band of an appropriate
 thickness can be used to enable inflation of the tube band to adjust the
 degree constriction thereby controlling the amount of venous outflow from
 the penis. A bulb at one end of such a tube band having a closed opposing
 end can be used to apply pressure within the tube band thereby inflating
 the band; an optional pressure sensor can monitor the amount of pressure
 and a release valve or other appropriate pressure release mechanism can
 additionally be included to decrease or eliminate penile constriction when
 sufficient erection is attained or so as to not cause discomfort. The term
 "elastic" or "elasticity" as used herein refers to the ability of a solid
 material to change shape or size under opposing forces, to sustain such
 deformation without permanent loss of size or shape, and to recover most
 or all of its original configuration when the forces are removed.
 Preferred elastic bands or straps are flexible and capable of regaining
 their original shape after being deformed within their elastic limits;
 elasticity of a material can be quantified in a variety of ways, and can
 be modified by altering the composition. The band, strap, clamp etc. can
 be covered in fabric or otherwise modified to increase user comfort.
 Various flow control devices that can be used to control penile venous
 flow are known in the art and it is specifically contemplated that the
 invention electrical apparatus can be modified to incorporate such
 devices, if desired (see e.g., U.S. Pat. No. 5,855,548).
 In addition to the various functional components that can be added to the
 invention electrical apparatus, each of the essential components of the
 invention apparatus can be modified, or can have additional functional
 components. For example, in the exemplary hand-held mini pulse
 generator/power source shown in FIG. 1, the pulse applicator 104
 comprising the sheath is separable from the cuff 102, and the mini
 generator 100 is affixed to the cuff. However, the pulse applicator
 optionally can be affixed to the cuff, and the mini generator optionally
 can be separable from the cuff. Additionally, the nature of the electrode
 that can be used in the pulse applicator can be varied so long as it is
 capable of delivering a sufficient electric pulse as set forth herein.
 Thus, a variety of electrode types and configurations are contemplated in
 the invention apparatus.
 In one embodiment, the electrode is a wire electrode (useful for in vitro
 studies, and the like). In another embodiment, the electrode is a
 plurality of electrodes (e.g., a micropatch electrode as described in U.S.
 patent application Ser. No. 09/134,245, filed on Aug. 14, 1998, which is
 hereby incorporated herein in its entirety by reference). In still yet
 another embodiment, the electrode comprises a meander electrode (e.g., an
 array of interweaving electrode fingers, with a typical electrode width in
 the range of about 0.2 up to about 1 mm, and an electrode gap of about 0.2
 mm, wherein the gap can be filled with an electrically insulating
 substance). In an additional embodiment, the electrode is a porous
 electrode. The various electrodes used herein are preferably insulated to
 protect against excess heat or burning, current leakage, shock, etc.
 Appropriate electric pulsing parameters are set forth herein or can be
 determined using the teachings herein and, in view of these parameters,
 the skilled artisan can select among various suitable electrode types
 (e.g., ceramic, metal, etc.) and configurations (single wire, multiple
 wire, etc.) available in the art.
 The cuff can be manufactured of essentially any material compatible with
 applying an electrical impulse to the penis. The cuff can be made of a
 single material type or can be made of multiple material types. In one
 embodiment, the cuff is manufactured of a single flexible cushioned or
 compressible material. In another embodiment, the inner cuff, which
 contacts the penis, is made of a cushioned or compressible material and
 the outer cuff is made of a rigid material, such as plastic, metal, an
 alloy, or a combination thereof. Although the cuff of the exemplified
 apparatus has a relatively fixed size, preferably the cuff is adjustable
 or compressible so as to accommodate various penis sizes and different
 states of penile tumescence. For example, in one embodiment, the apparatus
 has an inner cuff separable from an outer cuff, and has variously sized
 inner cuff pieces (e.g, different thickness), optionally compressible,
 that can be inserted into the outer cuff so as to be adjustable with
 respect to cuff size. Preferably, the various cuff embodiments of the
 invention apparatus are hypo-allergenic, non-allergenic or so modified to
 be non-allergenic.
 The invention apparatus can have an indicating means to ensure proper
 positioning of the apparatus relative to the penis. For example, a visible
 band on the apparatus can indicate where the apparatus should be located
 relative to the shaft and/or glans. A visible band additionally can
 indicate proper penile location relative to the electrodes used for
 applying the pulse to the penis. For example, referring to FIG. 14, two
 differently colored bands 302 and 304, each of which indicate the
 electrodes for the shaft and for the glans respectively, can be included.
 Alternatively, the apparatus can be modified or manufactured to have
 sufficient transluscence (e.g., clear polycarbonate) so that the penis can
 be visualized in order to achieve proper positioning. In another
 alternative, a "closed condom" or "cone" shaped apparatus can be
 manufactured such that inserting the penis all the way to the end of the
 cone ensures proper positioning within the apparatus (See, e.g., FIG. 14
 showing the open condom embodiment, as worn, and as viewed from the inside
 in an opened view).
 Mere pressure, such as that provided by hand, can be sufficient to secure
 the invention electrical apparatus about the penis. Alternatively, a
 fastening means, optionally adjustable, can be used for securing the
 electrical apparatus. For example, the exemplified apparatus has a
 snap-closure fastening means attached thereto (e.g., the cuff, FIG. 1).
 Additional contemplated fastening means include, for example, VELCRO,
 snap, buckle, clip, clamp, adhesive tape and coupling mechanism. An
 adjustable fastening means has the advantage of being able to accommodate
 various penis sizes and different states of penile tumescence as well as
 exerting pressure on the penis to drive more of the composition into the
 penis, or drive the composition into deeper areas of the penis.
 Alternatively or in addition, the pulse applicator, if desired, can be
 modified to include a fastening means as described herein. In a particular
 aspect, a pulse applicator fastening means is VELCRO.TM. (FIG. 2).
 As described herein, the separable pulse applicators optionally are
 disposable. Thus, in accordance with the present invention, a kit
 comprising at least one pulse applicator is further provided. The kit
 contains appropriate packaging material and instructions relevant to the
 enclosed pulse applicator. Preferably, the pulse applicator has been
 sterilely manufactured or treated to be sterile and packaged to maintain
 sterility. In addition to the above described components, the kit
 optionally contains one or more androgenic or vasoactive compositions,
 such as those described herein or known in the art, for use with the
 enclosed pulse applicator in the electrical apparatus.
 The invention apparatus can have a variety of other "user friendly"
 functionalities in addition to the optional controlling means ("activator
 button") for applying an electric pulse, indicating means and fastening
 means. For example, the apparatus can have an indicating means for
 indicating apparatus ready, the various pulse parameter settings (e.g.,
 voltage, capacitance, pulse duration, time delay between pulses, pulse
 wave type), pulse(s) applied, parameters of the applied pulse(s) (e.g.,
 voltage, capacitance, pulse duration, pulse wave type, number of pulses)
 or a combination thereof. Such indicating means can be visual, audible, or
 a combination thereof. For example, a single audible "beep" can indicate
 that the "apparatus is ready," two audible "beeps" can indicate that a
 pulse has been correctly applied and three audible "beeps" can indicate a
 malfunction or that the pulse was not or was improperly applied. Visual
 indicating means include analog or digital alpha-numeric displays (e.g.,
 LCD, LED and the like), as in watches, and further can include
 illuminating means for low light visualization, for example, by white
 light, electroluminescent backlighting for LCD or electroluminescent lamps
 (i.e. INDIGLO.TM.), or by various fluorescent or radioactive illuminating
 compositions, and the like.
 Additional "user friendly" functions include the aforementioned controlling
 means for applying an electric pulse (e.g., pushbutton, knob, lever
 switch, dial and the like) as well as means for adjusting parameters
 (e.g., pushbutton, knob, lever switch, dial and the like) including, for
 example, pulse duration, voltage, capacitance, field strength, number,
 wave type and penile location (e.g., one or both sides of the midshaft or
 shaft, the glans, or a combination thereof). Means for adjusting, setting,
 storing or retrieving one or more pulse parameters also are included
 herein. Such means include traditional mechanical electronic controls
 (e.g., a selector switch controlling each parameter in which the switch
 has a plurality of settings; exemplary pulse length settings, 5 msec, 10
 msec, 25 msec, 35 msec, 50 msec, for example.) as well as a chip control
 (e.g., silicon wafer types commonly used in the computer industry) which
 is controlled, for example, by a pushbutton interface, as in watches for
 example. A chip, optionally removable from the apparatus or, user and/or
 manufacturer programmable for control of the various pulse parameters set
 forth herein also is contemplated. Storage capacity of such a chip is
 sufficient to provide virtually unlimited fine control of the various
 parameters, as well as storing different pulse parameter settings for
 different compositions, users and the like. As each of the various
 electronic functionalities of the invention apparatus described herein can
 be controlled or managed by a computer chip, a chip affords the option of
 additionally incorporating software, if desired, said software optionally
 user programmable.
 In addition to efficacy, both sensation and user safety are important.
 Thus, in another embodiment, the invention further provides an apparatus
 having means for preventing applying excess pulse voltage, duration, field
 strength and/or number. Any means which passively or actively interrupts
 or disrupts the electric circuit, including fuses, circuit breaker
 switches, and the like, or devices that actively monitor the various pulse
 parameters and interrupt or disrupt the electric circuit to prevent excess
 pulse voltage, duration, field strength, pulse number from being applied
 can be incorporated into the circuit path. Those skilled in the art of
 electrical devices will know of other protective elements that prevent
 applying excess pulse voltage, duration, field strength or number.
 The electric pulse can be provided by any electronic device that provides
 an appropriate electric pulse or electric source sufficient for
 transdermally introducing a composition into the penis. Suitable electric
 pulses for transdermally introducing compositions into the penis therefore
 include, for example, square wave pulses, exponential waves, unipolar
 oscillating wave forms, bipolar oscillating wave forms, other wave forms
 generating electric fields, or a combination of any of these forms. Each
 pulse wave form has particular advantages; square wave form pulses provide
 increased efficiencies in transporting compounds into the cells in
 comparison to exponential decay wave form pulses, and the ease of
 optimization over a broad range of voltages, for example (Saunders, "Guide
 to Electroporation and Electrofusion," 1991, pp. 227-47). Preferably, the
 waveform used is an exponential or a square wave pulse.
 An exemplary electric impulse for transdermally introducing a composition
 into the penis is a pulsed electric field, such as that provided by an
 electroporation apparatus. Exemplary pulse generators capable of
 generating a pulsed electric field include, for example, the ECM600, which
 can generate an exponential wave form, and the ElectroSquarePorator
 (T820), which can generate a square wave form, both of which are available
 from BTX, a division of Genetronics, Inc. (San Diego, Calif.). Additional
 electroporation type apparatus are commercially available and can be used
 to generate the pulse for the invention apparatus and in practicing the
 invention methods. Such pulse generators can be operatively connected to
 the pulse applicator as shown in FIG. 3, for example, or alternatively can
 be physically connected to the cuff or pulse applicator. A pulse
 generator, physically connected, is preferably portable or lightweight, as
 in the exemplary mini- pulse generator 100 (FIG. 1), and an optional
 portable DC power source, such as batteries, optionally being
 rechargeable, can be included to provide the power source to the pulse
 generator.
 The results showing that an electrical impulse applied to the penis
 transdermally introduces topically applied PGE1 or trimix (papavarine,
 phentolamine and PGE1) into the penis thereby inducing or enhancing
 erectile function are shown in Examples I to III and in FIGS. 4 to 8.
 Exemplary pulse parameters for transdermally introducing a composition
 into rabbit penis, human skin and human penile skin are described herein
 in Examples I to IV.
 Thus, in accordance with the present invention, methods for delivering a
 composition into the penis of a subject are provided. In one embodiment,
 the method comprises applying an electric pulse to the penis substantially
 contemporaneously with a composition, in which the electric pulse has
 sufficient strength and duration for transdermally introducing the
 composition into the penis in an amount greater than passive diffusion.
 In another embodiment, methods for treating erectile dysfunction or for
 inducing, enhancing or maintaining erectile function in a subject are
 provided. A method comprises applying an electric pulse to the penis
 substantially contemporaneously with a vasoactive or androgenic
 composition of sufficient strength and duration for transdermally
 introducing an effective amount of the composition into the penis, thereby
 treating erectile dysfunction or inducing, enhancing or maintaining
 erectile function.
 As the invention methods for treating erectile dysfunction or for inducing,
 enhancing or maintaining erectile function also prevent or inhibit
 impotence, the invention further provides methods for preventing or
 inhibiting impotence in a subject. The method comprises applying an
 electric pulse to the penis substantially contemporaneously with a
 vasoactive or androgenic composition, said electric pulse having
 sufficient strength and duration for transdermally introducing an
 effective amount of the composition into the penis for preventing or
 inhibiting impotence. The methods for preventing or inhibiting impotence
 in a subject can be modified as described herein as with the various
 embodiments of the methods for treating erectile dysfunction or for
 inducing, enhancing or maintaining erectile function.
 In one aspect, the electric pulse is applied to the penile glans. In
 another aspect, the electric pulse is applied to one side of the penile
 shaft. In various other aspects, the pulse is applied to both sides of the
 shaft, either side of the midshaft, both sides of the midshaft and both
 the penile glans and the midshaft.
 Generally, the pulse strength applied to the penis will range from about 25
 to about 200 volts, preferably from about 40 to about 100 volts and more
 preferably from about 50 to about 80 volts. The pulse duration generally
 will be from about 100 microseconds (.mu.s) to 100 milliseconds (ms),
 preferably from about 500 .mu.s to about 50 ms and more preferably from
 about 1 ms to 30 ms. The capacitance will generally range from about 100
 to about 1000 .mu.F, preferably from about 200 to about 800 .mu.F, more
 preferably from about 400 to about 1000 .mu.F. There can be from about 1
 to about 25 pulses applied. Preferably, the number of pulses is from about
 1 to about 10 pulses and more preferably from about 1 to about 6 pulses
 per cycle. Most preferably, 5 to 15 pulse cycles are applied.
 The voltage, waveform type, pulse duration, capacitance, field strength and
 the number of pulses applied will vary depending on the location of the
 pulse and the nature of the composition to be transdermally introduced.
 For example, as the glans is more sensitive than the shaft, low voltage
 and short pulses, preferably in combination with iontophoresis, is
 preferred on the glans. The glans is less electrically resistant than the
 shaft and therefore, less voltage may be needed to transdermally introduce
 compositions into the glans. For the shaft, relatively higher voltages and
 longer pulses are tolerable. Particular electrical parameters for
 transdermally introducing a composition into the penis, other than those
 exemplfied herein, can be empirically determined if necessary, in view of
 the teachings herein and of the general knowledge of those having skill in
 the art, for example, relating to the electroporation of mammalian cells
 in vivo.
 The terms "androgenic" or "vasoactive" composition refers to a drug, agent,
 compound or chemical that has or that can produce or enhance one or more
 activities characterized as "androgenic" or "vasoactive" as is known in
 the art. When administered to a subject, such compositions induce or
 enhance an "androgenic" or "vasoactive" effect. As used herein, a
 "vasoactive composition" means a substance having the capability of
 altering the physiologic state, especially the tone and diameter, of a
 vessel. Thus, a "vasodilator" is a composition that induces or enhances
 vessel relaxation or dilation and a "vasoconstrictor " is a composition
 that induces or enhances vessel rigidity or constriction. As used herein,
 an "androgenic composition" refers to a substance having or capable of
 enhancing an erection. Various androgenic and vasodilating drugs and other
 compositions having such properties are described herein and are further
 known to those skilled in the art and as such are applicable in using the
 invention apparatus and in practicing the invention methods.
 Although not wishing to be bound by any theory, it is believed that the
 common channels for the drainage of the glans, corpus spongiosum, and the
 corpus cavernosum are the route for drug transfer from the spongiosal to
 the cavernosal compartment (Vardi et al., Urology vol. 49 (1997)). Thus,
 in all likelihood, the compositions transdermally introduced into the
 penis for treating erectile dysfunction or for inducing, enhancing or
 maintaining erectile function are driven into the corpus cavernosum or
 into the blood vessels that supply the corpuscavernosum thereby producing
 a local effect or function within the erectile tissue.
 As used herein, the term "local," when used in reference to a composition,
 refers to its function in a particular region. Thus, a vasoactive
 composition transdermally introduced into the penis is believed to exert
 its vasoactive function within the penis. Nevertheless, the skilled
 artisan will recognize that some transdermally introduced compositions may
 have a systemic effect or function, such that after transdermally
 introducing the composition into the penis, the composition is distributed
 to other areas of the subject thereby producing or contributing to
 treating erectile dysfunction or inducing, enhancing or maintaining
 erectile function by acting at a site other than the penis. As used
 herein, the term "systemic," when used in reference to a composition,
 means that the composition functions outside the penis. It is specifically
 contemplated that compositions that function systemically are included
 herein in addition to those functioning locally or both systemically and
 locally.
 Any composition can be used in the methods of the invention, so long as the
 composition, when transdermally introduced into the penis, is capable of
 treating erectile dysfunction or inducing, enhancing or maintaining
 erectile function, as set forth herein. Compositions contemplated for use
 include drugs (e.g., vessel vasodilators and androgenic compositions),
 polynucleotides (e.g., genes used in gene therapy, for example, those that
 are involved in the erectile function biochemical pathways or those that
 encode vasoactive or androgenic polypeptides or fragments thereof;
 antisense nucleotides to vasoconstrictor polypeptide including RNAi
 antisense; ribozymes), polypeptides (e.g., vasoactive peptides and
 proteins, functional derivatives thereof including, for example, protease
 resistant analogs). Modified compositions that are biologically functional
 analogs or derivatives of the compositions described herein (salts, esters
 etc.) also are useful in the methods of the invention (see also e.g.,
 Trampota et al., U.S. Pat. No. 5,618,959, which describes various
 PGE.sub.1 and PGE.sub.2 analogs and derivatives).
 Specific vasoactive compositions include, for example, prazosin and
 papeverine; naturally occurring protaglandins, PGE.sub.1, PGE.sub.2,
 PGE.sub.1, PGA.sub.1, PGB.sub.1, PGF.sub.1, 19-hydroxy-PGA.sub.1,
 19-hydroxy-PGB.sub.1, PGE.sub.2, PGA.sub.2, PGB.sub.2,
 19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2, PGE.sub.3, PGF.sub.3,
 PGI.sub.1, PGI.sub.2 ; prostaglandin derivatives, carboprost tromethamine,
 dinoprost tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost,
 sulprostone, tiaprost; nitric oxide releasing agents, nitroglycerin,
 isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, sodium
 nitroprusside, molsidomine, (Z)-1-{N-methyl-N-[6-(N-methyl
 -ammoniohexyl)amino]}diazen-1-ium-1,2-diolate (MAHMA/NO),
 (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate
 (PAPA/NO),(Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)
 butyl]-amino}diazen-1-ium-1,2-diolate (SPER/NO), sodium
 (Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (DEA/NO), linsidomine
 (SIN-1), S-nitrosothiols, S-nitroso-N-acetyl-D,L-penicillamine (SNAP),
 S-nitroso-N-cysteine and S-nitroso-N-glutathione (SNO-GLU); vasoactive
 intestinal peptide agonists and derivatives thereof; smooth muscle
 relaxants; leukotriene inhibitors; calcium channel blockers;
 .alpha.1-adrenergic antagonists; .alpha.2-adrenergic agonists;
 phosphodiesterase inhibitors; antihypertensive agents such as
 angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor
 antagonists; phenoxybenzamine, dibenamine, doxazosin, terazosin,
 phentolamine, tolazoline, prazosin, trimazosin, alfuzosin, indoramin,
 ergotamine analogs, ergotamine analogs, acetergamine, brazergoline,
 bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate,
 ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine,
 metergoline, metergotamine, nicergoline, pergolide, propisergide,
 proterguride, terguride, diazoxide, hydralazine and minoxidil, nimodepine,
 pinacidil, cyclandelate, dipyridamole, isoxsuprine, chlorpromazine,
 haloperidol, yohimbine, trazodone; dopamine antagonists such as
 apomorphine and bromocriptine; and opioid antagonists such as naltrexone.
 Other vasoactive compositions which can be appropriate for use may be
 found, for example, in Remington's Pharmaceutical Sciences, 18th ed., Mack
 Publishing Co., Easton, Pa., 1990; The Merck Index, 12th ed., Merck
 Publishing Group, Merck & Co., Inc., Whitehouse, N.J., 1996; and 51st ed.
 Physicians Desk Reference, Medical Economics Data Co., Montvale, N.J.,
 1997, which are herein incorporated by reference.
 Suitable androgenic compositions include, for example, androsterone,
 testosterone, dihydrotestosterone, testosterone analogs such as
 dehydroepiandrosterone (DHEA) and DHEA sulfate, enanthate, propionate,
 cypionate esters of testosterone, phenylacetate esters of testosterone,
 testosterone alkyls, methyltestosterone, testolactone, oxymetholone and
 fluoxymesterone. Other androgenic compositions which may be appropriate
 for use can be found, for example, in Remington's Pharmaceutical Sciences,
 supra; 1997 Physicians Desk Reference, supra; and The Merck Index, 12th
 ed., supra.
 The compositions used with the invention electrical apparatus and in the
 invention methods will be transdermally introduced into the penis in an
 amount effective to produce a desired therapeutic effect, i.e., an amount
 sufficient to induce, enhance or maintain an erection sufficient for
 sexual intercourse. As used herein, the term "effective" means an amount
 of drug or pharmacologically active agent that is sufficient to provide
 the desired effect (e.g., an androgenic or vasoactive effect) in which the
 signs or symptoms of the clinical situation are ameliorated (e.g.,
 sufficient erectile dysfunction is ameliorated so as to enable sexual
 intercourse). The amount should not be so large as to cause excessive
 adverse side effects, such as skin irratation, burning or tissue damage.
 The amount required will vary from subject to subject, depending on the
 species, age, and general condition of the subject (physiological and
 psychological), the severity of the condition being treated (e.g., chronic
 vs. acute erectile dysfunction), the drug or agent being employed, the
 mode of administration (e.g., if an oral drug such as VIAGRA is
 co-administered in conjunction with electropulsing, less vasoactive or
 androgenic composition may be required; the alternative also is true),
 etc. Thus, although it is not possible to specify an exact "effective
 amount," an appropriate "effective" amount in any individual case may be
 determined by one of ordinary skill in the art using the teachings herein.
 For example, by visual inspection or by measuring penile hemodynamic
 parameters in response to various amounts of the composition, an
 effectivew amount can be readily determined. The amount can be adjusted by
 the individual or, in the event of any complication, by the physician.
 The compositions used in a method of the invention are preferably
 administered by topical application to the penile skin. The term "topical"
 is used herein to refer to administration of a composition on the surface
 of the skin or mucosa which can be applied via direct application (i.e.
 spreading), via a drug impregnated skin patch (as in the nicotine patch,
 for example), or by an aerosol or other misting device, for example. Other
 modes of administration also are included, for example, by injection
 intravenously, intraperitoneally, intramuscularly, subcutaneously,
 intracavity, etc. Compositions also can be administered into the urethra,
 for example, with a suppository or urethral cathete having at least one
 port for introducing the composition into the urethra.
 Androgenic and vasoactive compositions, when administered in a method of
 the invention, will generally be in "pharmaceutically acceptable" or
 "physiologically acceptable" formulations for therapeutic use. As used
 herein, the terms "pharmaceutically acceptable" and "physiologically
 acceptable" refer to carriers, diluents, excipients and the like that can
 be administered to a subject, preferably without excessive adverse side
 effects (e.g., for a topically applied formulation, skin rash, irritation,
 etc.). Particular formulations include aqueous or non-aqueous solutions,
 suspensions, emulsions, waxes, creams, lotions, oils or other liquid and
 cosmetic formulations suitable for topical application known in the art.
 Such formulations are or can be made compatible with applying an
 electrical impulse,. For example, the conductivity should not be too high
 to produce heat or electrical arching or too low to provide resistance
 thereby inhibiting delivery of the pulse to the skin. Examples of
 non-aqueous solvents are propylene glycol, polyethylene glycol (PEG) in
 its various molecular weights (e.g., PEG 400, PEG 400 monostearate, PEG
 4000 etc.), glycerine, polyvinyl pyrrolidine (PVP), polyvinyl alcohol
 (PVA), mannitol, vegetable oils such as olive oil, and injectable organic
 esters such as ethyl oleate, and the like. Aqueous carriers include water,
 alcoholic/aqueous solutions, emulsions or suspensions, including saline
 and buffered media. Vehicles include sodium chloride solution, Ringer's
 dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
 Intravenous vehicles include fluid and nutrient replenishers, electrolyte
 replenishers (such as those based on Ringer's dextrose), and the like.
 Preservatives, surfactants and other additives may also be present such
 as, for example, antimicrobial, anti-oxidants (e.g., BHT, BHA), chelating
 agents (e.g. EDTA, EGTA), and inert gases and the like. It is also
 possible to entrap a vasoactive or androgenic composition into
 micro-capsules prepared by coacervation techniques or by interfacial
 polymerization, for example, by the use of hydroxymethylcellulose or
 gelatin-microcapsules or poly(methylmethacrolate) microcapsules,
 respectively, or in a colloid drug delivery system. Colloidal dispersion
 systems include macromolecule complexes, nano-capsules, microspheres, and
 lipid-based systems including oil-in-water emulsions, micelles, mixed
 micelles, and liposomes (e.g., stabilized liposome formulations of
 vasoactive intestinal peptide). The preparation of an appropriate
 pharmaceutical formulation for therapeutic use is well within the general
 knowledge in the art (see e.g., Remington's Pharmaceutical Sciences,
 supra; 1997)
 The above-described compositions and others not specifically described
 herein are useful in various clinical situations and can be administered
 alone, or in a combination with other compositions by a method of the
 invention. Combining low dose of oral pills with electropulsing can
 provide an additive or synergistic effect in the methods for treating
 erectile dysfunction or for inducing, enhancing or maintaining erectile
 function while minimizing some of the side effects of oral therapy and are
 therefore specifically included. An additive or synergistic effect also
 can be produced by administering a vasoactive or androgenic composition to
 the subject by injection or transurethrally in another embodiment. Vacuum
 treatment and/or topical cream can be employed with electrostimulation.
 Accordingly, in another embodiment, the invention provides a method for
 treating erectile dysfunction or for inducing, enhancing or maintaining
 erectile function by applying an electric impulse having sufficient
 strength and duration for transdermally introducing an effective amount of
 a vasoactive or androgenic composition into the erectile tissue in
 combination with administering a vasoactive or androgenic composition
 orally, by injection or transurethrally, or topical cream or vacuum,
 thereby treating erectile dysfunction or inducing, enhancing or
 maintaining erectile function.
 In addition, electrically-induced transdermal introduction of a vasoactive
 or androgenic composition into the penis can be increased over that of
 electropulsing alone by a variety of other means. For example, applying
 pressure on glans or midshaft can provide an additional driving force to
 transport drug into the glans and cross tunica albuginia, or into the
 midshaft. Restricting venous flow from the penis by applying a contriction
 at the base of penis prior to or after electropulsation using a penile
 rubber band, for example, can prevent penile venous flow while medication
 is administered and subsequently result in a better degree and duration of
 erection.
 Applying iontophoresis of the glans, midshaft or both, before or after
 electropulsing the glans, midshaft or both, can augment electrically
 induced transdermal introduction of a vasoactive or androgenic
 composition. Similarly, applying vibration or phonophoresis to the glans
 or midshaft or both prior to or after electropulsing can drive medications
 into deeper layers of the penis, such as into the spongiosum or tunica
 albuginia. Alone, or in any combination, these additional techniques can
 be used in conjunction with electropulsing to transdermally introduce a
 composition into the penis (e.g., electropulsing with iontophoresis,
 restricting venous flow or vibration; electropulsing with iontophoresis
 and restricting venous flow, and so forth).
 A "permeation enhancer" also can be included with electropulsing to
 increase transdermal introduction of a composition into the penis. As used
 herein, the term "permeation enhancer" refers to any action (e.g.,
 mechanical, physical, chemical) or any composition that can increase or
 "augment" transdermally introducing a composition into the penis. The term
 "augment," when used herein as a modifier of transdermal introduction,
 means that the rate (over time) or amount of composition transdermally
 introduced into the penis via electropulsing is greater than that produced
 by electropulsing in the absence of the permeation enhancer. Thus,
 administering a permeation enhancer prior to, substantially
 contemporaneously with or after applying a vasoactive or androgenic
 composition to the penis may "augment" electrically induced transdermal
 introduction of the composition into the penis. Alternatively, a
 permeation enhancer can be mixed with the composition in the
 pharmaceutical formulation to be transdermally introduced. Permeation
 enhancer compositions that increase skin permeability include, for
 example, alcohols (e.g., methanol), alkyl methyl sulfoxides (e.g., DMSO),
 pyrrolidones (e.g., 2-pyrrolidone), surfactants, urea, glycerol
 monolaurate, polyethylene glycol monolaurate, glycerol monolaurate,
 docainehydrochloride, hydrocortisone, menthol, methyl salicylate, and the
 like. Permeation enhancers further include mechanical or physical actions
 that function in association with an electrical impulse (i.e., generally
 require applying an electrical pulse to augment transdermal introduction
 of the compositions into the penis; e.g., vibration).
 The following examples are intended to illustrate but not limit the
 invention. While they are typical of those that might be used, other
 procedures and applications of the invention methods known to those
 skilled in the art may alternatively be used.
 EXAMPLE I
 This example describes initial studies of topical application of PGE1 on
 the penile glans, shaft or both of rabbits followed by application of a
 pulsed electric field, and the change in intracavernosal pressure
 associated with penile erection produced in response. Although rabbits
 were used in these studies, dogs, cats, and monkeys are also useful animal
 models for use in research.
 Three New Zealand White rabbits (n=3) weighing between 3-3.5 kg were used
 for these studies. Briefly, various concentrations of PGE1 were topically
 applied to the penis (shaft, glans or both) of rabbits anesthetized with
 intravenous administration of sodium pentobarbital. The electric pulse was
 applied by a meander electrode placed around the penis connected to a BTX
 600 pulse generator (Genetronics, Inc., San Diego, Calif.). Carotid artery
 was dissected for on-line measurement of systemic arterial pressure. A 21
 gauge minicatheter was inserted intracavernosally for measurement of
 intracavernosal pressure. To ensure erectile potency, rabbits #2 and #3
 were intracavernosally injected with papaverine and phentolamine
 injection, which caused a full penile erection in both rabbits. The
 procedures performed on the glans penis or on the penile shaft while
 recording systemic blood pressure and intracavernosal pressure are as
 follows:
 1. Application of electric pulse alone (without PGE1).
 2. Topical application of PGE1 alone (without electrical pulse).
 3. Topical application of PGE1 in conjunction with electric pulse.
 Rabbit #1
 Pulse stimulation alone at 13 ohm, 800 .mu.F and 90V on glans penis did not
 affect arterial blood pressure while causing a decrease in intracavernosal
 pressure from 25 mm Hg to 10 mm Hg. As those of skill in the art will
 understand, the resistance can be multiplied by the capacitance and the
 result divided by one thousand to give the pulse time in milliseconds.
 PGE1 (1 mg/20 .mu.l or 5 mg/20 .mu.l) alone on glans penis did not affect
 arterial or intracavernosal pressure. PGE1 (1 mg/20 .mu.l) on glans penis
 and pulse stimulation on glans penis at 13 OHM, 800 .mu.F and 90V caused a
 slight increase in arterial pressure while causing a decrease in
 intracavernosal pressure from 28 mm Hg to 10 mm Hg. PGE1 (5 mg/20 .mu.l)
 on glans penis and pulse stimulation on glans penis at 13 OHM, 400 .mu.F
 and 60V did not affect arterial pressure while causing an increase in
 intracavernosal pressure from 18 mm Hg to 32 mm Hg. Response duration was
 96 seconds. A second pulse stimulation at 13 OHM, 400 .mu.F and 60V with
 the same concentration of PGE1 (5 mg/20 .mu.l) on the glans caused an
 increase in intracavernosal pressure from 20 mm Hg to 32 mm Hg. Response
 duration was 115 seconds.
 Rabbit #2
 Pulse stimulation alone at 13 OHM, 400 .mu.F and 60V on glans penis did not
 affect arterial blood pressure or intracavernosal pressure. PGE1 (10 mg/20
 .mu.l) alone on glans penis did not affect arterial or intracavernosal
 pressure. PGE1 (10 mg/20 .mu.l) on glans penis and pulse stimulation on
 glans penis at 13 OHM, 400 .mu.F and 60V did not affect arterial pressure
 while increasing intracavernosal pressure from 15 mm Hg to 27 mm Hg.
 Response duration was 1 minute. A second pulse stimulation at 13 OHM, 400
 .mu.F and 60V in the presence of an additional 2 mg PGE1 on glans penis
 caused an increase in intracavernosal pressure from 22 mm Hg to 32 mm Hg.
 Response duration was 95 seconds.
 Pulse stimulation alone at 13 OHM, 400 .mu.F and 60V on penile shaft did
 not affect arterial blood pressure or intracavernosal pressure. PGE1 (5
 mg/20 .mu.l) alone on penile shaft did not affect arterial or
 intracavernosal pressure. PGE1 (5 mg/20 .mu.l) on penile shaft and pulse
 stimulation on penile shaft at 13 OHM, 400 .mu.F and 70V did not affect
 arterial pressure while causing an increase in intracavernosal pressure
 from 20 mm Hg to 28 mm Hg. Response duration was 32 seconds. A second
 pulse stimulation at 13 OHM, 400 .mu.F and 60V on penile shaft caused an
 increase in intracavernosal pressure from 26 mm Hg to 37 mm Hg. Response
 duration was 45 seconds.
 Rabbit #3
 Pulse stimulation alone at 13 OHM, 400 .mu.F and 60V on glans penis did not
 affect arterial blood pressure or intracavernosal pressure. PGE1 (5 mg/20
 .mu.l) alone on glans penis did not affect arterial or intracavernosal
 pressure. PGE1 (5 mg/20 .mu.l) on glans penis and pulse stimulation on
 glans penis at 13 OHM, 400 .mu.F and 60V did not affect arterial pressure
 while causing only a minor increase (5 mm Hg) in intracavernosal pressure.
 A second pulse stimulation at 13 OHM, 400 .mu.F and 60V on glans penis in
 the presence of an additional 5 mg PGE1 on the glans increased
 intracavernosal pressure from 15 mm Hg to 23 mm Hg. Response duration was
 30 seconds.
 PGE1 (10 mg/20 .mu.l) on glans penis and pulse stimulation on glans penis
 at 13 OHM, 400 .mu.F and 50V did not affect arterial pressure while
 causing only a minor increase (7 mm Hg) in intracavernosal pressure. PGE1
 (10 mg/20 .mu.l) on glans penis and pulse stimulation on glans penis at 13
 OHM, 200 .mu.F and 50V did not affect arterial pressure but increased
 intracavernosal pressure from 15 mm Hg to 20 mm Hg. A second pulse
 stimulation at 13 OHM, 150 .mu.F and 50V on glans penis in the presence of
 an additional 2 mg PGE1 on glans increased intracavernosal pressure from
 15 mm Hg to 22 mm Hg. Response duration was 45 seconds.
 Pulse stimulation alone at 13 OHM, 150 .mu.F and 50V on penile shaft did
 not affect arterial blood pressure on intracavernosal pressure. PGE1 (5
 mg/20 .mu.l) alone on penile shaft did not affect arterial or
 intracavernosal pressure. PGE1 (5 mg/20 .mu.l) on penile shaft and pulse
 stimulation on penile shaft at 13 OHM, 150 .mu.F and 50V did not affect
 arterial or intracavernosal pressure. A second pulse stimulation at 13
 OHM, 400 .mu.F and 60V on penile shaft in the presence of an additional 5
 mg PGE1 on penile shaft did not affect arterial or intracavernosal
 pressure. A third pulse stimulation at 13 OHM, 400 .mu.F and 60V in the
 presence of an additional 5 mg PGE1 on the penile shaft did not affect
 arterial or intracavernosal pressure.
 PGE1 (10 mg/20 .mu.l) on glans penis and penile shaft and pulse stimulation
 on glans penis and penile shaft at 13 OHM, 400 .mu.F and 60V did not
 affect arterial pressure while causing a remarkable increase in
 intracavernosal pressure. With this concentration of PGE1 and stimulation
 on the glans and shaft, intracavernosal pressure increased from 17 mm Hg
 to 48 mm Hg, resulting in a full erection (FIG. 4A). After 22 minutes
 there was a spontaneous detumescence. A second pulse stimulation at 13
 OHM, 400 .mu.F and 60 V on the glans and shaft in the presence of an
 additional 10 mg PGE1 on the glans and shaft caused an increase in
 intracavernosal pressure from 17 mm Hg to 48 mm Hg, resulting in full
 penile erection lasting for 15 minutes (FIG. 4B).
 EXAMPLE II
 This example shows that topical application of PGE1 or trimix (papavarine,
 phentolamine and PGE1) on the penile glans, shaft or both followed by
 application of a pulsed electric field induced penile erection in rabbits.
 New Zealand White rabbits (n=6) weighing between 3-3.5 kg were studied for
 studies the effect of topical PGE1 crystals, topical trimix and pulsed
 electrical field stimulation on penile erection. The concentration of PGE1
 for each topical application was 10 mg/100 .mu.l. The concentration of
 trimix for each topical application was 10 mg papavarine+0.5 mg
 phentolamine+0.2 mg PGE1 in 100 .mu.l.
 Animals were anesthetized with intramuscular injection of ketamine (35
 mg/KG) and xylazine (5 mg/kg) and maintained with 0.2 ml intravenous bolus
 injections of pentobarbital (25 mg/ml) as needed. A 25 gauge angiocatheter
 was placed into the ear vein for continuous administration of physiologic
 saline solution. A 20 gauge angiocatheter was placed into the carotid
 artery and connected to a transducer for online measurement of systemic
 arterial pressure. A 23 gauge minicatheter was placed intracavernosally
 and connected to a transducer for measurement of penile intracavernosal
 pressure. A meander electrode (1 mm electrode width and 0.2 mm gap between
 two electrodes) was modified in open condom shape and placed around penile
 shaft and glans and connected to a BTX ECM600 pulse generator. Systemic
 arterial pressure and intracavernosal pressure (ICP) were continuously
 recorded before during and after topical application of PGE1 or trimix and
 electropulsing using an Astromed chart recorder. Intracavernosal pressure
 changes were normalized for arterial pressure and are presented as the
 percentage (%) of mean arterial pressure (FIG. 7). Erectile potency of
 each animal was confirmed by intracavernosal trimix injection at the end
 of the study.
 One set of 6 electrical pulses without topical application of vasodilators
 on penile shaft and glans did not affect ICP. Six pulses with topical PGE1
 alone also did not affect ICP.
 PGE1 or trimix (100 .mu.l) was applied on the penile shaft, glans and on
 the electrode followed by pulsed electrical field stimulation. Three sets
 of six pulses at 13 OHM, 400 .mu.F, 50-60 V and 3 ms were applied and
 their effects on systemic and intracavernosal pressure were continuously
 recorded. The meantime of each set of six pulses was 1 minute. Stimulation
 with three sets of six pulses was repeated three times. If the animal
 failed to show erectile activity, additional PGE1 or trimix was applied on
 the glans and shaft and on the electrode and electric stimulation was
 repeated. This was continued until erectile activity was observed.
 Effect of Topical PGE1 and Pulse Electrical Field Stimulation on Penile
 Erection
 Of the three animals studied, one animal achieved full penile erection, one
 animal developed partial erection and one animal showed only minor
 erectile activity. The following specific changes in intracavernosal
 pressure and systemic arterial pressure were noted during the studies:
 PGE1 #1. Baseline systolic and diastolic arterial pressure was 111 and 84
 mm Hg respectively. Baseline intracavernosal pressure was 30% of arterial
 pressure (PGE #1, FIG. 7). After application of PGE1 and 6 pulses at 13
 OHM, 400 .mu.F and 60V, intracavernosal pressure was 26% of arterial
 pressure. After the second and third sets of 6 pulses intracavernosal
 pressure decreased to 24% and 22% of arterial pressure respectively.
 Additional PGE1 was applied and stimulation was repeated. Intracavernosal
 pressure after the first, second and third set of 6 pulses was 22%, 19%
 and 16% of arterial pressure respectively. Additional PGE1 was applied.
 Since stimulation at 13 OHM, 400 .mu.F and 60 V caused decrease of ICP,
 the remaining stimulations were performed at 13 OHM, 400 .mu.F and 50 V.
 Electric stimulation with these parameters produced better erectile
 activity causing a gradual increase in intracavernosal pressure.
 Intracavernosal pressure after the first, second and third set of 6 pulses
 was 27%, 24% and 24% of arterial pressure respectively. Additional PGE1
 was applied and pulsing was repeated at 13 OHM, 400 .mu.F and 50 V. The
 first set of 6 pulses caused an increase in intracavernosal pressure to
 58% of arterial pressure. The second set of 6 pulses caused further
 increase in intracavernosal pressure to 95% of systemic arterial pressure
 (PGE #1, FIG. 7). This animal developed full prolonged penile erection
 (FIG. 5A) and therefore did not require intracavernosal trimix injection
 to confirm erectile potency. At this time, the systolic and diastolic
 pressures were 120 mm Hg and 87 mm Hg respectively.
 PGE1 #2. Baseline systolic and diastolic arterial pressures were 90 and 60
 mm Hg respectively. Baseline intracavernosal pressure was 35% of arterial
 pressure (PGE #2, FIG. 7). After application of PGE1 and 6 pulses at 13
 OHM, 400 .mu.F and 50 V, the intracavernosal pressure was 47% of arterial
 pressure. After the second and third set of 6 pulses, intracavernosal
 pressure was 43% and 44% of arterial pressure respectively. Additional
 PGE1 was applied and pulsing was repeated. Intracavernosal pressure after
 the first, second and third set of 6 pulses was 36%, 42% and 40% of
 arterial pressure respectively. Another three sets of 6 pulses was
 applied. Intracavernosal pressure after the first, second and third set of
 6 pulses was 48%, 44% and 41% of arterial pressure respectively. Another
 set of pulses was applied. Intracavernosal pressure after first, second
 and third set of 6 pulses was 45%, 45% and 44% of arterial pressure
 respectively. Additional PGE1 was applied and stimulation was repeated.
 Intracavernosal pressure after first, second and third set of 6 pulses was
 43%, 47% and 47% of arterial pressure respectively. Additional PGE1 was
 applied and pulsing repeated. Intracavernosal pressure was first, second
 and third set of 6 pulses gradually increased to 57%, 58% and 60% of men
 arterial pressure respectively. Two additional sets of 6 pulses were
 applied. After the first set of pulses, intracavernosal pressure increased
 to 63% of arterial pressure. After the second set of stimulation,
 intracavernosal pressure increased to 65% of mean arterial pressure (PGE
 #2, FIG. 7). At this time, the animal was hypotensive (systolic and
 diastolic arterial pressure were 72 and 57 mm Hg respectively). This
 animal developed a partial penile erection (FIG. 5B). Intracavernosal
 trimix injection caused full penile erection.
 PGE1 #3. Baseline systolic and diastolic arterial pressures were 102 and 66
 mm Hg respectively. Baseline intracavernosal pressure was 35% of arterial
 pressure (PGE #3, FIG. 7). After application of PGE1 and 6 pulses at 13
 OHM, 400 .mu.F and 50 V, intracavernosal pressure was 39% of arterial
 pressure. After the second and third set of 6 pulses, intracavernosal
 pressure was 35% and 30% of arterial pressure respectively. Additional
 PGE1 was applied and pulsing was repeated. Intracavernosal pressure after
 the first, second and third set of 6 pulses was 35%, 36% and 39% of
 arterial pressure respectively. Additional PGE1 was applied and three sets
 of 6 pulses were repeated. Intracavernosal pressure after the first,
 second and third set of 6 pulses was 45%, 45% and 47% of arterial pressure
 respectively. Another set of pulses was applied. Intracavernosal pressure
 after the first, second and third set of 6 pulses was 47%, 48% and 48% of
 arterial pressure respectively. Additional PGE1 was applied and pulsing
 repeated. Intracavernosal pressure after the first, second and third set
 of 6 pulses was 43%, 41% and 41% of mean arterial pressure respectively.
 Since a large amount of PGE1 was already applied on the glans and shaft,
 additional PGE1 was avoided while stimulation was continued. Twelve
 additional sets of 6 pulses were applied. In the final stimulation,
 intracavernosal pressure after the first, second and third pulses was 46%,
 50% and 50% of arterial pressure respectively (PGE #3, FIG. 7). At this
 time, the systolic and diastolic pressure was 98 mm Hg and 63 mm Hg
 respectively. This animal showed some erectile activity but the quality of
 erection was poor (FIG. 5C). Intracavernosal trimix injection caused full
 penile erection.
 Effects of Topical Trimix and Pulse Electrical Field Stimulation on Penile
 Erection
 Of the three animals studied, one animal achieved full penile erection
 while the other two animals showed partial erection. The following
 specific changes in intracavernosal pressure and systemic arterial
 pressure were noted during the experiments:
 Trimix #1. Baseline systolic and diastolic arterial pressure was 105 and 84
 mm Hg respectively. Baseline intracavernosal pressure was 34% of arterial
 pressure (Trimix #1, FIG. 7). After one set of 6 pulses alone (without
 trimix) at 13 OHM, 400 .mu.F and 50 V, intracavernosal pressure was 33% of
 arterial pressure. After the second and third set of 6 pulses,
 intracavernosal pressure was 36% and 36% of arterial pressure
 respectively. After application of trimix, intracavernosal pressure after
 the first, second and third set of 6 pulses was 35%, 36% and 38% of
 arterial pressure respectively. Additional trimix was applied and pulsing
 was repeated. Intracavernosal pressure after the first, second and third
 set of 6 pulses was 40%, 40% and 42% of arterial pressure respectively.
 Additional trimix was applied and pulsing was repeated. After the first,
 second and third set of 6 pulses, intracavernosal pressure was 52%, 55%
 and 67% of arterial pressure respectively. Another three set of 6 pulses
 was applied. Intracavernosal pressure after the first, second and third
 pulses was 70%, 74% and 90% of arterial pressure respectively (Trimix #1,
 FIG. 7). At this time, systolic and diastolic pressures were 107 mm Hg and
 82 mm Hg respectively. This animal developed a full prolonged penile
 erection (FIG. 6A). Trimix #2. Baseline systolic and diastolic arterial
 pressure was 96 and 78 mm Hg respectively. Baseline intracavernosal
 pressure was 24% of arterial pressure (Trimix #2, FIG. 7). One set of 6
 pulses alone (without trimix) at 13 OHM, 400 .mu.F and 50 V did not affect
 intracavernosal pressure. After application of trimix and 6 pulses at 13
 OHM, 400 .mu.F and 50 V, intracavernosal pressure was 37% of arterial
 pressure. After the second and third set of 6 pulses, intracavernosal
 pressure was 41% and 40% of arterial pressure respectively. Another three
 sets of 6 pulses was intracavernosal pressure 39%, 42% and 43% of arterial
 pressure respectively. Additional trimix was applied and pulsing was
 repeated. Intracavernosal pressure after the first, second and third set
 of 6 pulses was 47%, 52% and 49% of arterial pressure respectively.
 Another three sets of 6 pulses were applied. Intracavernosal pressure
 after the first, second and third set of 6 pulses was 49%, 55% and 55% of
 arterial pressure respectively. Another three sets of 6 pulses were
 applied. Intracavernosal pressure after the first, second and third set of
 6 pulses was 55%, 55% and 64% of arterial pressure respectively.
 Additional three sets of 6 pulses were applied. Intracavernosal pressure
 after the first, second and third pulses was 53%, 53% and 59% of arterial
 pressure respectively. Additional trimix was applied and pulsing repeated.
 Intracavernosal pressure after the first, second and third set of 6 pulses
 was 63%, 65% and 69% of arterial pressure. Another three sets of 6 pulses
 were applied. Intracavernosal pressure after the first, second and third
 set of 6 pulses was 64%, 65% and 67% of arterial pressure respectively
 (Trimix #2, FIG. 7). At this time, systolic and diastolic arterial
 pressure were 90 and 57 mm Hg respectively. This animal developed a
 partial penile erection (FIG. 6B). Intracavernosal trimix injection caused
 full penile erection.
 Trimix #3. Baseline systolic and diastolic arterial pressure was 93 and 69
 mm Hg respectively. Baseline intracavernosal pressure was 28% of systemic
 arterial pressure (Trimix #3, FIG. 7). One set of 6 pulses at 13 OHM, 400
 .mu.F and 50 V did not affect intracavernosal pressure. After application
 of trimix and 6 pulses at 13 OHM, 400 .mu.F and 50 V, intracavernosal
 pressure was 33% of arterial pressure. After the second and third set of 6
 pulses, intracavernosal pressure was 34% and 33% of arterial pressure
 respectively. Another three sets of 6 pulses were applied. Intracavernosal
 pressure after the first, second and third set of 6 pulses was 45%, 43%
 and 43% of arterial pressure respectively. Another three sets of 6 pulses
 were applied. Intracavernosal pressure after the first, second and third
 set of 6 pulses was 43%, 43% and 43% of arterial pressure respectively.
 Additional trimix was applied and three sets of 6 pulses were repeated.
 Intracavernosal pressure after the first, second and third set of 6 pulses
 was 63%, 56% and 62% of arterial pressure respectively. Another three sets
 of 6 pulses were applied. Intracavernosal pressure after the first, second
 and third set of 6 pulses was 65%, 67% and 71% of arterial pressure
 respectively (Trimix #3, FIG. 7). Additional pulsing did not further
 increase intracavernosal pressure. At this time, the systolic and
 diastolic pressure was 93 mm Hg and 60 mm Hg respectively. This animal
 developed a partial short lived erection (FIG. 6C). Intracavernosal trimix
 injection caused full penile erection.
 To summarize, in the three animals with topical PGE1 application, pulsed
 electric field stimulation caused full penile erection in the first
 animal, partial erection in the second animal and relatively poor but
 detectable erectile activity in the third animal. In the three animals
 with topical trimix application, pulsed electric field stimulation caused
 full penile erection in the first animal while causing partial erection in
 the second and third animals. Pulsed electrical stimulation with topical
 trimix appears to be slightly more effective in producing erectile
 activity compared to pulsed electrical stimulation with topical PGE1.
 These studies show that topical application of vasodilators in conjunction
 with electric pulsing induces erectile activity in the rabbit. Although
 the effect of electric pulsing in producing erectile activity varied among
 the animals, at least some amount of erectile activity was produced up to
 a full prolonged erection in every animal.
 EXAMPLE III
 This example shows that topical application of PGE1 or trimix (papavarine,
 phentolamine and PGE1) on the penile glans or shaft without application of
 electric pulsing fails to induce penile erection in rabbits. This example
 also shows that applying electric pulsing alone (without application of
 vasodilator) fails to induce penile erection in rabbits.
 New Zealand White rabbits (n=6) weighing between 3-3.5 kg were divided into
 three groups for studies of the effect of topical PGE1 crystals on
 erectile function (n=2); for studies of the effect of topical trimix on
 erectile function (n=2); and for studies of the effect of electric pulsing
 on penile erection. The concentration of PGE1 for each topical application
 was 10 mg/100 1 and the concentration oftrimix for each topical
 application comprised 10 mg papavarine+0.5 mg phentolamine+0.2 mg PGE1 in
 100 .mu.l.
 Animals were anesthetized as before. A 25 gauge angiocatheter was placed
 into the ear vein for continuous administration of physiologic saline
 solution. A 20 gauge angiocatheter was placed into the carotid artery and
 connected to a transducer for on-line measurement of systemic arterial
 pressure. A 23 gauge minicatheter was placed intracavernosally and
 connected to a transducer for measurement of intracavernosal pressure. A
 meander electrode was placed around the penile shaft and glans and
 connected to a BTX ECM600 pulse electrical field generator. Arterial and
 intracavernosal pressures were continuously recorded on an Astromed chart
 recorder throughout the procedure. Intracavernosal pressure changes were
 normalized for arterial pressure and are presented as the percentage (%)
 of Systemic Arterial Pressure (FIG. 8). Erectile potency of rabbits was
 confirmed by intracavernosal trimix injection at the end of the studies.
 Studies with Topical PGE1 and with Topical Trimix without Electric Pulse
 Stimulation
 Baseline systemic arterial pressure and intracavernosal pressure were
 recorded. PGE1 (10 mg/100 .mu.l) or trimix (10 mg papaverine+0.5 mg
 phentolamine+0.2 mg PGE1 in 100 .mu.l) was applied to the glans, penile
 shaft and electrode. After three minutes, a second dose of PGE1 or trimix
 was applied. Topical application of PGE1 or trimix on penile glans, shaft
 and electrode was repeated up to four doses in three minute intervals.
 After topical application, systemic arterial and intracavernosal pressures
 were recorded for an additional ten minutes.
 In two animals, topical administration of four doses of PGE1 on the glans,
 penile shaft and electrode without pulsed electrical field stimulation did
 not affect systemic and intracavernosal pressures (PGE1 #1 and #2, FIG.
 8). Baseline intracavernosal pressures before administration of PGE1 in
 the two animals were 25% and 28% of systemic arterial pressure. After the
 fourth dose application of PGE1, systemic and intracavernosal pressures in
 the two animals were 27% and 30% of systemic arterial pressure. These
 differences after topical PGE1 were not statistically significant compared
 to those recorded before PGE1 administration. Intracavernosal pressures
 after intracavernosal trimix injection of the two animals, however,
 reached 92% and 95% of systemic arterial pressure, confirming erectile
 potency.
 In two animals, topical administration of four doses of trimix on the
 glans, penile shaft and electrode without pulsed electrical field
 stimulation did not affect systemic and intracavernosal pressures (Trimix
 #1 and #2, FIG. 8). Baseline intracavernosal pressures before
 administration of trimix in the two animals were 30% and 33% of systemic
 arterial pressure. After the fourth dose of topical trimix,
 intracavernosal pressures in the two animals were 25% and 35% of systemic
 arterial pressure. These differences after topical trimix were not
 statistically significant compared to those recorded before trimix
 administration. Intracavernosal pressures after intracavernosal trimix
 injection of in the two animals, however, reached 90% and 97% of systemic
 arterial pressure, confirming erectile potency.
 Studies with Electric Pulse Stimulation without Topical Vasodilators
 Baseline systemic arterial pressure and intracavernosal pressure were
 recorded. After application of 100 .mu.l buffer on glans, penile shaft and
 electrode, one set of six pulses (50 V, 13 OHM and 400 .mu.F) was applied.
 After this the second and third set 6 pulses were applied in one minute
 intervals. After three sets of six pulses were applied, additional buffer
 (100 .mu.l) was applied on the glans, penile shaft and electrode. The
 three sets of six pulses were repeated while adding buffer after every
 three sets of six pulses. This was repeated until a total of 20 sets of
 electric pulsing. After the 20th set of electric pulsing, systemic
 arterial and intracavernosal pressures were measured for an additional 10
 minutes.
 Without topical administration of vasodilators, 20 sets of six electric
 pulses applied to the glans and penile shaft of two animals did not affect
 systemic and intracavernosal pressures (EP#1 and #2, FIG. 8). Baseline
 intracavernosal pressures before electric pulsing in the two animals were
 18% and 34% of systemic arterial pressure. After the 20th set of electric
 pulsing intracavernosal pressures were statistically similar to those
 recorded before electrical field stimulation. After the 20th set of
 electric pulsing intracavernosal pressures in the two animals were 27% and
 38% of systemic arterial pressure. These differences after electric
 pulsing were not statistically significant compared to those recorded
 before stimulation. Intracavernosal pressures after intracavernosal
 administration of trimix in the two animals, however, reached to 91% and
 95% of systemic arterial pressure confirming erectile potency.
 These studies show that transdermal introduction of a topical application
 of vasodilators (e.g., PGE1 and trimix) require applying an electric pulse
 for inducing erectile activity. These studies also show that an electric
 pulse without topical PGE1 or trimix is not capable of producing erectile
 activity in the rabbit.
 EXAMPLE IV
 This example shows that PGE1, used for self-injection therapy in erectile
 dysfunction, can be transdermally introduced into human skin in vitro and
 human penile skin by electric pulsing alone, or in combination with
 iontophoresis, thereby providing a non invasive mode of drug delivery.
 Materials
 Prostaglandin E1 (PGE1) and tritium-labeled Prostaglandin E1 (.sup.3
 H-PGE1) was obtained from Sigma (St. Louis, Mo.). Labeled drug was
 received in 7:3 ethanol:water mixture. The drug was protected from light
 during all studies, which were done in triplicate. Scintillation cocktail
 (ULTIMA-GOLD.TM.) and SOLVABLE.TM. tissue and gel solubilizer were
 obtained from Packard (Meriden, CT). Human cadaver skin and penile skin
 obtained from skin banks had been frozen within 12 hours of death and
 supplied as full thickness skin, unless otherwise specified. Once
 received, the skin was stored at -80.degree. C. and then thawed just
 before use. Full thickness or dermatomed human cadaver skin or penile skin
 was used. Buffer components and other chemicals were obtained from Fisher
 Scientific (Pittsburgh, Pa.); silver-silver chloride electrodes were
 purchased from In Vivo Metric (Healdsburg, Calif.); and meander electrodes
 were from Genetronics, Inc. (San Diego, Calif.).
 Solution Studies
 For these studies, the drug was in solution though the final formulation
 may have been a suspension due to the addition of latex or dextran
 particles. PGE1 (5.6 .mu.g) was dissolved in ethanol:water (7:3) and
 spiked with .sup.3 H-PGE1. A few microliters of this solution was placed
 on full thickness human skin and covered with a meander electrode, which
 consists of an interweaving array of metal fingers coated on a thin
 plastic film. Pulses were applied via these metal fingers on the meander
 electrode creating an electric field that breaks down the stratum corneum
 of the skin. Slight pressure was applied on the electrode during pulsing
 either by clamping the whole set-up on a table top or by clamping the
 set-up on the upper half of a Franz cell. Further details on this
 pressure-mediated "electroincorporation" technique can be found in Hofmann
 et al., Bioelectrochem. Bioenerg. 38 (1995) 209-222 and Zhang et al.,
 Bioelectrochem. Bioenerg. 42 (1997) 283-292. Following table top pulsing,
 the skin was transferred in some cases to glass diffusion cells. In this
 case, the donor and receptor solutions were filled with 4 ml of HEPES
 buffer and iontophoresis was applied in some cases using silver/silver
 chloride electrodes.
 Suspension Studies
 For these studies, the drug was in suspension. In a typical suspension
 study, prostaglandin (PGE1 and .sup.3 H-PGE1) was dissolved in ethanol and
 then ethanol was removed by drying under nitrogen. This procedure helped
 to molecularly disperse PGE1 and .sup.3 H-PGE1 together. The dried powder
 was then resuspended in 10 mM phosphate buffer so that a suitable
 concentration of prostaglandin in a small volume (typically, few .mu.l) is
 achieved. The analysis was then done by liquid scintillation counting. In
 cases where immunoassay was used, .sup.3 H-PGE1 was not used but PGE1 was
 still recrystallized from ethanol so that a similar particle size
 distribution is obtained. Particles of the recrystallized suspension were
 mostly needle shaped, with a width of about 1 micron and a length of about
 5 microns. Some spherical particles of 1-2 micron size were also seen. The
 original particle size of PGE1 received from supplier was in the range of
 5-20 microns, seen as crystalline particles, though some particles as
 large as 45 micron were also seen. Recrystallization seems to have
 resulted in a more uniform particle size distribution. When the Franz cell
 set-up was used, the skin was cut into 1 inch square pieces (pulsing area
 0.64 cm.sup.2) for electroporation experiments, and appropriate controls
 were treated with PGE1 but not pulsed. The skin was placed on Franz cell,
 the drug suspension was added, meander electrode with a well created by a
 double-sided tape was placed on this solution, a parafilm was placed on
 meander electrode and then a metal disc was placed on the top before
 clamping the donor chamber for intimate contact. More consistent results
 were obtained when the suspension was contained in this well created on
 the meander electrode using double sided tape an the whole experiment was
 done on the Franz cell setup. In the absence of this well, the solution
 under meander electrode could be squeezed out by the applied pressure.
 The experimental group pieces of skin were typically pulsed with 6 pulses
 of 100 V or 120V and 10-20 ms duration. In some cases, 6 additional pulses
 were applied after a one minute rest. The skin was then left on the set-up
 for 15 minutes, at which time a receiver sample was taken and the skin was
 removed. In some studies, additional sampling was done to study the slow
 release of drug from the skin. Following the study, the skin was cleaned
 with three cotton swabs wetted with buffer (with dry tips in between) to
 wipe out the treated side, cut into several pieces, sometimes followed by
 one tape stripping. The blade used for cutting and the petridish in which
 the skin was cut were washed with the skin solubilizer and the skin and
 washings were transferred to solubilizer and digested at 75.degree. C. for
 2 days. For experiments using ELISA assay, the skin was not dissolved in
 solubilizer but rather extracted by the procedure described hereinbelow.
 Skin Extraction & Immunoassay
 Skin samples were weighed and then cut into small pieces. The skin was then
 placed into a beaker with 10 ml PBS buffer, homogenized using a
 homogenizer (OMNI 5100) at moderate speed and it was passed through
 samples for about 4-5 minutes. The homogenate was acidified with 1 N HCI
 to a pH of 3.5 to 4.0, and transferred to a siliconized glass tube; 2 ml
 of phosphate buffer was used to transfer the residue from the beaker. The
 skin homogenate was then extracted with 20 ml of ethyl acetate and 4500
 dpm of .sup.3 H-PGD2 was added for measurement of extraction efficiency.
 Sample was vortexed for 10 mins and centrifuge at 3000.times.g for 15 mins.
 The top layer was drawn off into a siliconized tube and extracted with
 another 20 ml ethyl acetate, followed by vortexing and centrifugation, as
 before. The ethyl acetate fractions were pooled, dried under nitrogen and
 resuspended in 3 ml of ethyl acetate; aliquots were removed for
 determination of extraction efficiency and prostaglandin analysis. PGE1
 content was determined using an enzyme immunoassay (EIA) kit (Assay Design
 Inc., MI). Samples were aliquoted as follows: 500 .mu.l (suspended in EIA
 buffer) for EIA, 1000 .mu.l (suspended in 10 mM Phosphate buffer) for
 measurement of recovery; the rest of the 1.5 ml sample was stored in ethyl
 acetate at -20.degree. C. The EIA aliquot was dried and suspended in 500
 .mu.l of assay buffer provided with the kit and the assay was performed
 according to kit instructions. The optical density of the samples was read
 using a BioRad microplate reader model 4500 and sample concentrations were
 calculated using microplate reader software version 2.03 by BioRad and
 Microsoft Excel, using dilution and extraction efficiency into
 consideration.
 Solution Formulation
 A solution study with iontophoresis in a diffusion cell was first carried
 out to establish the electrode polarity for optimal delivery. It was
 observed that 30 minutes of iontophoresis could increase the permeation of
 PGE1 across skin several fold over passive diffusion, with the highest
 delivery under cathode (FIG. 9). The corresponding amount in the skin at
 the end of the study was 1.21.+-.0.76 .mu.g/cm.sup.2 (passive),
 0.69.+-.0.14 .mu.g/cm.sup.2 (cathode), and 0.77.+-.0.1 .mu.g/cm.sup.2
 (anode). The use of pulsing (6 pulses of 100 V, 10 ms each) prior to
 iontophoresis increased the amount delivered into skin. This was true
 irrespective of whether pulses were applied by meander or wire (cathode)
 electrode. The amount with meander electrodes was 2.42.+-.1.09
 .mu.g/cm.sup.2 in skin and 2.77.+-.1.0 .mu.g/cm.sup.2 in receptor, while
 with wire electrodes, the amount in skin was 4.23.+-.2.09 .mu.g/cm.sup.2
 and in receptor was 1.02.+-.0.08 .mu.g/cm.sup.2.
 Pulsing Solution Formation with Particles
 PGE1 (5.6 .mu.g) was dissolved in 7:3 ethanol:water (20 .mu.l) and either
 latex (2.5%) or dextran (5%) particles were added. The formulation was
 placed on full-thickness human cadaver skin, and three pulses (120V, 10 ms
 each) were applied by meander electrodes. Following electroporation, the
 skin was mounted on transdermal glass diffusion cells. The exposed area of
 the skin to the receiver compartment was the same 0.64 cm.sup.2 to which
 the drug solution was applied. The receptor compartment contained 4 ml of
 HEPES buffer. The amount of prostaglandin coming out from skin into the
 receptor compartment was measured as a function of time (FIG. 10). Control
 experiments were also done in which all variables were same but no pulse
 was applied. Following the study, the skin was removed, incubated with a
 tissue solubilizer and then analyzed to quantitate the amount of PGE1
 remaining in the skin. Based on the cumulative perneation and the amount
 that remains in the skin at the end of the study, the amount of PGE1 in
 skin just after pulsing was 0.46.+-.0.03 .mu.g/cm.sup.2 for the latex
 particle study and 0.56.+-.0.09 .mu.g/cm.sup.2 or the dextran particle
 study. Thus, it appears that of the amount delivered into skin by pulsing,
 about 80% is released into receptor over a period of 5 days. This was
 followed by a higher concentration study, in which 200 .mu.g PGE1 was
 placed on the skin and pulsed with latex particles. The delivery was again
 higher in presence of pulsing.
 The effect of increasing concentration of prostaglandin was investigated,
 applying 5, 20, 100 and 200 .mu.g of PGE1 to full thickness skin, in a 8
 .mu.l volume. Six pulses (120V, 20 ms each) were applied with a 5-minute
 post pulse application of pressure. For the control group without dextran,
 everything was the same except pulses were not applied. Results indicate
 that a higher amount of PGE1 was delivered into the skin as the PGE1
 concentration increased.
 Electroporation of PGE1 Suspension
 In a study with full thickness skin (average thickness 0.73 mm), a 300
 .mu.g/6 .mu.l PGE1 suspension was applied with a meander electrode by six
 pulses (100 V, 20 ms) followed by another six pulses after a one minute
 rest. The amount of PGE1 in pulsed skin was found to be 3.08.+-.0.68
 .mu.g/cm.sup.2, while in control skin was 1.62.+-.0.47 .mu.g/cm.sup.2. No
 PGE1 was detected in receiver at the end of the study (15 minutes after
 pulsing), suggesting that the drug was not driven across the skin. The
 p-value on a two-tail test is 0.023. Thus, the data was still
 statistically significant in the 0.05 level.
 When this protocol was used on dermatomed skin and sampling time was
 increased to 24 hours, PGE1 was found to permeate into the receiver
 indicating traversal of the skin. The cumulative amount of PGE1 permeated
 into receiver as a function of time following pulsing is shown in FIG. 11.
 The total amount permeated into the receiver in 24 hours was 6.43.+-.2.17
 .mu.g for the pulsing group and 2.0.+-.0.57 .mu.g for the unpulsed control
 group. The amount of PGE1 in pulsed skin at 24 hours was 14.44.+-.4.29
 .mu.g, while in control skin was 5.68.+-.3.25 .mu.g. The p-value on a
 two-tail test is 0.048. Thus, the data is statistically significant at the
 0.1 level. If this data is adjusted for the amount permeated into receiver
 over 24 hours, then the amount of PGE1 delivered into skin following
 pulsing is 20.87 .mu.g for pulsed group and 7.68 .mu.g for control group.
 The amount in pulsed skin is about 6-7 times higher than an earlier study
 in which sampling was done in 15 minutes using full-thickness skin. In
 earlier studies (15 minutes sampling), no PGE1 was detected in receiver at
 the end of the study, suggesting that the drug slowly diffuses out of the
 skin over a period of several hours.
 Another suspension study analyzed the data by immunoassay. A concentration
 of 100 .mu.g/8 .mu.l of prostaglandin in distilled water was prepared, and
 the resulting product was observed to be a suspension. A volume of 8 .mu.l
 of this suspension was placed on skin for pulsing. The skin was placed on
 a metal plate and pulse was applied using meander electrodes under a lead
 weight (435 g). Pulsing studies were conducted on full-thickness human
 cadaver skin, using six pulses (120 V, 20 ms each). Control studies were
 then done in which the drug suspension was placed on skin and pressure
 applied for 2 minutes (to simulate the time it takes to give six pulses)
 but no pulse was applied. These six pieces of skin and one piece of
 untreated skin were then analyzed by enzyme immunoassay. The skin was not
 digested by the tissue solubilizer as the strong base used in these
 solubilizers may have deleterious effect on the stability of
 prostaglandins. This was not a consideration in earlier experiments as
 only the radioactivity (cpm) had to be quantitated following the
 experiment; the total cpm would not be affected even if prostaglandin
 degrades after the pulsing has been performed. The results show that the
 pulsed skin (2.19.+-.1.38 .mu.g/cm.sup.2) had a higher amount of PGE1 than
 the unpulsed control skin (1.19.+-.0.31 .mu.g/cm.sup.2). The efficiency of
 delivery has higher than that achieved by earlier studies with PGE1
 solution or PGE1 dextran/latex particles.
 Release of Drug from Pulsed Skin
 A concentration of 20 .mu.g/16 .mu.l of prostaglandin in 7:3 ethanol:water
 was spiked with .sup.3 H-PGE, and dextran particles (5% w/v) were added to
 this solution. A volume of 16 .mu.l of this solution was placed on
 full-thickness human cadaver skin (six pulses, 120 V, 20 ms) were applied
 by meander electrodes. Following pulsing, the skin was mounted on
 diffusion cells and samples were taken at periodic intervals (FIG. 12).
 The drug was allowed to be released from pulsed skin either by itself
 (pulses only) or by use of iontophoresis (20 minutes) to drive out the
 drug reservoir (pulses followed by iontophoresis). A control study also
 was done in which all variables were the same but no pulse or
 iontophoresis was applied. As shown in FIG. 12, the unpulsed control had
 much lower amounts as compared to pulsed skin, with the most drug being
 released by iontophoresis of pulsed skin. This is most likely because
 iontophoresis provided the driving force to push the drug reservoir out
 from the skin.
 Studies with Penile Skin
 A therapeutic dose could also be delivered within a short period of time.
 To accomplish this, however, the concentration of PGE1 had to be
 increased. To establish that aforementioned studies are predictive of the
 end use of this technology (e.g., treating erectile dysfunction or
 inducing, enhancing or maintaining erectile function), penile skin was
 examined. A concentration of 1.0 mg PGE1 suspension in 6.0 .mu.l was used
 in this case. Full thickness (average thickness 0.38 mm) human cadaver
 penile skin was used and pulsed on the Franz cell setup as before. Six
 pulses (10 ms each) of 100 V each were applied. The amount of PGE1 in
 pulsed skin and in control skin was 19.88.+-.0.93 .mu.g and 15.76.+-.0.05
 .mu.g, respectively. The p-value on a two-tail test is 0.017. Thus, the
 data is statistically significant at the 0.05 level. The high unpulsed
 control value may be due to the inability to wash the skin surface
 properly prior to analysis or driving particles into the skin by pressure
 in the absence of an electric pulse.
 This study was repeated using enzyme immunoassay and PGE1 directly from the
 vial. A concentration of 1 mg/6 .mu.l of prostaglandin in 10 mM phosphate
 buffer was prepared directly using the PGE1 material from Sigma, without
 any ethanol crystallization. The skin was then homogenized and extracted
 as before. The amount of PGE1 in pulsed skin and in control skin was
 12.02.+-.6.42 .mu.g and 15.09.+-.9.86 .mu.g, respectively. The p-value on
 a two-tail test is 0.67. Thus, the difference between pulsed and unpulsed
 control skin is not statistically significant. Since earlier studies gave
 a statistically significant difference, it appears that recrystallization
 from ethanol, which produces a more homogeneous drug distribution for the
 donor suspension, increases transdermal delivery. PGE1 directly from the
 vial may have a nonuniform particle size distribution, in which case the
 dose for each replicate will vary even though the same volume is used.
 Alternatively, the variation could result from skin homogenization not
 being very effective in releasing all the drug from the microstructure of
 the skin into solution. In earlier studies with PGE/.sup.3 H-PGE, the skin
 is dissolved which will result in complete release of the drug into
 solution. In any case, enzyme immunoassay data is still in the therapeutic
 range, which indicates that the end point therapeutic use is feasible. As
 the data is in therapeutic range with this assay, this suggests that
 significant degradation to the point of losing most of the drug is not
 occurring. When pulsed with six 100 V (20 ms) pulses are applied with a
 meander electrode, the penile skin was observed to develop slight burn
 marks, suggesting that penile skin is more sensitive and has lower
 resistance than skin from other sites; thus, pulse length has to be low
 when using meander electrodes that are in direct contact with penile skin.
 The variability between pulsed and unpulsed skin may have resulted from
 even one particle embedding in the skin in unpulsed control, which would
 significantly increase the amount of PGE1 calculated in the skin. A
 further confounding effect could have been due to the use of ethanol,
 which is a known penetration enhancer for transdermal delivery. However,
 it is not clear if ethanol could have exerted its effect in the short time
 it was on the skin before skin was digested by tissue solubilizer.
 Alternatively, inadequate skin washing could have increased the amount of
 PGE1 in unpulsed control skin.
 To summarize, these studies show that PGE1 in solution can be delivered
 into human skin by electric pulses. Further enhancement is achieved when
 inert particles are mixed with the formulation and delivered with a
 meander electrode (i.e. electropulsing in combination with iontophoresis).
 If a drug suspension is used, then relatively large amounts can be
 delivered into human skin by high voltage pulses. Trasndermal drug
 delivery via electrical pulsing is potentially useful in patients who do
 not respond to other treatments for erectile dysfunction such as
 VIAGRA.TM., or cannot tolerate the side effects.
 EXAMPLE V
 This example shows that electropulsing under conditions sufficient to
 transdermally introduce compositions into the rabbit penis is well
 tolerated by human subjects.
 Genetronics, Inc. has sponsored a Phase I feasibility study of human
 sensation tolerance on the method and the electrical apparatus (no drug
 was involved in this study). The institutional IRB approval and Patient
 Consent Form were generated prior to the study. The pain level of
 electrical therapy was assessed in 20 patients that had previously
 undergone either cavernosal injection therapy or transurethra insertion
 therapy, 10 patients per group. Sterile PBS was used as a placebo for all
 pulsing sensation tests. The setup of pulse applicator (shown in FIG. 3,
 where the cuff provided controlled pressure) ensured good contact between
 the electrodes and the skin (midshaft and partial glans).
 Patients were subjected to a single pulse of 50 to 80 volts in 10 volt
 increments delivered for 3 msec. The patients were asked to rate the pulse
 sensation on a scale of 0, no pain, to 10, excruciating. The results of
 this study shown in FIG. 13 and are summarized as follows: (1) All
 patients passed single pulsation tests (50 V-80 V, 3 ms) without rating
 the sensation excruciating pain. (2) The pulse sensation was tolerable;
 from 60 V to 80 V, 77.5% of subjects rated the electropulse from no pain
 to discomforting and only 10% rated the sensation from distressing to
 horrible. (3) No side effects of pulsing were observed or reported. It was
 concluded that the method and apparatus are safe and acceptable to
 patients under electrical pulse conditions sufficient to transdermally
 introduce a composition into the penis.
 While this invention has been described as having certain embodiments, it
 is understood that further modifications, uses and/or adaptations of the
 invention are possible, and are encompassed by the invention set forth in
 the following claims.