WO2002011729A1 - Compositions et methodes de traitement de la dyserection masculine - Google Patents

Compositions et methodes de traitement de la dyserection masculine Download PDF

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WO2002011729A1
WO2002011729A1 PCT/US2001/041638 US0141638W WO0211729A1 WO 2002011729 A1 WO2002011729 A1 WO 2002011729A1 US 0141638 W US0141638 W US 0141638W WO 0211729 A1 WO0211729 A1 WO 0211729A1
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Prior art keywords
sildenafil
erectile dysfunction
intracavernosal
individual
effective amount
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PCT/US2001/041638
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English (en)
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Irwin Goldstein
Abdul Traish
Noel Kim
Iain Mccauley
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The Trustees Of Boston University
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Priority to AU2001281396A priority Critical patent/AU2001281396A1/en
Publication of WO2002011729A1 publication Critical patent/WO2002011729A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines

Definitions

  • the present invention is directed to a novel method for the treatment of individuals suffering erectile dysfunction, wherein, no prior sexual stimulation is required.
  • this invention is directed to individuals suffering loss of penile neural input and/or where oral administration of sildenafil citrate is ineffective.
  • Impotence is the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. It has been estimated that approximately 10 million American men are impotent (R. Shabsigh et al., "Evaluation of Erectile Impotence,” Urology, 32:83-90, 1988; W.L. Furlow, "Prevalence of Impotence in the United States,” Med. Aspects Hum. Sex., 19:13-16,1985).
  • vasculogenic impotence which is caused by alterations in the flow of blood to and from the penis, is thought to be the most frequent organic cause of impotence.
  • Common risk factors for vasculogenic impotence include hypertension, diabetes, cigarette smoking, pelvic trauma and the like.
  • Neurogenic impotence is associated with spinal-cord injury, multiple sclerosis, peripheral neuropathy caused by diabetes or alcoholism and severance of the autonomic nerve supply to the penis consequent to prostate surgery.
  • Erectile dysfunction can also be associated with disturbances in endocrine function resulting in low circulating testosterone levels and elevated prolactin levels. More specifically, penile erection requires (1) dilation of the arteries that regulate blood flow to the lacunae of the corpora cavernosum, (2) relaxation of trabecular smooth muscle, which facilitates engorgement of the penis with blood, and (3) compression of the venules by the expanding trabecular walls to decrease venous outflow.
  • Trabecular smooth muscle tone is controlled locally by adrenergic (constrictor), cholinergic (dilator) and nonadrenergic, noncholinergic (dilator) innervation, and by endothelium-derived vasoactive intestinal polypeptide (VIP), prostanoids, endothelin and nitric oxide (NO).
  • VIP vasoactive intestinal polypeptide
  • NO nitric oxide
  • High sympathetic tone is implicated in erectile dysfunction, and, in some patients the disorder can be successfully treated with noradrenergic receptor antagonists (Krane et al., New England Journal of Medicine, 321:1648, 1989).
  • nitric oxide from penile non-adrenergic, non-cholinergic nerves and the endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis in erectile tissue trabecular smooth muscle cells.
  • Increased cGMP levels reduce intracellular calcium concentrations, inhibiting smooth muscle contractility and thereby initiating the erectile response.
  • Sildenafil citrate (Viagra®), which is a phosphodiesterase type V inhibitor was introduced to the US market in 1998, for management of erectile dysfunction, by oral ingestion. It is currently the preferred treatment.
  • Phosphodiesterase type V is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle relaxation, resulting ultimately in restoration of basal smooth muscle contractility and penile flaccidity.
  • Sildenafil citrate is a potent PDE type V reversible and selective inhibitor which blocks cGMP hydrolysis effectively at low concentrations.
  • sildenafil acts to enhance ⁇ O-mediated (nitric oxide) smooth muscle relaxation, resulting in improved penile erection in men with erectile dysfunction.
  • ⁇ O-mediated nitric oxide
  • the penis is flaccid as the input from the sympathetic nervous system exceeds that from the parasympathetic NANC nervous system. Accordingly, the mode of action of the oral drug is to maintain an erection by blocking cGMP hydrolysis. Thus, it has been accepted that in the absence of sexual stimulation, sildenafil citrate has no activity on corporal smooth muscle relaxation. Therefore, Viagra® has a poor response rate in patients who have lost neural penile input due to, for example, neurogenic causes or radical prostatectomy. Other methods of treating erectile dysfunction are described in: U.S. Pat. No.
  • Priapism is usually painful, irreversibly damages erectile tissue, and, to be relieved requires bleeding or pharmacologic intervention (e.g., injection of a sympathomimetic drug such as adrenaline). Even if priapism does not occur with use of papaverine, such use is associated with a painful, burning sensation in the first two or so minutes after the injection and there are indications that repeated use of papaverine causes undesirable, extensive intracavernous fibrosis.
  • a sympathomimetic drug such as adrenaline
  • penile implants are also widely used to treat impotence.
  • implants have been employed, especially in cases where injections of papaverine are ineffective, which are usually cases of severe atherogenic impotence.
  • treatment of impotence with penile implants also entail serious disadvantages. Such treatment requires surgery and entails total destruction of the erectile tissues of the penis, forever, precluding normal erection.
  • VIP human vasoactive intestinal peptide
  • intracavernosal injection of a PDE type V inhibitor such as sildenafil causes penile erection, in the absence of sexual stimulation.
  • a PDE type V inhibitor such as sildenafil
  • Administration of the pharmaceutical formulation is carried out within the context of a predetermined dosing regimen such that the agent is effective in the treatment of erectile dysfunction.
  • Drug delivery is preferably administered via intracavernosal injection.
  • the effective dose ranges from about 5 - 60 mg, preferably 10 - 50 mg, still more preferably about 10 - 40 mg, even more preferably about 15 - 40 mg and still more preferably about 20 - 30 mg.
  • a method for treating an individual who has lost penile neural input and who does not respond to oral doses of sildenafil comprising local administration to such an individual a pharmaceutical formulation containing a PDE type V inhibitor such as sildenafil citrate without the need for prior sexual stimulation.
  • Administration of the pharmaceutical formulation is carried out within the context of a predetermined dosing regimen such that the agent is effective in the treatment of erectile dysfunction, as described above.
  • Drug delivery is preferably administered via intracavernosal injection.
  • a kit is provided to assist an individual in drug administration to carry out the method of the invention.
  • the kit will include the following components: a pharmaceutical formulation comprising the sildenafil citrate to be administered; a device for effective delivery of the pharmaceutical composition; a container housing the pharmaceutical formulation during storage and prior to use; and instructions for carrying out drug administration in a manner effective to treat erectile dysfunction.
  • sildenafil was determined. Data are the mean + SEM.
  • FIGS 2 A, 2B, 2C and 2D Effects of intracavernosal sildenafil. Varying doses of sildenafil (0.3 - 1.3 mg) were administered to anesthetized adult male New Zealand White rabbits by intracavernosal injection. We measured the peak ICP and normalized it to the SAP (A). A normalized ratio of 1.0 indicates full erection and 0.27 indicates a flaccid penis. We also determined the time to reach peak ICP in minutes (B), the duration of erection in hours (C), and changes in SAP (mm Hg) with sildenafil administration (D). Data represent the mean of four separate experiments (*P ⁇ 0.5, relative to saline).
  • Figure 3 Effects of intracavernosal L-NAME and sildenafil on ICP. Anesthetized adult male New Zealand White rabbits were subjected to PNS to induce penile erection. Following detumescence, rabbits were administered 0.2 mL of 3 mM L-NAME by intracavernosal injection and subjected to PNS after 10 minutes. Some rabbits received intracavernosal administratio of L-NAME followed by sildenafil (1.3 mg) in the absence of
  • the method comprises locally administering to the individual, an effective amount of a pharmaceutical composition comprising a Type V phosphodiesterase inhibitor.
  • the preferred class of individuals for treating erectile dysfunction are male individuals, wherein the individual does not respond to physical sexual stimuli.
  • the preferred phosphodiesterase inhibitor is sildenafil citrate, wherein administration is effected via intracavernosal injection without the need for prior or concurrent sexual stimulation.
  • the preferred dose range of sildenafil citrate is preferably less than 60 mg, more preferably less than 50 mg, even more preferably 10 - 40 mg, still more preferably 15 - 40 mg, and most preferably 20 - 30 mg.
  • erectile dysfunction is intended to include any and all types of erectile dysfunction, including: vasculogenic, neurogenic, endocrinologic and psychogenic impotence; Peyronie's Syndrome; priapism; premature ejaculation; and any other condition, disease or disorder, regardless of cause or origin, which interferes with at least one of the three phases of human sexual response, i.e., desire, excitement, and orgasm (see Kaplan, Disorders of Sexual Desire, New York, N.Y.: Brunner Mazel Books Inc., 1979). Most preferably it includes the class of individuals having lost penile neural input and hence cannot respond to treatments requiring concurrent sexual stimulation for the treatment of erectile dysfunction.
  • active agent drug
  • drug pharmaceutically active agent
  • PDE type V inhibitor such as sildenafil citrate which is capable of being delivered locally, preferably by intracavernosal injection.
  • the preferred PDE type V inhibitor is sildenafil citrate.
  • intracavernosal refers to a mode of drug administration and involves injection into one or both corpora of the corpora cavernosal tissue of the penis.
  • Carriers or “vehicles” as used herein refer to carrier materials suitable for local drug administration. Carriers and vehicles useful herein include any such materials known in the art which is nontoxic and does not interact with other components of the composition in a deleterious manner.
  • an “effective" amount of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, i.e., treatment of erectile dysfunction.
  • sildenafil citrate is administered to an individual prone to erectile dysfunction by any known method of injection.
  • Sildenafil citrate is designated chemically as l-[[3-(6,7-dihydro-l-methyl-7-oxo-3- propyl- 1 H-pyrazolo [4,3 -d ]pyrimidin-5 -yl)-4-ethoxyphenyl] sulfonyl] -4-methylpiperazine citrate.
  • a commercial form of this is Viagra®, the citrate salt of sildenafil, which is sold by Pfizer.
  • the process for preparing Sildenafil has been described in U.S. Patent Nos. 5,955,611 and 6,066,735 to Dunn et al.
  • type V phosphodiesterase inhibitors include, but are not limited to, zaprinast, MY5445, dipyridamole.
  • Other type V phosphodiesterase inhibitors are disclosed in PCT Publication Nos. WO 94/28902 and WO 96/16644 and US Patent No.: 6,037,346 to Doherty et al.
  • Salts, esters, amides, prodrugs, and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described for example, by J. March, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4 th Ed. (New York, Wiley-Interscience, 1992). See also U.S. Patent No. 6,037,746.
  • acid addition salts are prepared from the free base using conventional methodology, and involves reaction with a suitable acid.
  • the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto.
  • the resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent.
  • Suitable acids for preparing acid addition of salts include both organic acids, e.g. acetic acid, propionic acid, glycolic acid and the like, as well as inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • An acid addition salt may be reconverted to the free base by treatment with a suitable base.
  • preparation of basic salts of acid moieties which may be present on a phosphodiesterase inhibitor molecule are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine or the like.
  • esters involves functionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure of the drug.
  • the esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties which are derived from carboxylic acids of the formula RCOOH where R is alkyl.
  • Esters can be reconverted to the free acids, if desired, by using hydrogenolysis or hydrolysis procedures.
  • Amides and prodrugs may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
  • Prodrugs are typically prepared by covalent attachment of a moiety which results in a compound that is therapeutically inactive until modified by an individual' metabolic system.
  • the preferred method of administration is via intracavernosal injection.
  • Intracavernosal injection can be carried out by use of a syringe or other suitable device.
  • An example of a hypodermic syringe useful herein, that can be used for simultaneous injection in both corpora is described in U.S. pat. No. 4,127,118 to Latorre. The injection is made on the dorsum of the penis by placement of the needle to the side of each dorsal vein and inserting deep into the corpora.
  • the active agent to be administered is incorporated into a sterile liquid preparation, typically a solution or suspension in an aqueous or oleaginous medium.
  • a sterile liquid preparation typically a solution or suspension in an aqueous or oleaginous medium.
  • the solution or suspension may be formulated according to techniques known in the art using suitable carriers, dispersants, wetting agents, diluents, suspending agents or the like.
  • suitable carriers dispersants, wetting agents, diluents, suspending agents or the like.
  • suitable carriers dispersants, wetting agents, diluents, suspending agents or the like.
  • suitable carriers dispersants, wetting agents, diluents, suspending agents or the like.
  • the acceptable vehicles and solvents that may be employed are water, isotonic saline, vegetable oil, fatty esters and polyols.
  • a PDE type V inhibitor such as sildenafil citrate
  • sildenafil at those levels is acting on smooth muscle by a mechanism other than that mediated by NO.
  • Animal studies using intracavernosal injection of sildenafil caused penile erection in the absence of sexual stimulation. These observations, indicate that the present method results in a new and novel mechanism of sildenafil action in corpus cavernosum.
  • the preferred time of injection is at least 5 minutes prior to sexual contact, more preferably at least 15 minutes.
  • the preferred dose range that would correct male erectile dysfunction without causing priapism is about 5 - 60 mg, preferably 10 - 50 mg, more preferably 15 - 40 mg, still more preferably 20 - 30 mg.
  • One preferred class of individuals to be treated by the present method are those individuals prone to erectile dysfunction or only partially respond to physical sexual stimulation and do not respond effectively to oral treatment by Viagra®.
  • Another preferred class of individuals to be treated are individuals prone to erectile dysfunction who cannot respond to physical sexual stimuli.
  • Yet another group of individuals who can be treated by the present method are individuals who have lost, at least some, penile neural input due to neurogenic or other causes relating to loss of neural input to the penis. For example, individuals who have undergone radical prostatectomy.
  • the invention also encompasses a kit for patients to carry out the present method.
  • the kit contains the pharmaceutical formulation to be administered, a device for admimstering the formulation, preferably a syringe and hypodermic needle as described supra (such as Latorre), a container, preferably sealed, for housing the drug and device during storage and prior to use, and instructions for carrying out drug administration in an effective manner.
  • the formulation may consist of the drug in unit dosage form.
  • the kit may also contain multiple formulations of different dosages of the same agent.
  • Example 1 Solubilized Viagra® was injected intracavernosally into the penis of several anesthetized animals which resulted in sustained penile erection.
  • Example 2 Solubilized Viagra® was injected intracavernosally into the penis of several anesthetized animals which resulted in sustained penile erection.
  • Example 2 Solubilized Viagra® was injected intracavernosally into the penis of several anesthetized animals which resulted in sustained penile erection.
  • a 27-gauge butterfly needle is placed in the left corpus cavernosum approximately 7 mm proximal to the 21 -gauge needle.
  • Sildenafil is dissolved in normal saline and injected directly into the left corpus cavernosum through the smaller needle. The injection volume is standardized at 0.2 ml to ensure minimal volume effect on the intracorporal pressure. The effect of sildenafil on the intracorporal pressure, the duration of the pressure increase and the change in arterial pressure with intracavernosal administration are then evaluated.
  • Sildenafil (0.3 mg, 0.6 mg, 1.0 mg and 1.3 mg) is administered intracavernosally and saline is used as a control.
  • the time interval between injection and the peak intracavernosal pressure and the duration of erection are read directly from the data charts.
  • the normalized intracavernosal pressure rise peak intracavernosal pressure subtract the pre-injection intracavernosal pressure divided by the systemic arterial pressure at the time of the peak intracavernosal pressure is calculated.
  • Example 3 In vitro Studies Organ chambers can be used to evaluate the effect of sildenafil on rabbit corpus cavernosal tissue. These tissues are obtained and prepared for organ bath studies as previously described. The effects of sildenafil on smooth muscle relaxation in the absence or presence of nitric oxide synthase inhibitors will be determined.
  • sildenafil at 0.25 mg/kg is effective in causing erections. This corresponds to an intracavernosal doses of 20 mg.
  • Intracavernosal sildenafil at this concentration may result in reduced levels of sildenafil in the systemic circulation and minimize the noted adverse effects observed with oral Viagra such as headaches, flushing, visual effects and gastro-esophageal reflux.
  • Penile corpus cavernosum tissue strips were obtained from male New Zealand White rabbits (3.5-4.0 kg; Pine Acres Rabbitry, Builford, Vt.) and prepared for organ bath studies, as previously described (Kim et al, 1991). Briefly, rabbit cavernosal tissue strips were mounted onto force transducers (Model FT03; Grass Instruments, Quincy, Mass.) and immersed in 25- mL baths of physiological salt solution (118.3 mM NaCl, 4.7 mM KC1, 0.6 mM MgSO 4 , 1.2 mM KH 2 PO 4 , 2.5 mM CaCl 2 , 25 mM NaHCO 3 , 0.026 mM CaNa 2 EDTA, and 11.1 mM
  • Cavernosal tissue strips were contracted with 1 ⁇ m
  • tissue strips were contracted again with phenylephrine and treated with either vehicle (distilled, deionized H O) or 0.6 mM of the
  • NOS inhibitor N ⁇ -nitro-L-arginine methyl ester (L-NAME) for 30 minutes. Tissue strips were then subjected to electrical field stimulation and exogenous acetylcholine. Tissues treated with L-NAME did not relax to either electrical field stimulation or acetylcholine, indicating effective blockade of NO synthesis (unpublished). Tissue strips were then exposed to increasing concentrations of sildenafil citrate (a generous gift from Dr. Farid Saad, Jenapharm GmbH, Jena, Germany) by cumulative addition. In a separate protocol, cavernosal tissue strips at optimal isometric tension were treated with vehicle (50% DMSO).
  • New Zealand White male rabbits (3.5 - 4.0) were sedated with subcutaneous ketamine (35 mg/kg) and xylazine (5 mg/kg), and anesthesia was maintained with intravenous pentobarbital (20 mg, as required: James Brudnick Co., Maiden, Mass.).
  • Lidocaine (4 mg/kg) was used for local infiltration at the base of the penis and the midline of the neck. Surgical dissection was performed to expose the left corpus cavernosum and the left carotid artery.
  • the nerve was localized on the antero-lateral rectal wall and a bipolar electrode was placed in the corpus cavernosum and a 20-gauge angiocatheter was introduced into the carotid artery. These were connected to a model 7400 physiologic recorder (Grass Instruments) for the simultaneous monitoring of intracavernosal pressure (ICP) and systemic arterial pressure (SAP).
  • ICP intracavernosal pressure
  • SAP systemic arterial pressure
  • a 27- gauge butterfly needle was placed in the left corpus cavernosum approximately 7-8 mm proximal to the 21-gauge needle.
  • Sildenafil 0.3, 0.6, 1.0, and 1.3 mg
  • Injection volumes were standardized to 0.2 mL to ensure minimal volume-related changes on ICP. The effect of sildenafil on ICP, the duration of the pressure increase, and the change in SAP with intracavernosal administration were measured.
  • Some rabbits were injected intracavernosally with 0.2 mL of 3 mM L-NAME 10 minutes prior to pelvic nerve stimulation (PNS) or sildenafil injection.
  • the pelvic nerve was stimulated for 30 seconds with a train of square waves at an amplitude of 10 volts, a pulse duration of 0.8 msec, and frequency of 32 Hz.
  • the ICP/S AP ration for PNS alone was compared with that of L-NAME treatment followed by PNS or 1.3 mg of sildenafil.
  • Three data parameters were analyzed. The time interval between injection and the peak ICP (time to peak) and the duration of erection were read from the data charts.
  • the normalized peak ICP peak ICP divided by SAP was calculated.
  • sildenafil caused dose-dependent relaxation at concentrations above 0.1 ⁇ M ( Figure 1 A). Little or no effect was observed at lower concentrations. This relaxation response may in part be mediated by the basal release of NO from the NANC nerves and the endothelium lining the lacunar spaces of the corpus cavernosum. To these this, tissue strips were treated with L- arginine derivative, L-NAME, to inhibit neuronal and endothelial NOS activity.
  • Activation of PDE type 5 terminates cGMP- mediated smooth muscle relaxation, resulting ultimately in restoration of basal smooth muscle contractility and penile flaccidity.
  • Sildenafil citrate a potent, reversible, and selective PDE type 5 inhibitor effectively blocks cGMP hydrolysis and has been shown to be a safe and effective oral drug in the treatment of erectile dysfunction (Goldstein et al, 1998).
  • the activation of the NO pathway be sexual stimulation is required for sildenafil to be effective in facilitating erections. This premise is based on the ability of oral sildenafil to inhibit PDE type 5.
  • sildenafil relaxed corpus cavernosum smooth muscle in organ baths in the absence of significant NOS activity. This relaxation response also persisted in the presence of ODQ at concentrations shown to completely inhibit cGMP production (Moro et al. 1996).
  • the relaxation response to sildenafil was, interestingly, potentiated by the addition of 50% DMSO vehicle, relative to saline vehicle.
  • Organ bath experiments using isolated rabbit aorta suggest that DMSO causes vascular smooth muscle relaxation by inhibiting calcium mobilization (Jackson et al, 1979). Similar mechanisms may cause the potentiation observed in our studies.
  • sildenafil administered intracavernosally caused erections in the absence of PNS as well as in the presence of L-NAME.
  • the inhibition constant of sildenafil for PDE 5 in human corpus cavernosum tissue extracts is approximately 3.5nM (Moreland et al, 1999).
  • the plasma level of sildenafil following oral administration of a 100 mg. Viagra tablet is 560 ng/mL (0.84 ⁇ M; Center for Drug Evaluation and Research, 1998).
  • intracavernosal injection of 1 mg In the rabbit model, intracavernosal injection of 1 mg.
  • sildenafil translates into a local plasma concentration of 2.1mM within the penile corpora cavernosa (assuming a rabbit penis volume of 0.7 mL).
  • This estimate of the intracavernosal concentration of sildenafil is 6000000 times greater than the K of this drug and 2500 times greater than the serum level following oral administration of the highest available does of Viagra.
  • This disparity in conjunction with our data, strongly suggests that pathways other than inhibition of PDE 5 activity mediate intracavernosal sildenafil-induced erections.
  • intracavernosal sildenafil Further anecdotal evidence for the effects of intracavernosal sildenafil is obtained from a case report of a 47- year old man who did not respond to oral sildenafil (personal communication, I. Goldstein). Following a self-administered intracavernosal injection of a crushed Viagra tablet (100 mg) suspended in saline, he experienced immediate pain in both corpora and developed a tender erection over the next 2 hours. A rigid and painful erection ensued. He sought medical attention after 6 days of priapsim, and was managed with intracavernosal saline lavage, alpha-adrenergic agonist therapy, a Winters shunt, and an Al- Ghorab shunt.
  • Tri-mix phentolamine 1 mg/mL, papaverine 30 mg/mL, and PGE, 100 ⁇ g/mL
  • PGE penile prosthesis
  • the insoluble talc filler contained in the tablet may have obstructed the subtunical venules, resulting in veno- occlusion and priapism. It is unlikely that trauma to a cavernosal artery causing high-flow priapism was responsible for the erection. Thus, further mechanistic studies are needed to elucidate the induction of cavernosal smooth muscle relaxation by high doses of sildenafil.
  • sildenafil may be interacting as a cGMP analogue with proteins (other than PDE 5) that are regulated by cGMP (eg, protein kinase G).
  • cGMP protein kinase G
  • G-protein coupled receptor agonists such as PGE (Caverject and Edex) or adenylate cyclase activators (forskolin) mediate smooth muscle relaxation and cause erection via the cAMP pathway.
  • PGE Caverject and Edex
  • adenylate cyclase activators forskolin
  • intracavernosal papaverine a nonspecific, low-affinity PDE inhibitor, causes smooth muscle relaxation and penile erection, presumably by a mechanism independent of the cyclic nucleotide pathway (Kim et al, unpublished observations). It is possible that intracavernosal sildenafil at high concentrations is acting in a similar manner.
  • sildenafil is useful as a intracavernosal agent for the treatment of male erectile dysfunction.

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Abstract

La présente invention concerne une découverte, selon laquelle une injection d'un inhibiteur V du type de la phosphodiestérase (PDE), tel que le sildenafil, dans l'artère caverneuse, provoque une érection du pénis, en l'absence de stimulation sexuelle. Ainsi, des individus qui ont un taux de réponse faible à une dose orale d'un inhibiteur V de type PDE, tel que le sildenafil, peuvent être traités par administration locale d'une préparation pharmaceutique contenant du citrate de sildenafil. On réalise l'administration de ladite préparation dans le cadre d'une posologie prédéterminée, de telle manière que l'agent est efficace dans le traitement de la dysérection. On administre le médicament, de préférence au moyen d'une injection dans l'artère caverneuse. Les marges posologiques efficaces sont comprises de préférence entre environ 5 à 60 mg, plutôt entre 10 et 50 mg de préférence ou même entre 15 et 40 mg et voire de préférence entre environ 20 et 30 mg.
PCT/US2001/041638 2000-08-08 2001-08-08 Compositions et methodes de traitement de la dyserection masculine WO2002011729A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011029A2 (fr) * 2002-07-26 2004-02-05 Adams Kenneth W Elargissement du penis
WO2014080161A1 (fr) * 2012-11-22 2014-05-30 Mens Health Ltd Vip et agent bloquant alpha-adrénergique pour leur utilisation dans le traitement de la dysfonction érectile post prostatectomie radicale
WO2018220232A1 (fr) * 2017-06-02 2018-12-06 Universite De Versailles-St Quentin En Yvelines Produit d'association pharmaceutique comprenant une toxine botulinique pour le traitement d'un dysfonctionnement érectile

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US6037346A (en) * 1997-10-28 2000-03-14 Vivus, Inc. Local administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011029A2 (fr) * 2002-07-26 2004-02-05 Adams Kenneth W Elargissement du penis
WO2004011029A3 (fr) * 2002-07-26 2004-05-21 Kenneth W Adams Elargissement du penis
US7671091B2 (en) 2002-07-26 2010-03-02 Adams Kenneth W Penis enlargement
WO2014080161A1 (fr) * 2012-11-22 2014-05-30 Mens Health Ltd Vip et agent bloquant alpha-adrénergique pour leur utilisation dans le traitement de la dysfonction érectile post prostatectomie radicale
WO2018220232A1 (fr) * 2017-06-02 2018-12-06 Universite De Versailles-St Quentin En Yvelines Produit d'association pharmaceutique comprenant une toxine botulinique pour le traitement d'un dysfonctionnement érectile

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