EP1079764A1 - Traitement des troubles de la sexualite chez certains groupes de patients - Google Patents

Traitement des troubles de la sexualite chez certains groupes de patients

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Publication number
EP1079764A1
EP1079764A1 EP99920266A EP99920266A EP1079764A1 EP 1079764 A1 EP1079764 A1 EP 1079764A1 EP 99920266 A EP99920266 A EP 99920266A EP 99920266 A EP99920266 A EP 99920266A EP 1079764 A1 EP1079764 A1 EP 1079764A1
Authority
EP
European Patent Office
Prior art keywords
flosequinan
subject
erection
impotence
male
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99920266A
Other languages
German (de)
English (en)
Other versions
EP1079764A4 (fr
Inventor
designation of the inventor has not yet been filed The
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RT Alamo Ventures I LLC
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RT Alamo Ventures Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/071,457 external-priority patent/US6110489A/en
Priority claimed from US09/166,703 external-priority patent/US6194433B1/en
Priority claimed from US09/175,395 external-priority patent/US6132753A/en
Priority claimed from US09/260,099 external-priority patent/US6132757A/en
Priority claimed from US09/262,715 external-priority patent/US6187790B1/en
Application filed by RT Alamo Ventures Inc filed Critical RT Alamo Ventures Inc
Publication of EP1079764A1 publication Critical patent/EP1079764A1/fr
Publication of EP1079764A4 publication Critical patent/EP1079764A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present invention provides relates to methods for the treatment of sexual dysfunction in males and females (including but not limited to erectile dysfunction in males) in particular treatment groups.
  • the methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
  • Impotence or erectile insufficiency is a widespread disorder that is thought to affect about twelve percent of adult men under age forty-five, about twenty percent of men at age sixty, and about fifty-five percent of men at age seventy- five.
  • erectile dysfunction can be psychological, resulting from anxiety or depression, with no apparent somatic or organic impairment.
  • erectile dysfunction which is referred to as "psychogenic” is responsible for about fifteen to twenty percent of cases of impotence.
  • the erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis; such dysfunction is referred to as "arteriogenic” or "atherosclerotic.”
  • arteriogenic or "atherosclerotic.
  • About forty to sixty percent of cases of impotence are arteriogenic in origin.
  • venous leakage or "abnormal drainage”.
  • nerve damage arising from, for example, surgery or a pelvic injury
  • nerve damage arising from, for example, surgery or a pelvic injury
  • Erectile insufficiency there is also a high incidence of erectile insufficiency among diabetics, particularly those with insulin-dependent diabetes mellitus. Erectile dysfunction in diabetics is often classified as "diabetogenic," although the underlying dysfunction is usually neurogenic associated with neuropathy, but may be arteriogenic or neurogenic and arteriogenic. About half of diabetic males suffer from erectile insufficiency, and about half of the cases of neurogenic impotence are in diabetics.
  • erectile insufficiency is sometimes a side effect of certain drugs, such as beta-blockers that are administered to reduce blood pressure in persons suffering from hypertension, or drugs administered to treat depression or anxiety. Excessive alcohol consumption has also been linked to erectile insufficiency. These forms of erectile insufficiency may be regarded as a subset of neurogenic or psychogenic insufficiency. A number of methods to treat impotence are available. These treatments include pharmacological treatments, surgery and, in cases of psychogenic dysfunction, psychological counseling is sometimes effective.
  • Psychogenic impotence often can be cured by counseling coupled with a demonstration to the patient that he is capable of having a full erection by inducing such an erection one of a few times in the patients. Insufficiency due to excessive alcohol consumption is sometimes cured by reducing or elimination such consumption.
  • insufficiency is physical because of venous leakage
  • surgery can usually be employed to repair the venous lesion and thereby either cure the insufficiency or, if there remains an erectile insufficiency after repair of the venous lesion, render the insufficiency amenable to treatment by pharmacological methods.
  • penile implants which provide a mechanical means to produce an erection sufficient for vaginal penetration
  • implants have been employed, especially in cases where pharmacological intervention is ineffective, which are usually cases of severe atherogenic impotence.
  • Treatment of impotence with penile implants entails serious disadvantages. Such treatment requires surgery and necessitates total destruction of the erectile tissues of the penis, forever precluding normal erection.
  • Papaverine is now widely used to treat impotence, although papaverine is ineffective in overcoming impotence due, at least in part, to severe atherosclerosis. Papaverine is effective in cases where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific blocker and hypotensive, into a corpus cavernosum has been found to cause an erection sufficient for vaginal penetration.
  • intracavemosal injection of phentolamine, an ⁇ -adrenergic blocker causes an erection sufficient for vaginal penetration.
  • the resulting erection is one of significantly shorter duration than that induced by intracavemosal injection of papaverine or phenoxybenzamine and is of such short duration that satisfactory sexual relations are difficult or impossible.
  • priapism Treatment of impotence with papaverine or phenoxybenzamine often results in priapism, a locking-up of an erection for a long period of time, typically a few hours and sometimes longer than twenty-four hours.
  • Priapism is a serious, deleterious side effect of treatment of erectile insufficiency with these drugs. Beyond the embarrassment that may be caused for some men, priapism is usually painful, irreversibly damages erectile tissue, and, to be relieved, requires bleeding or pharmacological intervention, such as injection of a sympathomimetic drug, such as adrenaline.
  • impotence is a ubiquitous problem, there are few satisfactory methods available for treating this disorder. Because of the relatively invasive intervention involved and the high failure rate of penile prostheses, surgical approaches provide unattractive alternatives. A safe pharmacological approach to the treatment of impotence is still to be achieved.
  • the present invention provides relates to methods for the treatment of sexual dysfunction in males and females (including but not limited to erectile dysfunction in males) in particular treatment groups.
  • the methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
  • the compositions comprise quinolines and quinolones, including derivatives thereof.
  • the quinolone is an oxoquinoline.
  • the oxoquinoline is cilostazol (6-[4-(l-cyclohexyl-l-H-tetrazol-5- yl)butoxyl]-3 ,4-dihydro-2( 1 H)-quinolinone; 6-[4-( 1 -cyclohexyl- 1 H-tetrazol-5 - yl)butoxy]-3,4-dihydrocarbostyril; 6-[4-(l-cyclohexyl-5-tetrazoyl)butoxy]- 1,2,3,4- tetrahydro-2-oxoquinoline) .
  • Metabolites of cilostazol include, but are not limited to monohydroxycilostazol, monohydroxydehydrocilostazol, 3,4-dihydro- 6-hydroxy-2(lH)-quinolinone, their conjugates and dehydrocilostazol.
  • the present invention contemplates halogenated quinolines (e.g., bromoquinoline) and isoquinolines (e.g., 1-methylisoquinoline and 5- nitroisoquinoline).
  • halogenated quinolones e.g., flosequinolone.
  • the quinolone is a thioquinolone or a sulphinyl or suphonyl derivatives thereof.
  • the halogenated quinolone is flosequinan (7-fluoro-l-methyl-3- methylsulphinyl-4-quinolone).
  • the present invention contemplates a method, comprising: a) providing: i) a male or female with symptoms of sexual dysfunction, and ii) flosequinan; and b) administering said flosequinan to said male or female. It is not intended that the present invention be limited to particular symptoms of sexual dysfunction. A variety of such symptoms are contemplated, including but not limited to, poor blood flow to the sexual organs and/or failure to achieve orgasm. In one embodiment, the present invention contemplates administering said flosequinan to said male or female under conditions such that blood flow to the sexual organs of said male or female is improved.
  • the method comprises providing: i) a male or female with erectile dysfunction, and ii) flosequinan; and introducing said flosequinan to said female such that an erection (i.e. penile or clitoral) is produced.
  • an erection i.e. penile or clitoral
  • the flosequinan is introduced into said male or female orally.
  • the male or female is an adult human and the oral dosage is in a single dose per day of up to approximately 100 milligrams, and more preferably, between approximately fifty to approximately seventy-five milligrams.
  • said flosequinan is introduced cutaneously, transurethrally, or by standard injection.
  • the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of sexual dysfunction who is free from cardiac disease; and ii) flosequinan; and b) introducing said flosequinan to said patient such that such symptoms are reduced.
  • the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of sexual dysfunction who is not being treated (and/or has not been treated in the past) with a drug that causes hypotensive effects, and ii) flosequinan; and b) introducing said flosequinan to said patient such that such symptoms are reduced.
  • the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of sexual dysfunction who is not being treated (and/or has not been treated in the past) with a nitrite or nitrate, and ii) flosequinan; and b) introducing said flosequinan to said patient such that such symptoms are reduced.
  • the present invention is not limited by the degree of response by the subject.
  • the male erection induced is sufficient for vaginal penetration.
  • the present invention also contemplates the use of sexual stimulation in addition to the application of a pharmaceutical composition.
  • one embodiment comprises a) providing: i) a male, having a penis, with erectile dysfunction, and ii) flosequinan, iii) sexual stimulation; and b) introducing said flosequinan and sexual stimulation to said male such that an erection is produced.
  • the present invention is not limited by the nature of the sexual stimulation.
  • the sexual stimulation is sexually explicit media.
  • the sexual stimulation involves manipulation of the penis, such as with vibration. It is not intended that the present invention be limited by the nature of the formulation.
  • the present invention contemplates a formulation comprising a quinoline or derivative thereof in a mixture comprising lactose.
  • quinoline refers to chemical compositions comprising quinoline as set forth in the following structure:
  • quinoline e.g., isoquinoline
  • derivatives of quinoline refers to chemical compositions comprising quinoline with a chemical group attached, including halogenated quinoline, e.g. , 5-bromoquinoline:
  • methylsulphinyl derivatives of quinoline refers to chemical compositions comprising quinoline with a methylsulphinyl group attached. Examples include flosequinan (7-fluoro-l-methyl-3-methylsulphinyl-4-quinolone):
  • a patient who is “free from cardiac disease” and a patient who is “free from symptoms of cardiac disease” indicate that the patient has not been diagnosed with angina, myocardial infarction, congestive heart failure and that symptoms of angina, ischemia, myocardial infarction, congestive heart failure have not been detected, respectively.
  • drug that have hypotensive effects are those drugs which, when administered, cause the patient's end-diastolic blood pressure to be reduced. Nitrates are commonly used drugs which have hypotensive effects.
  • nitrates are compounds that contain the -NO 3 - moiety. Nitrates typically used in the clinic are shown in Table 1. As used herein, “nitrites” are compounds that contain the -NO 2 - moiety.
  • Isosorbide-5- ono ⁇ itrate T 10 to 40 mg twice daily (IMDUR, ISMO, others) C: 60 mg daily
  • transdermal disc Inh. inhalant
  • IV intravenous injection: O, ointme S, lingual spray
  • T ublet for subltngual use
  • T(C) chcwable Ublet: T(O), oral tablet or capsule.
  • erectile dysfunction refers to certain disorders of the cavernous tissue of the penis and the associated facia which produce impotence, the inability to attain a sexually functional erection;
  • standard injection refers to the placement of a pharmaceutical composition into a subject (e.g., with a hypodermic needle).
  • a pharmaceutical composition e.g., a pharmaceutical composition into a subject (e.g., with a hypodermic needle).
  • such injection can be made subcutaneously, intravenously, intramuscularly, intracavernosally, etc.
  • intracavemosal injection is injection into the corpus cavernosum of the penis.
  • an “erection” refers to the condition of a penis whereby it is at least semi-rigid as opposed to being in a flaccid state.
  • oral administration refers to the introduction of a pharmaceutical composition into a subject by way of the oral cavity (e.g., in aqueous liquid or solid form).
  • oral cavity e.g., in aqueous liquid or solid form.
  • cutaneously refers to the introduction of a pharmaceutical composition into a subject by application to the surface of the skin such that the composition is absorbed into the subject.
  • transurethrally refers to the introduction of a pharmaceutical composition to the urethra of a subject such that the composition is absorbed into the subject.
  • intranasally refers to the introduction of a pharmaceutical composition within the nasal cavity.
  • respiratory inhalation refers to the introduction of a pharmaceutical composition within the respiratory tract.
  • sufficient for vaginal penetration refers to the state of an erection such that the penis is capable of entering a vagina without manual manipulation.
  • sexual stimulation refers to activity that would induce an erection in a male without erectile dysfunction (e.g., sexually explicit media, manual manipulation, vibration, live erotic entertainment, etc.)
  • sexually explicit media refers to films, videos, books, magazines, etc. that depict sexual activity.
  • single dosage refers to a pharmaceutical composition of a formulation that is capable of achieving its intended effect in a single application.
  • the present invention provides relates to methods for the treatment of sexual dysfunction in males and females (including but not limited to erectile dysfunction in males) in particular treatment groups.
  • the methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
  • the compositions comprise quinolines and quinolones, including derivatives thereof.
  • flosequinan is administered.
  • flosequinan may potentiate the hypotensive effects of nitrates, and its administration to patients who are concurrently using organic nitrates in any form may be contraindicated.
  • the present invention contemplates the use of compositions that are effective to induce an erection in a human male suffering from impotence of any origin, other than anatomical deficiencies (i.e., lacking a penis or a significant portion thereof) that preclude an erection sufficient for vaginal penetration.
  • these compositions may be used to induce an erection in a male suffering from impotence caused by severe atherosclerosis, and also impotence that is neurogenic or psychogenic in origin.
  • the compositions utilized in the methods of the present invention comprise quinolines and quinolones, including derivatives thereof.
  • the present invention encompasses the use of a variety of quinoline derivatives (e.g., 5-bromoquinoline, 5-nitroisoquinoline, 8-nitroisoquinoline and 1- methylisoquinoline).
  • quinoline derivatives e.g., 5-bromoquinoline, 5-nitroisoquinoline, 8-nitroisoquinoline and 1- methylisoquinoline.
  • One skilled in the art can readily produce such derivatives as set forth in McMurry, Organic Chemistry, 2nd Ed., Brooks/Cole Publishing, Belmont, CA (1988), pages 1044-1045 and 1076.
  • the present invention contemplates the use of methylthio and methylsulphinyl derivatives of quinoline.
  • the methylsulphinyl derivative is flosequinan (7-fluoro-l-methyl-3-methylsulphinyl-4- quinolone).
  • flosequinan The action of flosequinan in the body is not precisely understood. Its activity in the body is attributed to flosequinan itself, as well as its sulfone metabolite. It has been reported to be useful to some degree in the treatment of heart failure. [See Kelso et al, J. Cardiovasc. Pharmacol. 25:376 (1995)]. However, its action appears to have little effect in patients with end-stage failure [Perreault et al, Br. J. Pharmacol. 106:511 (1992)] and does not affect mortality or arrhythmias following coronary artery ligation [Jones et al, Br. J. Pharmacol. 108:1111 (1993)].
  • flosequinan has been reported to be a selective inhibitor of phosphodiesterase III [Gristwood et al, Br. J. Pharmacol. 105:985 (1992)].
  • a human male suffering from impotence is readily made by a person skilled in the art using a number of readily available diagnostic procedures.
  • a male suffering from impotence can first be given a physical examination with particular attention to possible penile and scrotal pathology, whereby any anatomical deficiency precluding an erection sufficient for vaginal penetration can be detected.
  • the male can be subjected to tests, whereby penile venous leakage or severe or untreatable atherosclerosis can be detected.
  • Such tests include determination of the penobrachial blood pressure index
  • PBPI penile systolic blood pressure divided by the systolic blood pressure determined at one of the arms. These blood pressures can be determined by any number of standard techniques.
  • the penile systolic blood y pressure can be determined by i) placing an inflatable cuff around the base of the free part of the penis in the flaccid state which is capable of being used to apply variable pressure, readable from a gauge, to an object around which the cuff is placed, ii) localizing the penile arteries with a Doppler ultrasound probe (e.g., 8 MHz probe, such as the Mini Doplex D500 available from Huntleigh Technology, Luton, United Kingdom), and then iii) inflating and deflating the cuff and ascertaining the pressure at which the Doppler sound reappears.
  • a Doppler ultrasound probe e.g., 8 MHz probe, such as the Mini Doplex D500 available from Huntleigh Technology, Luton, United Kingdom
  • the pressure at which the Doppler sound reappears is the penile systolic blood pressure.
  • a male's penile blood pressure is regarded as normal if his PBPI is >0.80.
  • each of the two penile cavernous arteries is investigated distal to the aforementioned cuff using the Doppler ultrasound problem.
  • the function of each of the two arteries is assessed by Doppler ultrasound using an arbitrary scale of 0, 1, 2 or 3, where 0 means that the function is so deficient that the artery cannot be located and 3 means that the artery is well enough that maximal Doppler sound is observed.
  • a tourniquet is placed at the base of the free part of the penis and tightened and then, with the patient seated, 30 mg of papaverine in 1 ml of a physiologically acceptable fluid (e.g., physiological saline or phosphate-buffered saline) is injected into the penile cavernous body.
  • a physiologically acceptable fluid e.g., physiological saline or phosphate-buffered saline
  • Gentofte Denmark is carried out for five to ten minutes and then erectile response is evaluated.
  • Erectile response is classified as full rigidity, if the angle between the penis and the legs in the standing position is >90°, and tumescence or no response if the angle is less than or equal to 45°.
  • An impotent male who does not have an anatomical deficiency that would preclude having an erection sufficient for vaginal penetration, who has a PBPI >0.80, who has scores of 2 or 3 in Doppler ultrasound investigations of both of the cavernous arteries of the penis, after papaverine injection as described above, and who has a fully rigid erection after papaverine injection and vibration as described above, is suffering from impotence that is "substantially only neurogenic or psychogenic" in origin.
  • Atherosclerosis or venous leakage contributes to such impotence, and atherosclerosis likely does contribute if the score is less than 3 in the Doppler investigation of one or both of the cavernous arteries after papaverine injection; but any venous leakage or atherosclerosis in such impotence is not untreatable and, consequently, is not a substantial factor in the impotence and such atherosclerosis, if any, is less than severe.
  • Impotence which is a side-effect of drugs such as beta-blockers, is deemed to be neurogenic impotence in the present specification.
  • impotence which is a result of alcoholism or excessive consumption of alcohol is deemed to be neurogenic or psychogenic impotence, for purposes of the present specification.
  • a male who is diagnosed in accordance with the present specification as suffering from impotence that is "substantially only neurogenic or psychogenic" in origin is suffering from impotence that is substantially only neurogenic, psychogenic or neurogenic and psychogenic in origin, even though an underlying cause of the impotence has been identified as a side-effect of a drug, alcoholism or excessive consumption of alcohol.
  • a male with a PBPI less than about 0.60 with scores of 0 in Doppler investigations of both penile cavernous arteries (after papaverine injection as described above), and with a less than fully rigid erection after papaverine injection and vibration will have impotence caused by "untreatable" atherosclerosis. Methods are available to ascertain whether impotence is untreatable because of venous leakage.
  • Cavemosometry can be done using, both before and after intracavemosal injection of 60 mg of papaverine (in 1 ml of physiological saline), infusion of physiological saline through a 19-gauge needle into one corpus cavernosum with a 21 -gauge needle inserted into the other corpus cavernosum for measurement of intracorporal pressure (which is recorded on a plotter).
  • the infusion rates needed to induce and maintain an erection are measured. If the infusion rate needed to maintain an erection is greater than 50 ml/min before administration of the papaverine and greater than 15 ml/min after administration of the papaverine, untreatable venous leakage is present.
  • the penis is X-rayed, both before and after intracavemosal injection of 60 mg papaverine (in 1 ml of physiological saline), while infusing contrast medium into the corpus cavernosum (e.g., through a 19-gauge needle) at a flow rate that maintains an erection during the x-raying.
  • contrast media suitable for the procedure are available in the art; these are typically aqueous solutions of iodinated compounds that provide between about 180 mg/ml and about 360 mg/ml of iodine. Examples are a solution of iohexol providing 240 mg/ml of iodine sold by Winthrop Pharmaceuticals,
  • the corporal body is surrounded by a fibrous sheath, tunica albuginea, which encases cavemosal tissue consisting of sinusoids and surrounding smooth muscle.
  • the clitoris responds to sexual excitement by tumescence and erection, although this does not occur with the degree of pressure elevation as found during penile erection.
  • the characteristics of the clitoral blood flow however, approximately parallel those of the male. See K. Park et al., "Vasculogenic female sexual dysfunction: The hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency," Int. J. Impotence Res. 9:27 (1997).
  • Post-menopausal women and women with a history of vascular risk factors have been shown to have significantly more complaints of self-reported female vaginal and clitoral dysfunctions than pre-menopausal women or women without vascular risk factors.
  • Such problems include, but are not limited to, athereosclerosis-induced vaginal engorgement insufficiency and clitoral erectile insufficiency syndromes.
  • a human female is suffering from poor blood flow or supply is readily made by a person skilled in the art using a number of readily available diagnostic procedures.
  • the human vagina receives arterial blood supply from the vaginal artery, the vaginal branch of the uterine artery, the internal pudendal artery, and the vaginal branches of the middle rectal artery. Blood flow in these areas can readily be assessed by a number of techniques. Arterial blood can be obtained and the blood levels of cholesterol and triglycerides can be analyzed as a first step. However, the preferred method is imaging.
  • vaginal wall blood flow can be measured by laser Doppler flow probes placed into the vaginal muscularis layer within the spongy region of blood-filled spaces and vascular smooth muscle.
  • Clitoral intracavemosal erectile tissue blood flow can be measured with a similar laser Doppler flow probe placed into the corporal bodies.
  • the flow probes are connected to a laser Doppler flowmeter (Transonic Systems, Inc.) which is calibrated against an internal standard reading flow in units of ml/min/100 gm of tissue.
  • the laser Doppler probe uses the Doppler shift of a projected beam of laser light that registers on a photodetector. Static tissues will produce no Doppler shift in wavelength but moving red blood cells will produce a shift proportional to the red cell velocity. TREATMENT OF MALE AND FEMALE ERECTILE DYSFUNCTION
  • the present invention be limited by the particular nature of the therapeutic preparation.
  • the quinolines or quinolone derivatives e.g., flosequinan
  • physiologically tolerable liquid, gel or solid carriers diluents, adjuvants and excipients.
  • quinoline or quinolone analogs may be used together with other chemotherapeutic agents.
  • formulations may also contain such normally employed additives as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers and excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
  • compositions typically contain l%-95% of active ingredient, preferably 2%- 70%.
  • the present invention is not limited by the method of introduction of the therapeutic compound to the body.
  • the present invention contemplates administering cutaneously, orally, intracavernosally, transurethrally or by standard injection.
  • the present invention also contemplates administering flosequinan to the patient intranasally or through respiratory inhalation.
  • Formulations suitable for intranasal administration include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils and other pharmaceutical carriers which accomplish direct contact between flosequinan or a pharmaceutical composition comprising flosequinan and the nasal cavity. Examples of pharmaceutical compositions administered intranasally are described in U.S. Patents 5,393,773 and 5,554,639 to Craig et al; and 5,801,161 to Merkus, all hereby incorporated by reference.
  • Formulations suitable for respiratory inhalation include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils and other pharmaceutical carriers which accomplish direct contact between flosequinan or a pharmaceutical composition comprising flosequinan and the respiratory tract.
  • Examples of pharmaceutical compositions administered through respiratory inhalation are described in U.S. Patent 4,552,891 to Hu et al; 5,869,479 to Kreutner et al, and 5,864,037 to Chasis et al, all hereby incorporated by reference.
  • intranasal administration and respiratory inhalation are the preferred modes of administration due to the ease of administration and faster onset of therapeutic activity.
  • intranasal administration and respiratory inhalation are advantageous as they may allow a smaller effective dosage to be administered than would be possible with the oral route of administration.
  • a preferred mode of administration comprises administration to the lung. Intrapulmonary delivery of pharmacologic agents to patients can be accomplished via aerosolization. Alternatively, the agent may be administered to the lung through a bronchoscope. Of course, the therapeutic agents may be investigated for their efficacy via other routes of administration, including parenteral administration.
  • Oral administration of flosequinan is effective, with a mean absolute bioavailability of 72% following a single does of fifty milligrams. Peak plasma concentrations of flosequinan are observed 1-2 hours following oral administration, while peak metabolite plasma levels are observed about seven hours following oral dosage. While the present invention is not limited to a specific dosage level, for adult humans, in one embodiment the dosage is a single dosage per day of 50 milligrams, while in another embodiment the dosage is a single dosage per day of 75 milligrams.
  • Flosequinan is water soluble and is soluble in many organic solvents.
  • aqueous and organic solution of flosequinan for oral administration is contemplated.
  • flosequinan can be associated with a solid pharmaceutical carrier for solid oral administration (i.e., in pill form).
  • the inactive ingredients include croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, methocel E5, microcrystalline cellulose, povidine, propylene glycol and titanium dioxide.
  • Flosequinan may also be administered cutaneously in a carrier adapted for topical administration.
  • carriers include creams, ointments, lotions, pastes, jellies, sprays, aerosols, bath oils, or other pharmaceutical carriers which accomplish direct contact between flosequinan and the pore of the skin.
  • pharmaceutical preparations may comprise from about 0.001% to about 10%, and preferably from about 0.01 to 5% by w/w of the active compound (e.g., flosequinan) in a suitable carrier.
  • the active compound e.g., flosequinan
  • the present invention can be incorporated in other products associated with sexual activity.
  • a coated, erection inducing condom as disclosed in U.S. Pat. No. 4,829,991, hereby incorporated by reference, and can be utilized with flosequinan or flosequinan in a pharmaceutical carrier as described above.
  • injection of flosequinan can be carried out by any conventional injection means (e.g., employing an hypodermic syringe and needle or a similar device such as the NovolinPen. sold by Squibb-Novo, Inc., Princeton, N.J., USA).
  • This injection may be by subject injecting himself or by another person (such as a partner during sexual relations or a physician prior to sexual relations) injecting the male whose erection is to be induced.
  • Methods for intracavemosal injection are described in U.S. Patent No. 5,447,912 to Gerstenberg et al, hereby incorporated by reference.
  • Flosequinan can be introduced intracavernosally in a physiologically acceptable composition.
  • Such compositions are aqueous solutions that are physiologically acceptable for administration by intracavemosal injection into the penis.
  • the physiologically acceptable carrier is selected such that it is not painful or irritating upon intracavemosal injection.
  • the physiologically acceptable compositions will preferably be sterile at the time of administration by intracavemosal injection.
  • physiologically acceptable compositions for use in the methods is physiological saline or phosphate buffered saline, in which flosequinan is dissolved or suspended, such that the resulting composition is suitable for intracavemosal injection.
  • Such a physiologically acceptable composition can also include a non-irritant preservative, such as, e.g., benzalkonium chloride at 0.05% (w/v) to 0./2% (w/v).
  • a non-irritant preservative such as, e.g., benzalkonium chloride at 0.05% (w/v) to 0./2% (w/v).
  • non-toxic salts of VIP, PHM and ⁇ -adrenergic blockers that can be employed in a physiologically acceptable composition for use in the methods herein, including, among others, the chloride, bromide, acetate, sulfate, and mesylate salts.
  • the penis is constricted near the base thereof and between the base and the point at which the injection into a corpus cavernosum occurs, in order to limit loss of injected fluid from the corpus cavernosum before the ingredients in the fluid, that are active in inducing erection, have been able to have erection-inducing effects.
  • the constriction can be effected by any means known in the art, such as with a tourniquet, cuff, rabber band or the like, or even manually, in order to slow the release of the injected fluid and the pharmacologically active substance(s) therein into the general circulation.
  • the present invention is not limited by a particular method for introducing flosequinan transurethrally.
  • flosequinan is introduced to the urethra in a carrier as described for cutaneous administration.
  • Devices and methods for transurethral introduction of pharmaceutical compositions is described in U.S. Patent No. 5,474,535 to Place et al; Voss, U.S. Pat. No. 4,801,587 and Kock, EPA 0357581, all hereby incorporated by reference.
  • Additional methods of introducing flosequinan transurethrally include the use of medicated catheters, such as those used to prevent or treat localized infections and irritation of the urethra and bladder (See U.S. Pat. No. 4,640,912, hereby incorporated by reference).
  • transurethral administration of pharmaceutical compositions is presented in U.S. Pat. Nos. 4,478,822, 4,610,868, 4,640,912 and 4,746,508, all hereby incorporated by reference, and medicated urethral suppositories, inserts or plugs, typically containing anti-infective agents or spermicide are disclosed in U.S. Pat. Nos. 1,897,423, 2,584,166, 2,696,209 and 3,373,746, all incorporated by reference.
  • While the present invention is not limited to the method of injecting flosequinan, in the preferred embodiment, it is injected with a standard syringe.
  • One skilled in the art would be capable of injecting flosequinan with a carrier as described for intracavemosal injection.
  • the administration of the compositions of the present invention is accompanied by sexual stimulation to induce an erection.
  • the sexual stimulation can begin before or after the introduction of flosequinan. If the stimulation begins after the injection, it is preferably begun within 5 to 10 minutes to insure that there is significant overlap of the pharmacological effects of the pharmaceutical composition administered and the stimulative effects of the sexual stimulation. Whether the stimulation begins before or after the injection, it will continue preferably at least until an erection sufficient for vaginal penetration is achieved.
  • Sexual stimulation as prescribed by these methods includes any form of sexual stimulation that would induce an erection in a normal male who is not suffering from erectile insufficiency.
  • the sexual stimulation can be that which occurs in the course of sexual relations between the subject and another person or can be outside sexual relations with another person.
  • Examples of methods of sexual stimulation include, alone or in combination, touching or erotically manipulating erogenous areas of the genital organs or other erogenous parts of the body; providing visual stimulation, as with a sexually explicit media (e.g., pornographic film) or other form of sexually stimulative show or display. Additionally, providing vibratory stimulation to the penis, at between about 30 Hz and about 100 Hz with an amplitude of about 1 mm to about
  • 5 ram as can be provided, for example, by resting the penis on the table of a vibrating apparatus such as that of a Vibrector system (Multicept, Genofte, Denmark).
  • a Vibrector system Multicept, Genofte, Denmark.
  • a preferred method of sexual stimulation includes providing visual stimulation, as with a pornographic film, simultaneously with vibratory stimulation of the penis, as with a Vibrector system set to between about 30 Hz and about 60 Hz (usually about 50 Hz)in frequency and between about 1 mm and about 2.5 mm (usually about 2.2 mm) in amplitude.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Reproductive Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Quinoline Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne des procédés de traitement des troubles de la sexualité chez certains groupes de patients. Ces procédés consistent à administrer des compositions pharmaceutiques à des patients ne présentant pas de maladie cardiaque et/ou auxquels on n'a pas administré de nitrates organiques.
EP99920266A 1998-05-01 1999-04-30 Traitement des troubles de la sexualite chez certains groupes de patients Withdrawn EP1079764A4 (fr)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US262715 1981-05-11
US71457 1998-05-01
US09/071,457 US6110489A (en) 1998-05-01 1998-05-01 Use of quinolines and quinolones to treat male erectile dysfunction
US166703 1998-10-05
US09/166,703 US6194433B1 (en) 1998-10-05 1998-10-05 Sexual dysfunction in females
US175395 1998-10-19
US09/175,395 US6132753A (en) 1998-05-01 1998-10-19 Treatment of sexual dysfunction in certain patient groups
US09/260,099 US6132757A (en) 1998-05-01 1999-03-02 Treatment of sexual dysfunction in certain patient groups
US260099 1999-03-02
US09/262,715 US6187790B1 (en) 1999-03-04 1999-03-04 Use of cilostazol for treatment of sexual dysfunction
PCT/US1999/009610 WO1999056666A1 (fr) 1998-05-01 1999-04-30 Traitement des troubles de la sexualite chez certains groupes de patients

Publications (2)

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EP1079764A1 true EP1079764A1 (fr) 2001-03-07
EP1079764A4 EP1079764A4 (fr) 2001-09-12

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EP (1) EP1079764A4 (fr)
JP (1) JP2002537231A (fr)
AU (1) AU3780699A (fr)
BR (1) BR9908716A (fr)
CA (1) CA2319542C (fr)
MX (1) MXPA00010254A (fr)
WO (1) WO1999056666A1 (fr)

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Publication number Priority date Publication date Assignee Title
US6548490B1 (en) * 1997-10-28 2003-04-15 Vivus, Inc. Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction
US6403597B1 (en) 1997-10-28 2002-06-11 Vivus, Inc. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US6541487B1 (en) * 1998-05-01 2003-04-01 R.T. Alamo Ventures I, Llc PDE III inhibitors for treating sexual dysfunction
WO2002058703A2 (fr) * 2001-01-26 2002-08-01 R.T. Alamo Ventures I, Llc Traitement de troubles sexuels et de maladie cardio-vasculaire avec des enantiomeres quinolinone
US6727262B2 (en) 2002-03-01 2004-04-27 R.T. Alamo Ventures I, Llc Dichlorinated heterocyclic compounds and methods of synthesis
US7041677B2 (en) 2002-03-01 2006-05-09 R.T. Alamo Ventures I, Llc Use of monochloroflosequinan in the treatment of sexual dysfunction
US6730790B2 (en) 2002-03-01 2004-05-04 R.T. Alamo Ventures I. Llc Chlorinated heterocyclic compounds and methods of synthesis
US6767914B2 (en) 2002-03-01 2004-07-27 R.T. Alamo Ventures I, Llc Fluorinated heterocyclic compounds and methods of synthesis
GB0208704D0 (en) * 2002-04-16 2002-05-29 Futura Medical Dev Ltd Condom
TWI323660B (en) * 2003-02-25 2010-04-21 Otsuka Pharma Co Ltd Pten inhibitor or maxi-k channels opener
TWI338583B (en) 2004-05-20 2011-03-11 Otsuka Pharma Co Ltd Solid pharmaceutical formulation

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US5270323A (en) * 1990-05-31 1993-12-14 Pfizer Inc. Method of treating impotence
WO1994002144A1 (fr) * 1992-07-21 1994-02-03 The Boots Company Plc Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
WO2000007595A1 (fr) * 1998-08-03 2000-02-17 Basf Corporation Utilisation de pyridinones pour traiter les dysfonctionnements sexuels

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US4801587A (en) * 1987-03-02 1989-01-31 Gene Voss Impotence ointment
US5270323A (en) * 1990-05-31 1993-12-14 Pfizer Inc. Method of treating impotence
WO1994002144A1 (fr) * 1992-07-21 1994-02-03 The Boots Company Plc Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
WO2000007595A1 (fr) * 1998-08-03 2000-02-17 Basf Corporation Utilisation de pyridinones pour traiter les dysfonctionnements sexuels

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Also Published As

Publication number Publication date
BR9908716A (pt) 2000-11-21
WO1999056666A1 (fr) 1999-11-11
JP2002537231A (ja) 2002-11-05
CA2319542C (fr) 2005-07-12
CA2319542A1 (fr) 1999-11-11
AU3780699A (en) 1999-11-23
MXPA00010254A (es) 2002-08-06
EP1079764A4 (fr) 2001-09-12
WO1999056666A8 (fr) 2000-08-10

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