WO2004069167A2 - Methode et compositions pour le traitement de l'infertilite masculine - Google Patents

Methode et compositions pour le traitement de l'infertilite masculine Download PDF

Info

Publication number
WO2004069167A2
WO2004069167A2 PCT/US2004/002400 US2004002400W WO2004069167A2 WO 2004069167 A2 WO2004069167 A2 WO 2004069167A2 US 2004002400 W US2004002400 W US 2004002400W WO 2004069167 A2 WO2004069167 A2 WO 2004069167A2
Authority
WO
WIPO (PCT)
Prior art keywords
apomorphine
ejaculate
sperm
enhancing agent
ovum
Prior art date
Application number
PCT/US2004/002400
Other languages
English (en)
Other versions
WO2004069167A3 (fr
Inventor
Steven C. Quay
Original Assignee
Nastech Pharmaceutical Company 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
Application filed by Nastech Pharmaceutical Company Inc. filed Critical Nastech Pharmaceutical Company Inc.
Publication of WO2004069167A2 publication Critical patent/WO2004069167A2/fr
Publication of WO2004069167A3 publication Critical patent/WO2004069167A3/fr

Links

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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

Definitions

  • Known causes of male infertility include primary testicular disease, disorders of sperm transport, and hypothalamic-pituitary disease resulting in hypogonadism.
  • the etiology is not ascertained in up to half of men with suspected male factor infertility.
  • the key initial diagnostic test is a semen analysis. Studies suggest that sperm counts of less than 20 million per milliliter of ejaculate, with a motility of less than 40%, are associated with an increased risk of infertility.
  • the present invention fills this need by providing for a method for promoting fertilization of an ovum by a male having a low sperm count comprising administering to the male an ejaculatory-enhancing agent.
  • the present invention further comprises determining the sperm count in a male, administering to the male an ejaculatory-enhancing agent male if the male has a sperm count lower than about 20 million spermatozoa per milliliter of ejaculate so as to produce the opportunity for the male to have an increase number of ejaculations thus obtaining an increased number of sperm.
  • An ejaculatory-enhancing agent is a pharmaceutical agent that when administered promotes sexual arousal or an erection in a male, which can lead to an ejaculation.
  • ejaculatory-enhancing agents are dopamine receptor agonists, cyclic GMP-specific phosphodiesterase-5 (PDE-V) inhibitors, organic nitrates and L-arginine.
  • PDE-V cyclic GMP-specific phosphodiesterase-5
  • At least two to three ejaculates obtained at intervals of not less than 1 week should be examined because the sperm count of a male varies.
  • Each ejaculate is obtained by masturbation into a clean glass jar, preferable a the laboratory site.
  • special condoms free of lubricants and chemicals toxic to sperm can be used.
  • ejaculate volume normal being 2 to 6 mL
  • viscosity normally it liquefies within 1 hour
  • gross and microscopic appearance normally it is opaque, cream colored, and has 1 to 3 white blood cells per high power field
  • pH normal is 7 to 8
  • sperm count normal is a quantity greater than 20 million per mL
  • an ejaculatory-enhancing agent is administered to the male to promote more frequent ejaculations for more frequent sexual intercourse with the female whom the male is trying to impregnate.
  • the ejaculates can be collected for in vitro fertilization or artificial insemination.
  • the ejaculates can be collected and the sperm concentrated using standard centrifugation techniques so that the concentration of the sperm is greater than 20 million per mL.
  • An example of a centrifuge-like device for the concentration of sperm in ejaculate is the CENTRIMOT® centrifuge sold by Andrology Laboratory Services, Inc., Chicago, IL.
  • CENTRIMOT® centrifuge sold by Andrology Laboratory Services, Inc., Chicago, IL.
  • the dopamine receptor agonist is preferably apomorphine or its functional equivalents including pharmaceutical salts and chemically modified equivalents thereof, including for example pro-drug forms of apomorphine.
  • Apomorphine is designated chemically as a 4H-dibenzo[de,g]quinoline-10,ll-diol, 5, 6, 6a, 7- tetrahydro-6-methyl-, hydrochloride, hemihydrate or (R)-(6a, R)-5, 6, 6a, 7- tetrahydro-6-methyl-4H-dibenzo [de,g] quinoline-10, 11-diol and has the molecular formula: C ⁇ 7 H ⁇ 7 NO 2 ⁇ Cl- 1 /2 H 2 O.
  • Methods for producing apomorphine are described in U.S. Patent No. 4,162,361 and in JOrg. Client. 5: 344 (1940).
  • Apomorphine has the chemical structure shown below.
  • apomorphine is preferred; however, other pharmacologically acceptable moieties thereof can be used as well.
  • apomorphine as used herein includes the free base for of this compound as well as the pharmacologicaly acceptable acid addition salts thereof.
  • other acceptable acid addition salts are the hydrobromide, the hydroiodide, the bisulfate, the phosphate, the acid phosphate, the lactate, the citrate, the tartrate, the salicylate, the succinate, the maleate, the gluconate and the like.
  • derivatives of apomorphine include but are not limited to apomorphine N-glucuronide, apomorphine O-glucuronide, apomorphine O-sulfate, apomorphine N-sulfate, norapomorphine, norapomorphine O-glucuronide, norapomorphine N-glucuronide, norapomorphine O-sulfate and norapomorphine N- sulfate as disclosed in U.S. Patent No.
  • diacylapmorphines including diacetylapomorphine, diisobutrylapomorphine, dicyclohexanoylapomorphine, divaleroylapomorphine, dipivaloylapomorphine, di-n-butyrylapomorphine, dicyclopropanoylapomorphine, dicyclobutanoylapomorphine and dicyclopentanoylapomorphine as disclosed in U.S. Patent No. 4,080,456.
  • dopamine receptor agonists that could be administered according to the process of the present invention include bromocriptine, ropinirole, cabergoline, pramipexole, roxindole and lisuride.
  • Apomorphine or its variants can be administered orally, sublingually, subcutaneously or intranasally. It should be administered at a concentration high enough to promote an erection but at a low enough dose so that vomiting or nausea is not induced.
  • a sublingual or oral dose of an apomorphine should be about 2-10 mg. However, it the apomorphine is administered intranasally the dose should range from about 0.25 to 2 mg (See U.S. Patent No. 6,436,950).
  • Other dopamine receptor agonists can be administered at the following doses: bromocriptine mesylate (Geneva Pharmaceuticals, Broomfield, CO) 2.5-10mg, ropinirole
  • a preferred apomorphine hydrochloride hemihydrate nasal formulation is comprised of the following as percent of total weight (% w/w):
  • a cyclic GMP-specific phosphodiesterase-5 inhibitor such as sildenafil, tadalafil or vardenafil
  • the dose should be according to the recommended manufacturer's recommendations.
  • the dosage of sildenafil is 25 - 100 mg.
  • organic nitrates can be administered in conjunction with a dopamine receptor agonist to promote firmer and more frequent erections.
  • examples of organic nitrates are glycerol trinitrate, amyl nitrite, isosorbide dinitrate, isosorbide-5- mononitrate and erythrityl tetranitrate.
  • Infertility Title To assess the effects of apomorphine hydrochloride delivered as a nasal spray for the treatment of infertility in men caused by hypospermia.
  • Spermatozoa availability comprises the product of the daily testicular production rate and those stored in the extra-gonadal reserve.
  • Hypospermia is defined as a decrease in the seminal fructose, asthenospermia (loss or reduction in motility of the spermatozoa, which causes infertility) and oligospermia (subnormal concentration of spermatozoa). Increase in the number of ejaculations in men with hypospermia, may increase the number of mobile spermatozoa available for fertility that are stored in the extra- gonadal reserve.
  • nasal apomorphine will be given in an in-clinic setting once a week for two months. Patients would be required to attempt multiple ejaculations while masturbating. They must refrain from sexual activity 48 hours before admission into the clinic. Analyses of seminal fluid samples will be obtained and compared to baseline values for ejaculate volume, spermatozoa density, spermatozoa motility and percentage of morphological normal spermatozoa.
  • Study Population 50 males, age 18 years or over, diagnosed with hypospermia and who have been in a heterosexual relationship for at least the past six months.
  • This study will be an open label, in-clinic study involving 50 male patients diagnosed with hypospermia. After a two month baseline analysis of seminal fluid, the patients will take nasal apomorphine in an in-clinic setting once weekly and attempt to achieve multiple ejaculations while performing masturbation. The seminal fluid will be analyzed and compared to the two month baseline values.
  • the patient is a heterosexual male in good health and age 18 years or over;
  • the patient has a diagnosis of hypospermia based on seminal fluid analysis over a two month period; o The patient has normal nasal mucosa;
  • IIEF International Index of Erectile Function Questionnaire
  • Visit 1 Screening The study procedures will be explained to each patient and each patient will be required to sign an Informed Consent Form. The patient will undergo the following screening assessments:
  • Visit 2-9 In-clinic Baseline Evaluations: A total of eight visits, one visit per week for two months. Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic:
  • Visits 2-17 Nasal Apomorphine: A total of sixteen visits, one visit per week for two months. Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic:
  • the primary efficacy endpoint would be the change from baseline in ejaculate volume, spermatozoa density, spermatozoa motility and percentage of morphological normal spermatozoa.
  • the secondary efficacy endpoint would be the following:
  • Spermatozoa availability comprises the product of the daily testicular production rate and those stored in the extra-gonadal reserve.
  • Hypospermia is defined as a decrease in the seminal fructose, asthenospermia (loss or reduction in motility of the spermatozoa, which causes infertility) and oligospermia (subnormal concentration of spermatozoa). Increase in the number of ejaculations in men with hypospermia, may increase the number of mobile spermatozoa available for fertility that are stored in the extra- gonadal reserve. Diagnosis of hypospermia is confirmed with baseline analysis over a two month period.
  • Peak age of fertility in the female is 25 years. There is a decline in both female and male reproductive performance after age 25 years. This study will recruit patients in the height of their sexual and reproductive performance in both study groups. For nulliparous women of this age the average time during which unprotected intercourse occurs until conception is 5.3 months.
  • nasal apomorphine or placebo will be given in an at-home setting for a six month period. The average patients would be required to attempt sexual intercourse frequently during the partner's ovulation period.
  • Study Population 150 males, age 20-30 years, diagnosed with hypospermia and who have been in a heterosexual relationship for at least the past six months and are trying to conceive.
  • This study will be an double blind, parallel, placebo controlled, at- home study involving 150 male patients diagnosed with hypospermia who are seeking medical assistance for infertility. After a two month baseline analysis of seminal fluid, the patients will take nasal apomorphine or placebo in an at-home setting once weekly for six months.
  • the patient is a heterosexual male in good health and age 20 to 30. • Female partners in good health and age 20 to 30.
  • the patient has a diagnosis of hypospermia based on seminal fluid analysis over a two month period;
  • IIEF International Index of Erectile Function Questionnaire
  • Visit 2 In-clinic: Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic:
  • Visits 3-8 Nasal Apomorphine: A total of 6 visits, one visit per month for six months. Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic for each visit:
  • the primary efficacy endpoint would be the rate of conception of the nasal apomorphine group versus the placebo.
  • the secondary efficacy endpoint would be the following:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'utilisation d'agents permettant d'améliorer l'éjaculation permet de traiter des hommes présentant des spermatogrammes présentant un faible décompte de spermatozoïdes pour favoriser la fertilisation d'un ovule. Des agents d'amélioration de l'éjaculation sont utilisés pour favoriser des éjaculations plus fréquentes, ce qui permet de produire plus de sperme, et ainsi d'accroître la probabilité de fertilisation de l'ovule, puisque plus de sperme est disponible. La fertilisation de l'ovule peut s'effectuer par un rapport sexuel avec une femme, ou par fertilisation in vitro ou par insémination artificielle. Des exemples d'agents d'amélioration de l'éjaculation sont des agonistes du récepteur de la dopamine, des inhibiteurs spécifiques de la phosphodiestérase-5 (PDE-V), des nitrates organiques, de l'arginine L et des combinaisons de ceux-ci. Les agonistes du récepteur de la dopamine comprennent de l'apomorphine, un sel d'ajout pharmaceutiquement acceptable de l'apomorphine, et un dérivé de l'apomorphine, de la bromocriptine, du ropinirole, de la cabergoline, du pramipexole, du roxindole et du lisuride. Des exemples d'inhibiteurs de PDE-V comprennent le sildenafil, le tadalafil et le vardenafil. Des exemples de nitrates organiques comprennent du trinitrate de glycérol, du nitrure d'amyle, du dinitrate d'isosorbide, de l'isosorbide-5-mononitrate et du tétranitrate d'érythrityle.
PCT/US2004/002400 2003-01-31 2004-01-27 Methode et compositions pour le traitement de l'infertilite masculine WO2004069167A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44403203P 2003-01-31 2003-01-31
US60/444,032 2003-01-31

Publications (2)

Publication Number Publication Date
WO2004069167A2 true WO2004069167A2 (fr) 2004-08-19
WO2004069167A3 WO2004069167A3 (fr) 2004-10-28

Family

ID=32850819

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/002400 WO2004069167A2 (fr) 2003-01-31 2004-01-27 Methode et compositions pour le traitement de l'infertilite masculine

Country Status (1)

Country Link
WO (1) WO2004069167A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015715A1 (fr) * 2004-08-06 2006-02-16 Bayer Healthcare Ag Nouvelles utilisations de derives d'imidazotriazinones substituees par 2-phenyle
EP2120570A1 (fr) * 2007-02-12 2009-11-25 DMI Biosciences, Inc. Traitement destiné à une éjaculation précoce et aux troubles de l'érection comorbides
EP2324886A1 (fr) 2005-07-29 2011-05-25 Concert Pharmaceuticals Inc. Nouveaux analogues deutériés de tadalafil

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6338862B1 (en) * 2001-03-26 2002-01-15 Sarfaraz K Niazi Composition and method of use in treating sexual dysfunction using cGMP-specific phosphodiesterase type 5 inhibitors
US6506765B2 (en) * 2000-04-07 2003-01-14 Tap Pharmaceutical Products, Inc. Apomorphine derivatives and methods for their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506765B2 (en) * 2000-04-07 2003-01-14 Tap Pharmaceutical Products, Inc. Apomorphine derivatives and methods for their use
US6338862B1 (en) * 2001-03-26 2002-01-15 Sarfaraz K Niazi Composition and method of use in treating sexual dysfunction using cGMP-specific phosphodiesterase type 5 inhibitors

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015715A1 (fr) * 2004-08-06 2006-02-16 Bayer Healthcare Ag Nouvelles utilisations de derives d'imidazotriazinones substituees par 2-phenyle
EP2324886A1 (fr) 2005-07-29 2011-05-25 Concert Pharmaceuticals Inc. Nouveaux analogues deutériés de tadalafil
EP2120570A1 (fr) * 2007-02-12 2009-11-25 DMI Biosciences, Inc. Traitement destiné à une éjaculation précoce et aux troubles de l'érection comorbides
EP2120570B1 (fr) * 2007-02-12 2012-05-16 DMI Biosciences, Inc. Traitement destiné à une éjaculation précoce et aux troubles de l'érection comorbides
EP2486927A1 (fr) * 2007-02-12 2012-08-15 DMI Biosciences, Inc. Traitment Destiné Á Une Éjaculation Précoce Et Aux Troubles De L'Érection Comorbides

Also Published As

Publication number Publication date
WO2004069167A3 (fr) 2004-10-28

Similar Documents

Publication Publication Date Title
KR100374924B1 (ko) 남성발기기능장애를회복시키고진단하기위한설하용량형
RU2239424C2 (ru) Композиция для модулирования сексуальной реакции человека
US6323211B1 (en) Compositions and methods for treating sexual dysfunctions
KR101497509B1 (ko) 트라마돌의 부작용을 감소시키는 방법
US20090318469A1 (en) Use of Flibanserin for the Treatment of Sexual Disorders in Females
NO342986B1 (no) Farmasøytiske sammensetninger omfattende testosteron ved behandlingen av kvinnelig seksuell dysfunksjon
AU749703B2 (en) Combination therapy for modulating the human sexual response
US20230181583A1 (en) Treating liver disorders with an ssao inhibitor
JP2008519810A (ja) 顔面紅潮の治療のためのｓミルタザピン
CA2351897A1 (fr) Utilisation de secretagogues d'hormone de croissance pour le traitement de la perte de performance physique
WO2004069167A2 (fr) Methode et compositions pour le traitement de l'infertilite masculine
JP2002518435A (ja) 女性の性機能不全の治療または改善のための方法および組成物
Kjærgaard et al. Prazosin, an adrenergic blocking agent inadequate as male contraceptive pill
US6214849B1 (en) Use of nicorandil in treatment of sexual dysfunction or for enhancement of sexual function in mammals including humans
CA2973087C (fr) Formulations pharmaceutiques a base de xanthine ou de derives de xanthine pour le traitement de la maladie de dupuytren
US20100311785A1 (en) Combination Therapy For Modulating The Human Sexual Response
US20030152643A1 (en) Combination of an alpha-adrenergic antagonist and a nitrogen oxide donor for treating female sexual dysfunctions
Gupta et al. Phenelzine-induced sexual dysfunction treated with sildenafil
TW202313017A (zh) 治療自發性震顫的方法
Steggall et al. Erectile dysfunction: Attendance and management at an East London clinic
US20090247498A1 (en) Pharmaceutical Compositions Primarily for the Treatment and Prevention of Genitourinary Infections and their Extragenital Complications

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
122 Ep: pct application non-entry in european phase