WO1998040076A1 - Compositions de traitement des troubles du climatere comprenant des substrats et/ou des donneurs de monoxyde d'azote synthetase, combines avec des antagonistes partiels d'oestrogene - Google Patents

Compositions de traitement des troubles du climatere comprenant des substrats et/ou des donneurs de monoxyde d'azote synthetase, combines avec des antagonistes partiels d'oestrogene Download PDF

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Publication number
WO1998040076A1
WO1998040076A1 PCT/US1998/004586 US9804586W WO9840076A1 WO 1998040076 A1 WO1998040076 A1 WO 1998040076A1 US 9804586 W US9804586 W US 9804586W WO 9840076 A1 WO9840076 A1 WO 9840076A1
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nitric oxide
administered
composition
mammal
partial estrogen
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PCT/US1998/004586
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English (en)
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Kristof Chwalisz
Robert E. Garfield
Christa Hegele-Hartung
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Schering Aktiengesellschaft
Board Of Regents The University Of Texas System
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Priority to AU66942/98A priority Critical patent/AU6694298A/en
Publication of WO1998040076A1 publication Critical patent/WO1998040076A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/28Compounds containing heavy metals
    • A61K31/295Iron group metal compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/26Iron; Compounds thereof

Definitions

  • This invention relates to a method for the treatment and prevention of climacteric disorders such as hot flushes, abnormal clotting patterns, urogenital discomfort, increased incidence of cardiovascular diseases, etc., associated with the reduction in ovarian function in middle-aged women during menopause, and climacteric disorders such as increased incidence of cardiovascular diseases, etc., which may be associated with the continuous reduction in serum testosterone levels in men as they age, and becomes problematic in middle-age, with a nitric oxide synthase substrate (e.g. , L-arginine), a nitric oxide donor or both, in combination with a partial estrogen antagonist (e.g. , raloxifen).
  • a nitric oxide synthase substrate e.g. , L-arginine
  • a nitric oxide donor e.g. , nitric oxide donor or both
  • a partial estrogen antagonist e.g. , raloxifen
  • HRT such as estrogen treatment
  • Estrogens have also been shown to improve mood and psychological well-being in postmenopausal women and they also prevent atrophic changes in the genital tract. Estrogens have been shown to affect arterial tone and this may help to explain the reduction in hot flushes observed in postmenopausal women with estrogen therapy.
  • unopposed estrogen therapy has been associated with endometrial hyperplasia and endometrial cancer.
  • progesterone to estrogen HRT decreases the risk of endometrial cancer and even reverses endometrial hyperplasia.
  • progestins are not without their own untoward side effects. Progestins may oppose the beneficial effects of estrogens on the cardiovascular system by inducing an atherogenic profile in plasma lipids. Moreover, persistent irregular or withdrawal bleedings are common with continuous or sequentially combined estrogen-progestin therapy. In any event, modern HRT now employs combinations of an estrogen and a progestin as in the general case for most contraceptives.
  • nitric oxide is produced by endothelial cells and that it is involved in the regulation of vascular tone, platelet aggregation, neurotransmission and immune activation (Furchgott and Zawadzki, 1980; Moncada, Palmer and Higgs, 1991; Ignarro, 1991).
  • Nitric oxide is an important mediator of relaxation of the muscular smooth muscle (Montada, Palmer and Higgs, 1991) and was formerly known as EDRF (endo- thelin-derived relaxing factor) (Furchgott and Zawadzki, 1980; Moncada, Palmer and Higgs, 1991).
  • Nitric oxide is synthesized by the oxidative deamination of a guanidino nitrogen of L-arginine by at least three different isoforms of a flavin-containing enzyme, nitric oxide synthase (Montada, Palmer and Higgs, 1991).
  • nitric oxide has been shown to be competitively inhibited by analogues of L-arginine; NG-nitro-L-arginine methyl ester (L-NAME), NG-monoethyl-L-arginine (LMMA), N-iminoethyl-L-ornithine (L-NIO), L-monomethyl-L-arginine (L-NNMA) and L-NG- methylarginine (LNMA) and Nw-nitro-L-arginine (L-NA).
  • L-NAME NG-nitro-L-arginine methyl ester
  • LMMA NG-monoethyl-L-arginine
  • L-NIO N-iminoethyl-L-ornithine
  • L-NNMA L-monomethyl-L-arginine
  • LNMA L-NG- methylarginine
  • L-NA Nw-nitro-L-arginine
  • Nitric oxide elevates levels of cGMP (1 ,3 ,5-cyclic guanosine monophosphate) within the vascular smooth muscle to produce relaxation and to reduce blood vessels tone (Moncada, Palmer and Higgs, 1991). Nitric oxide binds to heme and thus activates soluble guanylate cyclase (Ignarro, 1991) to increase the cellular content of cGMP. It has long been recognized that nitro vasodilators, such as nitroprusside and nitroglycerin, inhibit vascular smooth muscle contractility to produce relaxation or to reduce vascular tone. These agents have been used since the late 1800's as vasodilators. However, only recently has the mechanism of action of these compounds been realized.
  • Nitro vasodilators are now classified as nitric oxide donors because they are metabolized to release nitric oxide (Moncada, Palmer and Higgs, 1991). The long- used nitrovasodilators may be regarded as substitution therapy for a failing physiological mechanism. Nitric oxide is also produced by macrophages and other immune cells.
  • Nitric oxide synthesis and nitric oxide effector system are thought to be regulated by steroid hormones.
  • cardiovascular diseases in women following menopause which may be related to the decrease in sex steroids and an alteration in nitric oxide.
  • Female steroid hormones have been shown to modulate endothelium-dependent relaxation of vascular smooth muscle by nitric oxide.
  • Estradiol treatment of rats causes increased nit- ric oxide production by vascular tissues, whereas progesterone counteracts this phenomenon (Miller and Van Houtte, 1991). It is well known that pregnancy is associated with an increase in cardiac output and a decrease in the resistance of virtually all the vascular beds in the body.
  • Hot flushes are a primary symptom in menopausal, postmenopausal women and they are relieved by both estrogen and progesterone (Avis et al., 1993).
  • nitric oxide substrates and/or donors alone or in combination with estrogen and progesterone are particularly efficacious for hormone replacement therapy to prevent climacteric symptoms (climacterium) such as atherosclerosis, hypertension, hot flushes, etc. in women.
  • Agonistic antiestrogens exert a combination of effects, both by blocking binding of estrogen to certain estrogen receptors, and at the same time providing agonistic estrogenic effects at other locations.
  • EP 0441 119 A2 discloses the use of L-arginine in the treatment of hypertension and other vascular disorders. It suggests that the mechanism by which L-arginine is effective for this purpose is because it may be the physiological precursor of "the most powerful endothelial-derived releasing factor, nitric oxide. " The use of L-arginine in combination with other pharmaceutically active agents is not discussed in this publication.
  • this invention relates to a method of treating climacterium (climacteric symptoms) in a male mammal or a non-pregnant female mammal, com- prising administering to a patient in need of such treatment an effective amount of
  • an androgen and/ or aroma- tase inhibitor can also be administered.
  • this invention relates to pharmaceutical compositions comprising an admixture of effective amounts of
  • an androgen and/or aroma- tase inhibitor can also be included. It is thus an object of the invention to provide a method for the prevention and treatment of climacterium (climacteric symptoms) in mammals, e.g., an a pre- or post-menopausal non-pregnant human female, or a human male, suffering from or at risk of developing climacteric symptoms or disorders, such as hot flushes (females) or increased incidence of cardiovascular diseases (both sexes), etc., with a nitric oxide substrate and/or donor, in combination with a partial estrogen antagonist and optionally, a progestin.
  • climacterium climacteric symptoms
  • mammals e.g., an a pre- or post-menopausal non-pregnant human female, or a human male, suffering from or at risk of developing climacteric symptoms or disorders, such as hot flushes (females) or increased incidence of cardiovascular diseases (both sexe
  • HRT hormone replacement therapy
  • HRT hormone replacement therapy
  • a further object is the provision of pharmaceutical compositions useful in practicing the methods of this invention.
  • compositions of this invention treat or prevent climacterium (climacteric symptoms) in a menopausal/postmenopausal female mammal, e.g., a nonpregnant female human, who is manifesting the symptoms thereof or who is a high risk candidate for doing so, e.g., based on rate of bone loss rate, as well as climacteric disorders such as hot flushes, abnormal clotting patterns, uro- genital discomfort, increased incidence of cardiovascular diseases, etc., associated with the reduction in ovarian function in middle-aged women during menopause; and climacteric disorders, such as increased incidence of cardiovascular diseases, etc., in a male mammal, e.g., an aging male human, who is manifesting the symptoms thereof or who is a high risk candidate for doing so, e.g., based on increased blood pres- sure and which may be associated with the continuous reduction in serum testosterone levels, with a nitric oxide synthase
  • nitric oxide synthase substrates e.g., L-arginine, or nitric oxide donors, e.g., sodium nitroprusside, nitroglycerin, glycerin trinitrate, SIN-1, iso- sorbid mononitrate, isosorbid dinitrate and diethylenetriamine/NO (DETA/NO), are useful for ameliorating the symptoms thereof and, in one aspect of the method of this invention, a combination of both are employed.
  • nitric oxide synthase substrates e.g., L-arginine
  • nitric oxide donors e.g., sodium nitroprusside, nitroglycerin, glycerin trinitrate, SIN-1, iso- sorbid mononitrate, isosorbid dinitrate and diethylenetriamine/NO (DETA/NO)
  • a progestational agent is administered concurrently with the nitric oxide substrate and/or nitric acid donor.
  • a progestin can be administered concurrently with the partial estrogen antagonist.
  • an andro- genie agent is administered concurrently with the nitric oxide substrate and/or nitric acid donor and a progestin.
  • an androgen and or aromatase inhibitor can be administered concurrently with the progestin if the latter causes down regulation of testosterone levels.
  • an androgen e.g., testosterone or testosterone ester
  • an aromatase inhibitor e.g., atamestane
  • the method aspect of this invention and the pharmaceutical composition aspect of this invention employ (a) either or both of a nitric oxide donor (e.g. , nitroglycerin) and a nitric oxide synthase substrate (e.g., L-arginine), and (b) a partial estrogen antagonist (e.g., raloxifen), and, (c) optionally, a progestin (e.g. , progesterone or norgestrel).
  • a progestin e.g. , progesterone or norgestrel
  • an androgen e.g., testosterone or testosterone ester
  • an aromatase inhibitor e.g., atamestane
  • this invention relates to a method of treating the climacter- ium symptoms in a human mammal, which comprises administering to an individual manifesting the symptoms thereof one or both of a nitric oxide donor, in combination with a partial estrogen antagonist, optionally in combination with a progestin, in amounts effective to ameliorate the symptoms thereof.
  • the amount of the nitric oxide synthase substrate, nitric oxide donor or both administered is effective to, respectively, either raise the blood level of circulating L-arginine in a female to whom the composition is administered to at least about 10 - 50 nmole above the normally 50 - 100 nmolar circulating levels or raise nitric oxide donor levels to about 1 - 1000 nmolar; the amount of partial estrogen antagonist administered is bioequivalent to approximately 1 - 200 mg per day of raloxifen; and the amount of progestational agent (progestin) optionally administered is bioequivalent to 50 - 300 mg of injected progesterone.
  • progestational agent progestin
  • this invention relates to a method of treating the climacterium symptoms in a male mammal, which comprises administering to an individual manifesting the symptoms thereof one or both of a nitric oxide donor, in combi- nation with a partial estrogen antagonist, optionally in combination with a progestin, in amounts effective to ameliorate the symptoms thereof.
  • the amount of the nitric oxide synthase substrate, nitric oxide donor or both administered is effective to, respectively, either raise the blood level of circulating L-arginine in a male to whom the composition is administered to at least about 10 - 50 nmole above the normally 50 - 100 nmolar circulating levels or raise nitric oxide donor levels to about 1 - 1000 nmolar; the amount of partial estrogen antagonist administered is bioequivalent to approximately 1 - 200 mg per day of raloxifen; the amount of progestational agent (progestin) optionally administered is bioequivalent to 50 - 300 mg of injected progesterone.
  • an androgen and an aromatase inhibitor may be administeredn with a progestin, whereby the amount of androgen and/or aromatase inhibitor is effective to raise blood serum total testosterone level to between about 100 and about 600 mg/dl.
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising effective amounts of at least one of the nitric oxide synthase substrate and a nitric oxide donor, in combination with a partial estrogen antagonist, optionally in further combination with a progestin.
  • the progestin may optionally be administered further in combinations with an androgen and/or an aromatase inhibitor.
  • the amount of the nitric oxide synthase substrate, a nitric oxide donor or both per unit dosage is effective to, respectively, either raise the blood level of circulating
  • L-arginine to at least about 10 - 50 nmole above the normally 50 - 1000 nmolar circulating levels or raise the nitric oxide donor levels to about 1 to 1000 nmolar; the amount of partial estrogen antagonist per unit dosage is bioequivalent to approximately 1 - 200 mg per day of raloxifen; the optional progestational agent (progestin) per unit dosage is bioequivalent to 50 - 300 mg of injected progesterone.
  • the optional androgen and/or aromatase inhibitors per unit dosage is effective to raise blood serum total testosterone levels to between about 100 and about 600 mg/dl, and/or to raise the endogenous testosterone levels by at least 30% .
  • Examples of dosage ranges of typical NO-substrates and NO-donors are: dose
  • nitric oxide donors e.g. , nitroglycerin
  • a transdermal patch e.g. , Deponit 5/10/T [Schwarz Pharma], Nitroderm TTS 5/Nitroderm TTS 10 [CIBA]
  • orally e.g., Corangin [CIBA], Nitrolingual forte or mitte [Pohl]
  • Typical dosage ranges for partial estrogen agonists are daily dosages bioequivalent to about 0.1 - 600 mg/day, more preferably 1 - 200 mg/day, and most preferably 10 - 100 mg/day of raloxifen ([6-hydroxy-2-(4-hydroxyphenyl)-3-benzothienyl][4-[2-(l- piperidinyl)ethoxy]phenyl]methanon-hydrochloride).
  • Suitable partial estrogen agonists/antagonists and typical dosage ranges include, e.g.: dose tamoxifen ((Z)-N,N-dimethyl-2-[4-(l ,2-di- 1 - 200 mg/day per os pheny 1- 1 -buteny l)phenoxy] ethanamine centchroman ((3R-trans)-3,4-dihydro-2,2-di- 1 - 200 mg/day per os methyl-7-methoxy-3-phenyl-4-[4-[2-(l-pyrroli- dinyl)ethoxy] pheny 1] -2H- 1 -benzopyran) clomiphene citrate 1 - 200 mg/day zuclomiphene citrate 1 - 200 mg/day
  • Still other suitable partial estrogen agonists/antagonists include, e.g., nafoxidin (l-[2- [4-(3,4-dihydro-6-methoxy-2-phenyl-l-naphthalinyl)phenoxy]ethyl]pyrrolidin-hydro- chloride) ; Mer-25 (a- [4- [2-(diethy lamino)ethoxy]phenyl] -4-methoxy-a-pheny lbenzene- thanol); droloxifene (3-hydroxy-tamoxifen) and RU 39411, as well as the dissociated "Jungblut estrogens" ZK 115 776 and ZK 131 712.
  • Typical dosages of progestins, per os, i.m., s.c, or transdermally are daily dosages bioequivalent to 50 - 300 mg of progesterone/day, e.g., an injectable suspension of medroxyprogesterone acetate to provide a weekly dose of thereof of 100 - 1000 mg or tablets or dragees providing an oral dose thereof of 5 - 10 mg/day, an injectable solution of hydroxyprogesterone caproate which provides a weekly dose of
  • Dydrogesterone 10 - 20 mg per day Examples of dosages for typical androgens (per os or transdermally) are: total dose:
  • Testosterone 1-10 preferably 4-6 mg/day transdermal Testosterone esters:
  • Testosterone enanfhate 100-250 mg i.m. every 2 weeks
  • Testosterone cypionate 100-250 mg i.m. every 1-3 weeks
  • Testosterone Testoderm, Alza Pharmaceuticals, testosterone transdermal system, release rate 4 and 6 mg/day, preferably 4 mg/day; testosterone propionate: Testoviron-Depot-250, Schering; testosterone enanthate: Delatestryl; testosterone cypionate: Depo-Testosterone, Upjohn; testoster- one undecanoate: Andriol, Organon; Mesterolon: Proviron 25, Schering.
  • suitable amounts of L-arginine and testosterone are those which produce blood plasma levels of about 50 - 5000 ⁇ molar L-arginine, and about 100 - 600 mg/dl testosterone.
  • suitable dosages of aromatase inhibitors are those which, when administered to a male in conjunction with an NO donor and/or substrate, raise the endogenous testosterone levels by at least 30%.
  • Other aromatase inhibitors can be administered in amounts bioequivalent to 20 - 200 mg/day off atamestane, and optionally can be administered together with an androgen in amounts bioequivalent to 1 - 10 mg of testosterone transdermally.
  • suitable amounts of L-arginine and atamestane (or a bioequivalent of another aromatase inhibitor) are those which produce blood plasma levels of about 50 - 5000 ⁇ molar L-arginine, and are effective to raise the endogenous testosterone levels by at least 30%.
  • Many other examples of compounds in each of the four foregoing categories are well known and can be employed in this invention.
  • the pharmacologically active agents employed in this invention can be administered in admixture with conventional excipients, i.e., pharmaceutically acceptable liquid, semi-liquid or solid organic or inorganic carriers suitable, e.g. , for parental or enteral application and which do not deleteriously react with the active compound in admixture therewith.
  • conventional excipients i.e., pharmaceutically acceptable liquid, semi-liquid or solid organic or inorganic carriers suitable, e.g. , for parental or enteral application and which do not deleteriously react with the active compound in admixture therewith.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, penta- erythritol fatty acid esters, hydroxy mefhylcellulose, polyvinyl pyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifi- ers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances, etc. which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifi- ers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances, etc. which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifi- ers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances, etc. which do not deleteriously react with the active compounds.
  • unit dosage forms e.g. , tablets, dragees or capsules having talc and/or carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch; paniculate solids, e.g., granules; and liquids and semi-liquids, e.g., syrups and elixirs or the like, wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active compound is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • Suitable for oral administration are, inter alia, tablets, dragees, capsules, pills, granules, suspensions and solutions.
  • Each unit dose, e.g. , each tablespoon of liquid or each tablet, or dragee contains, for example, 5 - 5000 mg of each active agent.
  • Solutions for parenteral administration contain, e.g., 0.01 - 1 % of each active agent in an aqueous or alcoholic solution.
  • the nitric oxide substrate and/or donor can be administered as an admixture with an agonistic antiestrogen, and with the optional progestin, androgen and/or aro- matase inhibitor and/or any other optional active agent or as a separate unit dosage form, either simultaneously therewith or at different times during the day from each other.
  • the combination of active agents is preferably administered at least once daily (unless administered in a dosage form which delivers the active agents continuously) and more preferably several times daily, e.g., in 2 to 6 divided doses.
  • the typical dose is about 0.5 to 1000 mg of each active agent, although some less active agents, e.g., L-arginine, require much higher oral dosages, e.g. , 500 to 10,000 mg, and others, e.g., sodium mtroprusside, require lower doses, e.g., 500 - 2,000 ⁇ g/kg/day.
  • Doses for nitroglycerine typically are orally 2.6 mg 2 x daily; sublingually, 0.8 mg, 1 - 4 x daily; and transdermally, 0.2 - 0.5 mg/hr. Since the LD 50 dosages of most of these active agents is known in the prior art, a lower dosage regimen can be initiated and the dosage increased until a positive effect is achieved or a higher dosage regimen can initially be employed, e.g. , in a crisis situation, and the dosages regulated downward as relief from the symptoms is achieved. Combinations of agents can be employed either continuously or sequentially.
  • nitric oxide synthesis with L-NAME significantly elevates blood pressure and reduces fetal weights. Both blood pressure and fetal weights are improved in L-NAME treated rats given a nitric oxide substrate (L-arginine) alone or in combination with progesterone (R-5020). Since nitric oxide is known to control atherosclerosis, L-NAME-treatment is identical with preeclampsia and this condition is associated with other sclerosis and atherosclerosis hypertension is accelerated in climacterium, treatment with nitric oxide substrates and/or nitric oxide donors alone or in combination with estrogens and progesterone has tremendous advantages for climacterium therapy.
  • L-NAME is an inhibitor of nitric oxide synthesis, which is known to increase blood pressure in male mammals. It is known that blood pressure is improved in L-NAME treated rats given a nitric oxide substrate
  • L-arginine is the substrate for nitric oxide synthesis, which is known to reduce blood pressure; therefore, one can deduce that nitric oxide substrates as well as nitric oxide donors will also decrease blood pressure. Since nitric oxide is known to control atherosclerosis, that L-NAME-treatment is identical with preeclamp- sia, which is associated with other sclerosis, and that atherosclerosic hypertension is accelerated in climacterium, treatment with nitric oxide substrates and/or nitric oxide donors in combination with androgens and/or aromatase inhibitors will also have advantages for climacterium therapy.
  • the method of treatment employed in this invention can also be employed for the treatment of hypertension (in both females and males), as an adjuvant in contraceptive therapy, thrombotic disorders, menstrual disorders (dysmenorrhea, functional uterine bleeding), and hemorrhage, etc., following the dosage regime described herein.
  • Example 1 Treatment of Climacterium (Climacteric Symptoms) in a Male
  • a human male (ca 50 years; 80 - 120 kg) displaying the signs of climacterium symptoms, e.g., high blood pressure, administer 0.5 to 40 g of L-arginine per os with 10 to 100 mg/day of raloxifen per os daily, in three divided doses, until the symptoms are ameliorated. Thereafter, administer 0.5 to 10 g of L-arginine and 10 to 25 mg raloxifen daily.
  • Example 2 Treatment of Climacterium (Climacteric Symptoms) in a Male
  • Example 2 To a male comparable to and displaying the same symptoms as Example 1, administer 2 x 5 mg of nitroglycerine per os daily instead of L-arginine.
  • Example 3 Treatment of Climacterium (Climacteric Symptoms) in a Male
  • Example 2 To a male similar to and displaying the same symptoms as Example 1, administer daily 5 to 10 mg of nitroglycerine and 10 to 100 mg of raloxifen transdermally.
  • Example 4 Hormone Replacement Therapy in a Male To a male similar to and displaying the same symptoms as Example 1 , administer daily 0.5 to 20 g of L-arginine in combination with 10 to 100 mg of raloxifen and 50 to 300 mg of progesterone, per os; and 1 to 10 mg of testosterone transdermally.
  • Example 5 Hormone Replacement Therapy in a Male To a male after orchidectomy administer L-arginine 0.5 to 20 g daily and/or a nitric oxide donor, e.g., nitroglycerine at 2 x 2.5 mg daily, in combination with 100 mg of raloxifen and 150 mg of norgestrel per day, with one or more of the following: an androgen, e.g., transdermal testosterone at 4 mg/day or testosterone propionate at 250 mg i.m. 2 - 3 times/week, and/or an aromatase inhibitor, e.g., atamestane at 20 to 200 mg/day.
  • an androgen e.g., transdermal testosterone at 4 mg/day or testosterone propionate at 250 mg i.m. 2 - 3 times/week
  • an aromatase inhibitor e.g., atamestane at 20 to 200 mg/day.
  • the sex steroids and/or aromatase inhibitor are to be given either continuously with L-arginine and/or a nitric oxide donor and raloxifen, or sequentially.
  • Example 6 Treatment of Climacterium (Climacteric Symptoms) in a female
  • a nonpregnant human female (ca 60 years; 50 - 90 kg) displaying the signs of menopause or postmenopausal symptoms, e.g., amenorrhea, hot flushes, etc., administer 0.5 to 20 g of L-arginine and with 10 to 100 mg/day of raloxifen per os daily in three divided doses until the symptoms are ameliorated. Thereafter, administer 0.5 to 5 g of L-arginine and 10 to 100 mg raloxifen daily.
  • Example 7 Treatment of Climacterium (Climacteric Symptoms) in a Female
  • Example 6 To a female comparable to and displaying the same symptoms as Example 6, administer daily 5 - 10 mg of nitroglycerine transdermally instead of L-arginine.
  • Example 8 Treatment of Climacterium (Climacteric Symptoms) in a Female
  • Example 6 To a female comparable to and displaying the same symptoms as Example 6, administer daily 2 x 2.5 mg of nitroglycerine per os daily instead of L-arginine.
  • Example 9 Treatment of Climacterium (Climacteric Symptoms) in a Female
  • Example 6 To a female similar to and displaying the same symptoms as Example 6, administer daily 0.5 to 20 g of L-arginine in combination with a partial estrogen agonist (e.g., raloxifen) 100 mg daily and a progestin (e.g. , norgestrel) 150 mg per day.
  • a partial estrogen agonist e.g., raloxifen
  • a progestin e.g. , norgestrel
  • Example 10 Treatment of Climacterium (Climacteric Symptoms) in a Female
  • Example 6 To a female similar to and displaying the same symptoms as Example 6, administer daily 2 x 5 mg nitroglycerine transdermally in combination with a partial estrogen agonist (e.g., raloxifen) 100 mg daily and a progestin (e.g., norgestrel) 150 mg per day.
  • a partial estrogen agonist e.g., raloxifen
  • a progestin e.g., norgestrel
  • HRT Hormone Replacement Therapy
  • Example 6 To a female similar to and displaying the same symptoms as Example 6, administer daily 0.5 to 20 g of L-arginine in combination with a partial estrogen agonist (e.g., raloxifen) 100 mg daily.
  • a partial estrogen agonist e.g., raloxifen
  • HRT Hormone Replacement Therapy
  • Example 6 To a female comparable to and displaying the same symptoms as Example 6, administer L-arginine 0.5 to 20 g daily and/or a nitric oxide donor (e.g., nitro- glycerine, 2 x 2.5 mg) daily in combination with a partial estrogen agonist (e.g., raloxifen) 100 mg daily and a progestin (e.g., norgestrel, at 150 mg per day).
  • the partial estrogen agonist is to be given either continuously with L-arginine and/or a nitric oxide donor, or sequentially, while the progestin is taken for only 6 - 12 days per month.
  • L-arginine 0.5 to 20 g daily and/or a nitric oxide donor, e.g. , nitroglycerine at 2 x 2.5 mg daily, in combination with 100 mg of raloxifen and 150 mg of norgestrel per day.
  • the progestin is to be given either continuously with L-arginine and/or a nitric oxide donor and raloxifen, or sequentially.

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Abstract

Les symptômes du climatère sont améliorés par l'administration au patient nécessitant un tel traitement d'un substrat de monoxyde d'azote et/ou d'un donneur de monoxyde d'azote, combiné(s) à un antagoniste partiel d'oestrogène, et éventuellement à une progestine.
PCT/US1998/004586 1997-03-10 1998-03-10 Compositions de traitement des troubles du climatere comprenant des substrats et/ou des donneurs de monoxyde d'azote synthetase, combines avec des antagonistes partiels d'oestrogene WO1998040076A1 (fr)

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AU66942/98A AU6694298A (en) 1997-03-10 1998-03-10 Compositions for the treatment of climacteric disorders with nitric oxide synthase substrates and/or donors, in combination with partial estrogen anta gonists

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US81291097A 1997-03-10 1997-03-10
US08/812,910 1997-03-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7030157B2 (en) 2001-07-31 2006-04-18 Pfizer Inc. Pharmaceutical compositions, kits and methods comprising combinations of estrogen agonists/antagonists, estrogens and progestins
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013800A1 (fr) * 1993-11-16 1995-05-26 Schering Aktiengesellschaft Traitement des troubles climateriques avec des substrats et/ou donneurs de synthase d'oxyde nitrique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013800A1 (fr) * 1993-11-16 1995-05-26 Schering Aktiengesellschaft Traitement des troubles climateriques avec des substrats et/ou donneurs de synthase d'oxyde nitrique

Non-Patent Citations (2)

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Title
BIOLOGICAL ABSTRACTS, vol. 65, Philadelphia, PA, US; abstract no. 14408, KAUPPILA A ET AL: "TAMOXIFEN AND NATURAL PROGESTERONE AS SUPPLEMENTS TO LOW-DOSE POSTMENOPAUSAL ESTROGEN THERAPY" XP002066788 *
GYNECOL OBSTET INVEST, 25 (1). 1988. 58-65. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US9132089B2 (en) 2000-08-30 2015-09-15 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US7030157B2 (en) 2001-07-31 2006-04-18 Pfizer Inc. Pharmaceutical compositions, kits and methods comprising combinations of estrogen agonists/antagonists, estrogens and progestins

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