CA2243245A1 - Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors - Google Patents
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Abstract
The invention provides a method for the treatment and prevention of urinary incontinence in mammals, e.g., human males and females, especially nonpregnant female mammals, by administering a nitric oxide synthase substrate and/or nitric oxide donor, alone or in combination with an estrogenic agent and/or a progestational substance, with or without supplementation with an alpha-adrenergic agonist, beta-adrenergic receptor blocking agent, cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug, as well as pharmaceutical compositions useful in practicing the methods of this invention.
Description
CA 0224324~ 1998-07-16 TREATMENT OF URINARY INCONTINENCE WITH NITRIC OXIDE
SYNTHASE SUBSTR~TES AND/OR NITRIC OXIDE DONORS
Backqround o~ the Invention This invention relates to a method for the treatment and/or pre-vention of urinary incontinence usually in women during the post meno-pausal period or during pregnancy or postpartum with a nitric oxide syn-thase substrate ~e.g., L-arginine), a nitric oxide donor or both, alone or in combination with estrogen and/or progestin (e.g., hormone replace-ment therapy ~HRT)), or with supplementation with alpha-adrenergic agonists, beta-adrenergic receptor blocking agents, cholinergic-receptor-blocking compounds and/or cholinergic-receptor-stimulating drugs.
Women in industrialized nations can now expect to spend over a third of their lives in the postmenopausal period. One of the major prob-ierns women face during the climacteric period is urinary incontinence.
Urinary incontinence is aiso a problem during pregnancy or postpartum.
In pregnancy, this condition may be related to altered steroid and nitric oxide levels rather than the physical presence and pressure of the grow-ing fetus.
~ 20 Urinary incontinence is the inability of the biadder to retain urine resulting in urine loss as a consequence of either urge (urge i~conti-~ nence), or physical or mental stress (stress incontinence). There have been many studies of the effects of estrogen and progesterone therapy for incontinence (Barbieri, 1 994; Sartori et al., 1 99~ . These studies 2~ indicate that estrogen and/or progesterone replacement ther~py can par-CA 0224324~ 1998-07-16 tially alleviate incontinence in some women (Elia and Bergman, 1993;
Sartori et al, 1995). However, there is no conclusive evidence that hormone therapy alone is sufficient to cure incontinence (Cardozo and Kelleher, 1995). Some studies have shown that hormone replacement therapy helps prevent postmenopausal recurrent urinary tract infections and improves urinary incontinence (Cardozo and Kelleher, 1994). Other studies suggest hormone supplementation with alpha-adrenergic agon-- ists, beta-adrenergic-receptor blocking agents, cholinergic-receptor-blocking compounds and cholinergic-receptor-stimulating drugs (Barbieri, 1 0 91 94; Brandeis and Resnick, 1 9g2).
The normal bladder fills at a physiological rate dictated by the function of the kidneys and the bladder can accommodate large volumes of urine. This phenomenon has been attributed to physical properties of the bladder as well as a neural inhibitory system. The inhibitory mechanism may involve inhibition of parasympathetic activity or an increase in sympathetic tone to produce detrusor relaxation and allow filling to occur. During filling the outlet neck of the bladder and urethra are contracted preventing leakage. Voiding or micturition is characterized by a relaxation of the outlet neck and the urethra followed by contraction of the detrusor muscle. ~he process begins again when the bladder is empty and the detrusor relaxes and the outlet neck and urethra contract to seal off the bladder and maintain continence.
It is now well known that HRT (hormone replacement therapy), such as estrogen treatment, improves or reverses the adverse effects of the decrease of sex steroid secretion by the ovaries during menopause.
Estrogens have also been shown to improve mood and psychological well-being in postmenopausal women and they also prevent atrophic changes in the urogenital tract. Estrogens have been shown to effect arterial tone and this may help to explain the reduction in hot flushes observed in postmenopausal women with estrogen therapy. On the other hand, unopposed estrogen therapy has been associate~l-wjth endometrial hyperplasia and endometrial cancer. Many studies have shown that the addition of progesterone to estrogen HRT decreases the risk of endometrial cancer and even reverses endometrial hyperplasia.
SYNTHASE SUBSTR~TES AND/OR NITRIC OXIDE DONORS
Backqround o~ the Invention This invention relates to a method for the treatment and/or pre-vention of urinary incontinence usually in women during the post meno-pausal period or during pregnancy or postpartum with a nitric oxide syn-thase substrate ~e.g., L-arginine), a nitric oxide donor or both, alone or in combination with estrogen and/or progestin (e.g., hormone replace-ment therapy ~HRT)), or with supplementation with alpha-adrenergic agonists, beta-adrenergic receptor blocking agents, cholinergic-receptor-blocking compounds and/or cholinergic-receptor-stimulating drugs.
Women in industrialized nations can now expect to spend over a third of their lives in the postmenopausal period. One of the major prob-ierns women face during the climacteric period is urinary incontinence.
Urinary incontinence is aiso a problem during pregnancy or postpartum.
In pregnancy, this condition may be related to altered steroid and nitric oxide levels rather than the physical presence and pressure of the grow-ing fetus.
~ 20 Urinary incontinence is the inability of the biadder to retain urine resulting in urine loss as a consequence of either urge (urge i~conti-~ nence), or physical or mental stress (stress incontinence). There have been many studies of the effects of estrogen and progesterone therapy for incontinence (Barbieri, 1 994; Sartori et al., 1 99~ . These studies 2~ indicate that estrogen and/or progesterone replacement ther~py can par-CA 0224324~ 1998-07-16 tially alleviate incontinence in some women (Elia and Bergman, 1993;
Sartori et al, 1995). However, there is no conclusive evidence that hormone therapy alone is sufficient to cure incontinence (Cardozo and Kelleher, 1995). Some studies have shown that hormone replacement therapy helps prevent postmenopausal recurrent urinary tract infections and improves urinary incontinence (Cardozo and Kelleher, 1994). Other studies suggest hormone supplementation with alpha-adrenergic agon-- ists, beta-adrenergic-receptor blocking agents, cholinergic-receptor-blocking compounds and cholinergic-receptor-stimulating drugs (Barbieri, 1 0 91 94; Brandeis and Resnick, 1 9g2).
The normal bladder fills at a physiological rate dictated by the function of the kidneys and the bladder can accommodate large volumes of urine. This phenomenon has been attributed to physical properties of the bladder as well as a neural inhibitory system. The inhibitory mechanism may involve inhibition of parasympathetic activity or an increase in sympathetic tone to produce detrusor relaxation and allow filling to occur. During filling the outlet neck of the bladder and urethra are contracted preventing leakage. Voiding or micturition is characterized by a relaxation of the outlet neck and the urethra followed by contraction of the detrusor muscle. ~he process begins again when the bladder is empty and the detrusor relaxes and the outlet neck and urethra contract to seal off the bladder and maintain continence.
It is now well known that HRT (hormone replacement therapy), such as estrogen treatment, improves or reverses the adverse effects of the decrease of sex steroid secretion by the ovaries during menopause.
Estrogens have also been shown to improve mood and psychological well-being in postmenopausal women and they also prevent atrophic changes in the urogenital tract. Estrogens have been shown to effect arterial tone and this may help to explain the reduction in hot flushes observed in postmenopausal women with estrogen therapy. On the other hand, unopposed estrogen therapy has been associate~l-wjth endometrial hyperplasia and endometrial cancer. Many studies have shown that the addition of progesterone to estrogen HRT decreases the risk of endometrial cancer and even reverses endometrial hyperplasia.
3~; However, progestins are not without their own untoward side effects.
CA 0224324~ 1998-07-16 Progestins may reinforce the beneficial effects of estrogens on the cardiovascular system. Modern HRT now employs combinations of an estrogen and a progestin as in the general case for most contraceptives.
One of the most exciting recent advances in biology and medicine is the discover;r that nitric oxide is produced by endothelial cells and ~hat it is invoived in the regulation of vascular tone, platelet aggre~a-tion, neurotransmission and immune activation ~Furchgott and Zaw~d-zki, 1980; Moncada, Palmer and Hig9s, 1991; Ignarro, 1991). Nitric oxide is an important mediator of relaxation of the muscu~ar smooth m~scle (Montada, Palmer and Higgs, 1991) and was formerly known as E~RF (endothelin-derived relaxing factor) (Furchgott and Zawadzki, 1 980; 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, 19~1). Synthesis of nitric oxide has been shown to be competitively inhibited by analogues of L-argi-nine; NG-nitro-L-arginine methyl ester lL-NAME), NG-monoethyl-L-argi-nine (LMMA), N-iminoethyl-L-ornithine (L-NIO), L-monomethyl-L-arginine (L-INNMA) and L-NG-methylarginine (LNMA) and Nw-nitro-L-arginine (L-INA~.
Nitric oxide elevates levels of cGMP (1,4,5-cyclic guanosine monophosphate) within the vascular smooth muscle to produce relaxa-tiOI1 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 nitrovasodilators, such as nitro-prusside and nitroglycerin, inhibit vascular smooth muscle contractility to produce relaxation or to reduce vascular tone. These agents have been used since the late 1 980s as vasodilators. However, only recently has the mechanism of action of these compounds been realized. Nitrovasodila-tors are now classified as nitric oxide donors because they aFe metabo-lized or spontaneously 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.
CA 0224324~ 1998-07-16 There is a substantial body of evidence from animal experiments that a deficiency in nitric oxide contributes to the pathogenesis of a number of diseases, including hypertensionJ atherosclerosis and diabe-tes (Montada, Palmer and Higgs, 1991). There are many recent studies showing that the inhibitibn of nitric oxide synthase dramatically increa-ses blood pressure.
Nitric oxide may also be involved in accommodation of the bladder during filling or relaxation of the bladder neck and urethra during voiding. The bladder is innervated by nonadrenergic and noncholinergic nerves (NANC nerves) and nitric oxide is thought to be a neurotransmit-ter in these types of nerves (Ehren et al, 1994; Andersson and Persson, 199~; Smet, et al, 1994; Lee et al., 1994). There is evidence showing that nitric oxide containing nerves are localized to a greater extent in the outlet region and urethra compared to the detrusor (Andersson and Per-sson, 1994; Lee et al., 1994). However, whether nitric oxide is in-volved in voiding by reiaxing the urethra and bladder neck or in bladder filling by relaxing the detrusor is unclear. There have been few studies -of the effects of nitric oxide donors on either the urethra, bladder neck or detrusor muscle.
Summarv of the Invention Our studies suggest that nitric oxide donors effectively relax the detrusor muscle (see below). Further our studies of the uterus, cervix and vascular tissues suggest that the steroid hormones control nitric oxide synthesis, release and the effector system for nitric oxide (Chwa-lisz and Garfield, 1994). Therefore, we have discovered that the sub-strate for nitric oxide, nitric oxide donors, or both in combination with steroid hormones (estrogen and/or ~rogesterone) are useful for treat-ment and prevention of urinary or urethra incontinence.
It is an object of the invention to provide a method for the treatment and prevention of urinary incontinence with a nitriG-oxide substrate and/or donor in mammals, e.g., human males and females, especially nonpregnant female mammals.
CA 0224324~ 1998-07-16 -5'984 - PCT/US97/00795 It is another object of the invention to provide a method for treatment and prevention of urinary incontinence with a nitric oxide substrate and/or donor in pregnant or postpartum female mammals.
It is a further object of the invention to provide a method for treatment and prevention of urinary incontinence with a n;tric oxide sub-strate and/or donor in which an estrogenic agent in combination with a nitric oxide substrate and/or donor is used for urinary incontinence in bo~h nonpregnant or pregnant female mammais.
It is a further object of the invention to provide a method for treatment and prevention of urinary incontinence with a nitric oxide sub-stri~te and/or donor in which a partial estrogenic agent (e.g. raloxifen) in combination with a nitric oxide substrate and/or donor is used for uri-nary incontinence in both nonpregnant or pregnant femaie mammals.
In another aspect of this invention, a progestational agent is used in oombination with a nitric oxide substrate and/or nitric oxide donor for treatment and prevention of urinary incontinence in female mamma~s.
In a further aspect of this invention, an estrogen and a progestin are used in combination with a nitric oxide substrate and/or nitric oxide donor for the treatment and prevention of urinary incontinence in female mammals.
It is another object of this invention to provide a method for the treatment and prevention of urinary incontinence with a nitric oxide sub-strate and/or nitric oxide substrate alone or in combination with an estrogenic agent and/or a progestational substance, and with or without supplementation with an alpha-adrenergic agonist, beta-adrenergic receptor blocking agent, cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug.
A further object is to provide pharmaceutical compositions useful in practicing the methods of this invention. Upon further study of the specification and appended claims, further aspects, objects and advan-tages of this invention will become apparent to those skilled in the art.
Thus, in a method aspect, this invention relates to a method of treating urinary incontinence in a mammal, e.g., nonpregnant or preg-nant female mammal, which comprises administering to an individual manifesting the symptoms thereof one or both of a nitric oxide sub-CA 0224324~ 1998-07-16 WO 97/25984 . PCTIUS97/0079S
strate and a nitric oxide donor, alone or in combination with an estrogen or a progestin, or both, and with or without supplementation with an alpha-adrenergic agonist, a beta adrenergic receptor blocking agent, a cholinergic-receptor blocking compound or a cholinergic-receptor stimu-lating drug, all in amounts effective to ameliorate the symptoms thereof;
typically, the amount of the nitric oxide synthase substrate and nitric oxide donor or both is effective to increase urinary continence by raising the blood level of circulating L-arginine in a female to whom the compo-sition is administered to at least 10 to 500 ~mole above the normally 50 to 1000 ,umole circulating levels, or to raise nitric oxide donor levels to -about 10 nM to 100 ,uM (micromolar), the amount of the estrogen being bioequivalent to approximately 2 mg per day of estradiol ~e.g., Progy-nova, Schering), the amount of a partial estrogen being bioequivalen~ to approximately 1 - 200 mg per day of raloxifen, and the amount of the progestational agent administered being bioequivalent to 50 - 300 mg of injected progesterone.
In a product aspect, this invention relates to a pharmaceutical composition comprising at least one of a nitric oxide synthase substrate (L-arginine) and a nitric oxide donor (eg. sodium nitroprusside or glyceryl trinitrate), alone or in further combination with one or more of a estro-gen and/or progestin with and without added supplements of an alpha-adrenergic agonist, a beta-adrenergic receptor blocking agent, a choli-nergic receptor blocking compound or a cholinergic stimulating drugs with the amount of the nitric oxide synthase substrate, a nltric oxide donor or both per unit dosage being equivalent to either raise the blood level of circulating L-arginine to least 10 to 500 ~mole above the nor-mally 50 to 1000 ,umole circulating or raise nitric oxide donor levels to about 10 nM to 100 ,uM, the amourlt of the estro~en being bioequiva-lent to about 2 mg of estradiol le.g., Progynova, Schering), the amount of a partial estrogen being bioequivalent to approximately 1 - 200 mg per day of raloxifen, with the amount of the progesterone bioequivalent to 50 to 300 mg of injected progesterone and the amount of the supplemental alpha-adrenergic agonist, beta-receptor blocking agent, cholinergic-receptor blocking compound or cholinergic stimulating drug as indicated below.
CA 0224324~ l998-07-l6 wo s7/25s~84 pcT/uss7loo795 The methods of this invention treat urinary incontinence in a menopausal/postmenopausal, nonpregnant or pregnant, andlor postpar-t~lm female, who is manifesting the symptoms thereof.
Because the conditions of menopause/postmenopause, pregnancy or postpartum are produced or aggravated by subnormal nitric oxide synthesis, both nitric oxide synthase substrates, e.g., L-arginine and nitric oxide donors, e.g., sodium nitroprusside, nitroglycerin, glyceryl tri-nitrate, SIN-1, isosorbid mononitrate, isosorbid dinitrate and diethylene-triamine/NO (DETA/N0), are useful for ameliorating the symptoms there-o~ and, in one respect of this method of this invention, a combination of both are employed.
An additive effect is achieved when an estrogenic agent is admin-istered concurrently with a nitric oxide substrate and/or nitric oxide donor. In the case of a female mammal, an estrogen can be admini-stered concurrently with or in lieu of a progestin. The latter can also be used alone.
An additional effect is achieved when a nitric oxide substrate or a nitric oxide donor is administered either with estrogen or progestin and supplemented with one of a alpha-adrenergic agonist, a beta receptor blocking agent, a cholinergic-receptor blocking agent or a cholinergic stimulating drug.
Thus, the method aspects of this invention and the pharmaceuti-cal composition aspects of this invention employ either or both of a nitric oxide substrate and a nitric oxide donor and, optionally one or more of, e.g., an estrogen (e.g., Progynova, Schering) or a progestin ~e.g., progesterone or norgestrel), with or without one of the following:
an-alpha-adrenergic agonist, a beta-receptor blocking agent, a choliner-gic-receptor blocking compound or a cholinergic stimulating drug.
Examples of dosage ranges of typical NO-substrates and NO-donors (per os or transdermally) are:
CA 0224324~ 1998-07-16 total dose:
L-Arginine500 mg - 10 g p.o.
Sodium Nitroprusside ran~e 500 - 2000,u~/kg/day p.o.
Nitroglycerin 0.5 - 10 mg p.o.
Nitroglycerin 0.1 - 10 mg/24 hours transdermal Isosorbid mononitrate 10 - 100 mg/day p.o.
Isosorbid dinitrate 10 - 100 mg/mg p.o.
The nitric oxide donors (e.g., nitroglycerin) can be administered preferentially by a transdermal patch (e.g., Deponit 5/1 0/T ~Schwarz Pharma], Nitroderm TTS 5/Nitroderm TTS 10 lCl~A]), orally (e.g., Corangin [CIBAl, Nitrolingual forte or mitte [Pohl],) etc.
Examples of combinations of active agents which can be admini-stered concurrently with a nitric oxide substrate and/or nitric oxide donor are the following estrogens and progestins and typical oral dosage ranges of the active agents of the estrogen and progestin type with the nitric oxide substrate or donor:
Estrogens: A daily dose bioequivalent to about 1-2 mg per day estradfol, e.g., Premarin, Wyeth-Ayerst, 0.625 mg~day; estradiol valer-ate, 50 ,ug/day transdermally; vaginal estradiol creams, 1.25 mg/day and vaginal estradiol rings, 0.2 mg/day and the natural occurring estrogens used in hormone replacement therapy currently available.
Partial estrogen agonists (partial estrogens): A daily dose bioequivalent to about 1-200 mg per day, e.g. raloxifen ([6-hydroxy-2-(4-hydroxyphenyl)-3-benzothienyll[4-[2-(1 -piperidinyl~ethoxy]phenyl}-methanon-hydrochloride), tamoxifen ((Z)-N,N-dimethyl-2-[4-( 1 ,2-diphen-yl- 1 -butenyl) phenoxy]ethanamine, nafoxidin ( 1-[2-[4 (3,4-dihydro-6-methoxy-2-phenyl-1 -naphthalinyl)phenoxy]ethyllpyrrolidin-hydrochlor-ide), Mer-2~ ~a-[4-[2-(diethylamino)ethoxy]phenyll-4-methoxy-a-phenyl-benzenethanol) and centchroman ((3R-trans)-3,4-dihydro-2,2-dimethyl 7-methoxy-3-phenyl-4-[4-[2-(1-pyrrolidinyl)ethoxylphenyll-2H-1-benzopyran) .
WO 97/25984 PCT/US97/0079~;
Progestins: A daily dose bioequivalent to 50 - 300 mg of proges-terone/day, e.g., an injectable suspension of medroxyprogesterone ace-tate to provide a weekly dose thereof of 100 - 1000 mg or tablets or dragees providing an oral dose thereof of 5 -100 mg/day, an injectable solution of hydroxypro~esterone caproate which provides a weekly dose of 250 - 500 mg; tablets, capsules or dragees of noreth;ndrone acetate which provide a daily dose of 5 - 20 mg.
Examples of estrogen and progestin combinations are listed below:
Product Composition Dose (mg per day) Climaval (Sandoz) Estradiol valerate 1 or 2 Progynova (Schering) Estradiol valerate 1 or 2 Harmogen (Abbott) Piperazine estrone 1.05 or 2.5 Hormonin (Shire) Estradiol 0.6 ~ Estrone + Estriol Premarin (Wyeth-Ayerst~ Conjugated equine Estrogens 0.625, 1.25 or 2.5 Commercially available combination calendar packs for hormone replacement therapy include " Estrapak", " Prempak-C ", "Trisequens", "Trisenquens forte" and "Cycloprogynova". The following are illustra-tive compositions of such products:
Estradiol 50 mg per day (28 days, 8 patches) conjugated equine estrogens 0.625 mg per day (28 days) 2~ Estradiol valerate 2 mg per day (11 days) Estradiol valerate 2 mg per day Norgestrel 0.5 mg per day (10 days) .
Norgestrel 0.1 5 mg per day ( 1 2 days) conjugated equine Estrogens 1.25 mg per day (28 days) CA 0224324~ l998-07-l6 WO 97/25984 ' PCT/US97/0~795 Norgestrel 0.15 mg per day (12 days) estradiol 2 mg per day + estriol 1 mg per day (22 days) Norethisterone acetate 1 mg per day ( 1 0 days) estradiol 1 mg per day + estriol 0.5 mg per day (6 days) estradiol 4 mg per day + estriol 2 mg per day (21 days~
Norethisterone acetate 1 mg per day ( 1 0 days) Estradiol 1 mg per day + estriol 0.5 mg per day (6 days) Estradiol valerate 1 mg per day (21 days) Levonorgestrel 0.25 mg per day (10 days~
Estradiol valerate 2 mg per day (21 days) Levonorgestrel 0.5 mg per day (10 days) Daily doses of progestogens taken for 12 days per month in patients receiving oral or transdermal estrogens:
Norethisterone 0.7 - 2.5 mg per day Medroxyprogesterone acetate 10 mg per day Norgestrel 150 ,ug per day Dydrogesterone 10 - 20 mg per day Typical dosages of exemplary supplemental agents include those shown below, other bioequivalent amounts of analogous such agents being routinely determinable:
Alpha-adrenergic-receptor-agonists:
Phenylpropanolamine 25 - 100 mg daily Phenylephrine 5 - I 5 mg daily Beta-receptor-blocking agents:
Propranolol 20 - 1 20 mg daily Befaxolol 10 - 40 mg daily Acebutolol 400 mg daily Atenolol 50 - 100 mg daily Bisoprolol 5 - 10 mg daily CA 0224324~ 1998-07-16 WO 97/2~;984 - PCT/US97/00795 Cholinergic-receptor blocking compounds:
Benztropine 0.5 - 1 mg daily Biperiden 3 - 6 mg daily Propantheline 30 - 1 20 mg daily Cholinergic-stimulating drugs:
Bethanecol 3(~ - 1 20 mg daily Many other examples of compounds in each of the four ~oregoing ca~:egories 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-li~uid or solid organic or inor-ganic carriers suitable, e.g., for parental or enteral application and which do not deleteriously react with the active compound in admixture there-wil:h. 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 diglycer-ides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
The pharmaceutical preparations can be sterilized and if desired mbced with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buf-fers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
For parental application, particularly suitable are solutions, prefer-ably oily or aqueous solutions, as well as suspensions, emulsions, or im-plants, including suppositories, transdermal patches, and vaginal gels, creams and foams. Ampoules are convenient unit dosages.
In a preferred aspect, the composition of this invention is adapted for ingestion.
For enteral application, particularly suitable are 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; particulate solids, e.g., granules; and liquids CA 0224324~ 1998-07-16 and semi-liquids, e.g., syrups and elixirs or the like, wherein a sweet-ened vehicle is employed. Sustained release compositions can be for-mulated 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 estrogen and/or progestational agent 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. l~he 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 ~0,000 mg, and others, e.g., sodium nitroprusside, require lower doses, e.g., 500 - 2,000 ,ug/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~o dosages of most of these active agents is known in the prior art, a lower dosage regimen can be initiated and the dosage in-creased until a positive effect is acl~ieved 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. Combi-nations of agents can be employed either continuously or sequentially In humans, both L-arginine and progesterone ~or bioequivalent of another progestin) should be given in a ratio which produces blood plasma leveis of 50 - 5000 ,umolar L-arginine, 30 - 100 nmolar proges-terone and 500 to 1000 nmolar of estradiol.
CA 0224324~ 1998-07-16 Brief DescriPtion of the Drawinqs Various other objects, features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood when considered in coniunction with the accompany-in~ drawings, in which lilce reference characters designate the same or similar parts throughout the several views, and wherein:
Figure 1: Figure 1 shows the effects of sodium nitroprusside (SNP) (103M) on contractions of the rat detrusor muscle after stimulating the muscle with methylcholine (MC at 10-6M
and 1o-5M).
Figure 2: Data similar to Figure 1 is demonstrated in Figure 2.
Figure 3: Effects of DETA/N0 ~diethylenetriamine/N0) a nitric oxide donor compound on spontaneous contractions of the rat detrusor muscle.
, 1~ Detailed Descrir~tion of the Invention - In the experiments whose results are shown in Figure ~, rat blad-der detrusor muscle was obtained from ovariectomized and normal non-pre~nant animals~ The tissues were suspended in muscle baths to re-cord in vitro contractility and drugs were added to the baths to estimate their effects on the mechanical events. In the experiments shown in Fig~lres 1 and 2, methylcholine ~MC at 1 o-6M and 1 o-5M) was added to precontract the bladder samples, then the nitric oxide donor sodium nitroprusside (SNP at 10-3 M) was added to the bath.- SNP caused an immediato and significant decrease in contractility. The relaxation response was transient which is typical of SNP for this preparation.
Similar data was obtained from 16 other strips of tissues suspended in v;tro and treated with SNP.
In the results shown in Figure 3, tissues were contracting spon-taneously in vifro. When DETA/N0, a nitric oxide donor compound, was added to the muscle bath, spontaneous contractions abruptly dis-appeared and did not reappear during the recording period, about 30 minutes. Similar results were obtained from tissues from 16 rats.
Additionally, tissues from ovariectomized rats treated with estrogen showed more pronounced effects than untreated ovariectomized rats (n=8).
CA 0224324~ l998-07-l6 It can be concluded from these results that nitric oxide has a pro-found relaxation effect on the rat detrusor muscle. Since L-arginine is the substrate for nitric oxide one can deduce that nitric oxide substrates will also relax detrusor muscle. Further, since the effects of nitric oxide are much greater after treating rats with estrogen it can be concluded that estrogen plus a nitric oxide donor or a nitric oxide substrate may have greater effects when an nitric oxide substrate or donor are com-bined with estrogen. Furthermore, since estrogen and progesterone often act synergistically one can infer that estrogen and/or progesterone combinations would be useful. Relaxation of the detrusor muscle with nitric oxide donors indicates that nitric oxide may be involved in detru-sor relaxation during the filling phase of bladder function. Therefore, nitric oxide donors and/or substrates alone or in combination with ster-oids will prove effective for urinary incontinence. Furthermore, since the bladder is innervated by adrenergic and cholinergic nerves combina-tions with alpha adrenergic agonists, beta-receptor blocking agents, cholinergic-blocking compounds or cholinergic stimulating drugs will be useful to treat incontinence.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indi-cated, all parts and percentages are by weight.
The entire disclosures of all applications, patents and publica-tions, cited above and below, if any, are hereby incorporated by reference .
CA 02243245 l998-07-l6 EXAMPLES
ExamPle 1: Treatment of urinary iricontinence To a nonpregnant human female (ca 60 years; 50 - 90 kg) dis-playing the signs of menopause or postmenopausal symptoms, including amenorrhea, and urinary incontinence, administer L-arginine 0.5 to 20 g of L-arginine per os daily in three divided doses until the symptoms are ameliorated. Thereafter, administer 0.5 to 5 9 of L-arginine daily.
Example 2: Treatment of urinary incontinence To a female comparable to and displaying the same symptoms as Example 1, administer daily 5 - 10 mg of nitroglycerine transdermally.
ExamPle 3: Treatment of ur;nary ;ncontinence To a female comparable to and dlsplaying the same symptoms as Example 1, administer daily 2 x 2.5 mg of nitroglycerine orally.
ExamPle 4: Treatment of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 0.5 to 20 g of L-arginine in combination wi~h estrogen (e.g.r estradiol valerate) 1 - 2 mg daily.
Ex;amPle 5: Tre~ e.lt of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 2 x 5 mg nitroglycerine transdermally in combination with a partial estrogen agonist (e.g., raloxifen) 100 mg daily.
Example 6: Treatment of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 0.5 to 20 g o~ L-arginine in com~ination wil:h a partial estrogen agonist le.g., raloxi~en) 100 mg daily.
CA 0224324~ l998-07-l6 ExamPle 7: Treatment of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 2 x 2-~ mg nitroglycerin with a progestin (e.g., norgestrel) 150 ,ug per day.
ExamPle 8: Treatment of urinary incontinerlce To a female comparable to and displaying the same symptoms as Example 1, administer ~-arginine 0.5 to 20 g daily and/or a nitric oxide donor (e.g., nitroglycerine, 2 x 2.5 mg) daily with or without one of the following, an estrogen (e.g., estradiol valerate) 1 - 2 mg daily, on a pro-gestin (e.g., norgestrel, at 150 mg per day). The latter sex steroids to be given either continuously with L-arginine and/or a nitric oxide-donor, or sequentially - the progestins taken for only 6 - 12 days per month.
Example 9: Treatrnent of urinary incontinence To a female comparable to and displaying the same symptoms of 1 ~i Example 1, administer L-arginine (0.5 to 20 g daily) and/or a nitric oxidedonor (e.g. nitroglycerine, 2 x 2.5 mg daily) with or without one or more of the following, an estrogen (e.g., estradiol valerate, 1 --2 mg daily) or a progesterone (e.g. norgestrel, at 150 mg per day~, an alpha-adrenergic agonist) (e.g. phenylpropanolamine, 25 to 100 mg daily), a beta-receptor blocking agent (e.g. propranolol 20 - 120 mg daily), a cholinergic receptor blocking compound (e.g. propantheline 30 - 120 mg daily) or a cholinergic stimulating drug (e.g. bethanecol 30 - 120 mg daily) .
The preceding examples can be repeated with similar success by substituting the.generically or specifically described reactants and/or operating cond;tions of this invention for those used in the preceding examples .
From the foregoing description, one skilled in the art can easily ascertain the essentiai characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
REFERENCES
1. Barbieri, R.L. The bladder in menopause: Lower urinary tract dysfunction during the climacteric. Curr. Problems Obstet. Gynecol.
Fertil. 1994; 17(6): 196-228.
2. Eli, G. and Bergman, A. Estrogen effects on the urethra:
beneficial effects in women with genuine stress incontinence. Obstet.
Gynecol. 1993; 48(7):509-517.
3. Sartori, M.G., Baracat, E.C., Girad, M.J., Gonccalves, W.J., Sartori, J.P., d~ Lima, G.R. Menopausal genulne stress urinary inconti-nence treated with conju~ated estrogens plus progestogens. Int. J.
Gynecol. Obstet. 1995; 49(2): 165-169.
4. Cardozo, L.D. and Kelleher, C.J. Sex hormones, the meno-pause and urinary problems. Gynecol. Endocrinol.1995; 9(1):75-84.
5. Cardozo, L. and Kelleher, C. Sex hormones and the female io~,ver urinary tract. Physiotherapy 1994; 80: 135-138.
CA 0224324~ 1998-07-16 Progestins may reinforce the beneficial effects of estrogens on the cardiovascular system. Modern HRT now employs combinations of an estrogen and a progestin as in the general case for most contraceptives.
One of the most exciting recent advances in biology and medicine is the discover;r that nitric oxide is produced by endothelial cells and ~hat it is invoived in the regulation of vascular tone, platelet aggre~a-tion, neurotransmission and immune activation ~Furchgott and Zaw~d-zki, 1980; Moncada, Palmer and Hig9s, 1991; Ignarro, 1991). Nitric oxide is an important mediator of relaxation of the muscu~ar smooth m~scle (Montada, Palmer and Higgs, 1991) and was formerly known as E~RF (endothelin-derived relaxing factor) (Furchgott and Zawadzki, 1 980; 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, 19~1). Synthesis of nitric oxide has been shown to be competitively inhibited by analogues of L-argi-nine; NG-nitro-L-arginine methyl ester lL-NAME), NG-monoethyl-L-argi-nine (LMMA), N-iminoethyl-L-ornithine (L-NIO), L-monomethyl-L-arginine (L-INNMA) and L-NG-methylarginine (LNMA) and Nw-nitro-L-arginine (L-INA~.
Nitric oxide elevates levels of cGMP (1,4,5-cyclic guanosine monophosphate) within the vascular smooth muscle to produce relaxa-tiOI1 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 nitrovasodilators, such as nitro-prusside and nitroglycerin, inhibit vascular smooth muscle contractility to produce relaxation or to reduce vascular tone. These agents have been used since the late 1 980s as vasodilators. However, only recently has the mechanism of action of these compounds been realized. Nitrovasodila-tors are now classified as nitric oxide donors because they aFe metabo-lized or spontaneously 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.
CA 0224324~ 1998-07-16 There is a substantial body of evidence from animal experiments that a deficiency in nitric oxide contributes to the pathogenesis of a number of diseases, including hypertensionJ atherosclerosis and diabe-tes (Montada, Palmer and Higgs, 1991). There are many recent studies showing that the inhibitibn of nitric oxide synthase dramatically increa-ses blood pressure.
Nitric oxide may also be involved in accommodation of the bladder during filling or relaxation of the bladder neck and urethra during voiding. The bladder is innervated by nonadrenergic and noncholinergic nerves (NANC nerves) and nitric oxide is thought to be a neurotransmit-ter in these types of nerves (Ehren et al, 1994; Andersson and Persson, 199~; Smet, et al, 1994; Lee et al., 1994). There is evidence showing that nitric oxide containing nerves are localized to a greater extent in the outlet region and urethra compared to the detrusor (Andersson and Per-sson, 1994; Lee et al., 1994). However, whether nitric oxide is in-volved in voiding by reiaxing the urethra and bladder neck or in bladder filling by relaxing the detrusor is unclear. There have been few studies -of the effects of nitric oxide donors on either the urethra, bladder neck or detrusor muscle.
Summarv of the Invention Our studies suggest that nitric oxide donors effectively relax the detrusor muscle (see below). Further our studies of the uterus, cervix and vascular tissues suggest that the steroid hormones control nitric oxide synthesis, release and the effector system for nitric oxide (Chwa-lisz and Garfield, 1994). Therefore, we have discovered that the sub-strate for nitric oxide, nitric oxide donors, or both in combination with steroid hormones (estrogen and/or ~rogesterone) are useful for treat-ment and prevention of urinary or urethra incontinence.
It is an object of the invention to provide a method for the treatment and prevention of urinary incontinence with a nitriG-oxide substrate and/or donor in mammals, e.g., human males and females, especially nonpregnant female mammals.
CA 0224324~ 1998-07-16 -5'984 - PCT/US97/00795 It is another object of the invention to provide a method for treatment and prevention of urinary incontinence with a nitric oxide substrate and/or donor in pregnant or postpartum female mammals.
It is a further object of the invention to provide a method for treatment and prevention of urinary incontinence with a n;tric oxide sub-strate and/or donor in which an estrogenic agent in combination with a nitric oxide substrate and/or donor is used for urinary incontinence in bo~h nonpregnant or pregnant female mammais.
It is a further object of the invention to provide a method for treatment and prevention of urinary incontinence with a nitric oxide sub-stri~te and/or donor in which a partial estrogenic agent (e.g. raloxifen) in combination with a nitric oxide substrate and/or donor is used for uri-nary incontinence in both nonpregnant or pregnant femaie mammals.
In another aspect of this invention, a progestational agent is used in oombination with a nitric oxide substrate and/or nitric oxide donor for treatment and prevention of urinary incontinence in female mamma~s.
In a further aspect of this invention, an estrogen and a progestin are used in combination with a nitric oxide substrate and/or nitric oxide donor for the treatment and prevention of urinary incontinence in female mammals.
It is another object of this invention to provide a method for the treatment and prevention of urinary incontinence with a nitric oxide sub-strate and/or nitric oxide substrate alone or in combination with an estrogenic agent and/or a progestational substance, and with or without supplementation with an alpha-adrenergic agonist, beta-adrenergic receptor blocking agent, cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug.
A further object is to provide pharmaceutical compositions useful in practicing the methods of this invention. Upon further study of the specification and appended claims, further aspects, objects and advan-tages of this invention will become apparent to those skilled in the art.
Thus, in a method aspect, this invention relates to a method of treating urinary incontinence in a mammal, e.g., nonpregnant or preg-nant female mammal, which comprises administering to an individual manifesting the symptoms thereof one or both of a nitric oxide sub-CA 0224324~ 1998-07-16 WO 97/25984 . PCTIUS97/0079S
strate and a nitric oxide donor, alone or in combination with an estrogen or a progestin, or both, and with or without supplementation with an alpha-adrenergic agonist, a beta adrenergic receptor blocking agent, a cholinergic-receptor blocking compound or a cholinergic-receptor stimu-lating drug, all in amounts effective to ameliorate the symptoms thereof;
typically, the amount of the nitric oxide synthase substrate and nitric oxide donor or both is effective to increase urinary continence by raising the blood level of circulating L-arginine in a female to whom the compo-sition is administered to at least 10 to 500 ~mole above the normally 50 to 1000 ,umole circulating levels, or to raise nitric oxide donor levels to -about 10 nM to 100 ,uM (micromolar), the amount of the estrogen being bioequivalent to approximately 2 mg per day of estradiol ~e.g., Progy-nova, Schering), the amount of a partial estrogen being bioequivalen~ to approximately 1 - 200 mg per day of raloxifen, and the amount of the progestational agent administered being bioequivalent to 50 - 300 mg of injected progesterone.
In a product aspect, this invention relates to a pharmaceutical composition comprising at least one of a nitric oxide synthase substrate (L-arginine) and a nitric oxide donor (eg. sodium nitroprusside or glyceryl trinitrate), alone or in further combination with one or more of a estro-gen and/or progestin with and without added supplements of an alpha-adrenergic agonist, a beta-adrenergic receptor blocking agent, a choli-nergic receptor blocking compound or a cholinergic stimulating drugs with the amount of the nitric oxide synthase substrate, a nltric oxide donor or both per unit dosage being equivalent to either raise the blood level of circulating L-arginine to least 10 to 500 ~mole above the nor-mally 50 to 1000 ,umole circulating or raise nitric oxide donor levels to about 10 nM to 100 ,uM, the amourlt of the estro~en being bioequiva-lent to about 2 mg of estradiol le.g., Progynova, Schering), the amount of a partial estrogen being bioequivalent to approximately 1 - 200 mg per day of raloxifen, with the amount of the progesterone bioequivalent to 50 to 300 mg of injected progesterone and the amount of the supplemental alpha-adrenergic agonist, beta-receptor blocking agent, cholinergic-receptor blocking compound or cholinergic stimulating drug as indicated below.
CA 0224324~ l998-07-l6 wo s7/25s~84 pcT/uss7loo795 The methods of this invention treat urinary incontinence in a menopausal/postmenopausal, nonpregnant or pregnant, andlor postpar-t~lm female, who is manifesting the symptoms thereof.
Because the conditions of menopause/postmenopause, pregnancy or postpartum are produced or aggravated by subnormal nitric oxide synthesis, both nitric oxide synthase substrates, e.g., L-arginine and nitric oxide donors, e.g., sodium nitroprusside, nitroglycerin, glyceryl tri-nitrate, SIN-1, isosorbid mononitrate, isosorbid dinitrate and diethylene-triamine/NO (DETA/N0), are useful for ameliorating the symptoms there-o~ and, in one respect of this method of this invention, a combination of both are employed.
An additive effect is achieved when an estrogenic agent is admin-istered concurrently with a nitric oxide substrate and/or nitric oxide donor. In the case of a female mammal, an estrogen can be admini-stered concurrently with or in lieu of a progestin. The latter can also be used alone.
An additional effect is achieved when a nitric oxide substrate or a nitric oxide donor is administered either with estrogen or progestin and supplemented with one of a alpha-adrenergic agonist, a beta receptor blocking agent, a cholinergic-receptor blocking agent or a cholinergic stimulating drug.
Thus, the method aspects of this invention and the pharmaceuti-cal composition aspects of this invention employ either or both of a nitric oxide substrate and a nitric oxide donor and, optionally one or more of, e.g., an estrogen (e.g., Progynova, Schering) or a progestin ~e.g., progesterone or norgestrel), with or without one of the following:
an-alpha-adrenergic agonist, a beta-receptor blocking agent, a choliner-gic-receptor blocking compound or a cholinergic stimulating drug.
Examples of dosage ranges of typical NO-substrates and NO-donors (per os or transdermally) are:
CA 0224324~ 1998-07-16 total dose:
L-Arginine500 mg - 10 g p.o.
Sodium Nitroprusside ran~e 500 - 2000,u~/kg/day p.o.
Nitroglycerin 0.5 - 10 mg p.o.
Nitroglycerin 0.1 - 10 mg/24 hours transdermal Isosorbid mononitrate 10 - 100 mg/day p.o.
Isosorbid dinitrate 10 - 100 mg/mg p.o.
The nitric oxide donors (e.g., nitroglycerin) can be administered preferentially by a transdermal patch (e.g., Deponit 5/1 0/T ~Schwarz Pharma], Nitroderm TTS 5/Nitroderm TTS 10 lCl~A]), orally (e.g., Corangin [CIBAl, Nitrolingual forte or mitte [Pohl],) etc.
Examples of combinations of active agents which can be admini-stered concurrently with a nitric oxide substrate and/or nitric oxide donor are the following estrogens and progestins and typical oral dosage ranges of the active agents of the estrogen and progestin type with the nitric oxide substrate or donor:
Estrogens: A daily dose bioequivalent to about 1-2 mg per day estradfol, e.g., Premarin, Wyeth-Ayerst, 0.625 mg~day; estradiol valer-ate, 50 ,ug/day transdermally; vaginal estradiol creams, 1.25 mg/day and vaginal estradiol rings, 0.2 mg/day and the natural occurring estrogens used in hormone replacement therapy currently available.
Partial estrogen agonists (partial estrogens): A daily dose bioequivalent to about 1-200 mg per day, e.g. raloxifen ([6-hydroxy-2-(4-hydroxyphenyl)-3-benzothienyll[4-[2-(1 -piperidinyl~ethoxy]phenyl}-methanon-hydrochloride), tamoxifen ((Z)-N,N-dimethyl-2-[4-( 1 ,2-diphen-yl- 1 -butenyl) phenoxy]ethanamine, nafoxidin ( 1-[2-[4 (3,4-dihydro-6-methoxy-2-phenyl-1 -naphthalinyl)phenoxy]ethyllpyrrolidin-hydrochlor-ide), Mer-2~ ~a-[4-[2-(diethylamino)ethoxy]phenyll-4-methoxy-a-phenyl-benzenethanol) and centchroman ((3R-trans)-3,4-dihydro-2,2-dimethyl 7-methoxy-3-phenyl-4-[4-[2-(1-pyrrolidinyl)ethoxylphenyll-2H-1-benzopyran) .
WO 97/25984 PCT/US97/0079~;
Progestins: A daily dose bioequivalent to 50 - 300 mg of proges-terone/day, e.g., an injectable suspension of medroxyprogesterone ace-tate to provide a weekly dose thereof of 100 - 1000 mg or tablets or dragees providing an oral dose thereof of 5 -100 mg/day, an injectable solution of hydroxypro~esterone caproate which provides a weekly dose of 250 - 500 mg; tablets, capsules or dragees of noreth;ndrone acetate which provide a daily dose of 5 - 20 mg.
Examples of estrogen and progestin combinations are listed below:
Product Composition Dose (mg per day) Climaval (Sandoz) Estradiol valerate 1 or 2 Progynova (Schering) Estradiol valerate 1 or 2 Harmogen (Abbott) Piperazine estrone 1.05 or 2.5 Hormonin (Shire) Estradiol 0.6 ~ Estrone + Estriol Premarin (Wyeth-Ayerst~ Conjugated equine Estrogens 0.625, 1.25 or 2.5 Commercially available combination calendar packs for hormone replacement therapy include " Estrapak", " Prempak-C ", "Trisequens", "Trisenquens forte" and "Cycloprogynova". The following are illustra-tive compositions of such products:
Estradiol 50 mg per day (28 days, 8 patches) conjugated equine estrogens 0.625 mg per day (28 days) 2~ Estradiol valerate 2 mg per day (11 days) Estradiol valerate 2 mg per day Norgestrel 0.5 mg per day (10 days) .
Norgestrel 0.1 5 mg per day ( 1 2 days) conjugated equine Estrogens 1.25 mg per day (28 days) CA 0224324~ l998-07-l6 WO 97/25984 ' PCT/US97/0~795 Norgestrel 0.15 mg per day (12 days) estradiol 2 mg per day + estriol 1 mg per day (22 days) Norethisterone acetate 1 mg per day ( 1 0 days) estradiol 1 mg per day + estriol 0.5 mg per day (6 days) estradiol 4 mg per day + estriol 2 mg per day (21 days~
Norethisterone acetate 1 mg per day ( 1 0 days) Estradiol 1 mg per day + estriol 0.5 mg per day (6 days) Estradiol valerate 1 mg per day (21 days) Levonorgestrel 0.25 mg per day (10 days~
Estradiol valerate 2 mg per day (21 days) Levonorgestrel 0.5 mg per day (10 days) Daily doses of progestogens taken for 12 days per month in patients receiving oral or transdermal estrogens:
Norethisterone 0.7 - 2.5 mg per day Medroxyprogesterone acetate 10 mg per day Norgestrel 150 ,ug per day Dydrogesterone 10 - 20 mg per day Typical dosages of exemplary supplemental agents include those shown below, other bioequivalent amounts of analogous such agents being routinely determinable:
Alpha-adrenergic-receptor-agonists:
Phenylpropanolamine 25 - 100 mg daily Phenylephrine 5 - I 5 mg daily Beta-receptor-blocking agents:
Propranolol 20 - 1 20 mg daily Befaxolol 10 - 40 mg daily Acebutolol 400 mg daily Atenolol 50 - 100 mg daily Bisoprolol 5 - 10 mg daily CA 0224324~ 1998-07-16 WO 97/2~;984 - PCT/US97/00795 Cholinergic-receptor blocking compounds:
Benztropine 0.5 - 1 mg daily Biperiden 3 - 6 mg daily Propantheline 30 - 1 20 mg daily Cholinergic-stimulating drugs:
Bethanecol 3(~ - 1 20 mg daily Many other examples of compounds in each of the four ~oregoing ca~:egories 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-li~uid or solid organic or inor-ganic carriers suitable, e.g., for parental or enteral application and which do not deleteriously react with the active compound in admixture there-wil:h. 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 diglycer-ides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
The pharmaceutical preparations can be sterilized and if desired mbced with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buf-fers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
For parental application, particularly suitable are solutions, prefer-ably oily or aqueous solutions, as well as suspensions, emulsions, or im-plants, including suppositories, transdermal patches, and vaginal gels, creams and foams. Ampoules are convenient unit dosages.
In a preferred aspect, the composition of this invention is adapted for ingestion.
For enteral application, particularly suitable are 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; particulate solids, e.g., granules; and liquids CA 0224324~ 1998-07-16 and semi-liquids, e.g., syrups and elixirs or the like, wherein a sweet-ened vehicle is employed. Sustained release compositions can be for-mulated 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 estrogen and/or progestational agent 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. l~he 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 ~0,000 mg, and others, e.g., sodium nitroprusside, require lower doses, e.g., 500 - 2,000 ,ug/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~o dosages of most of these active agents is known in the prior art, a lower dosage regimen can be initiated and the dosage in-creased until a positive effect is acl~ieved 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. Combi-nations of agents can be employed either continuously or sequentially In humans, both L-arginine and progesterone ~or bioequivalent of another progestin) should be given in a ratio which produces blood plasma leveis of 50 - 5000 ,umolar L-arginine, 30 - 100 nmolar proges-terone and 500 to 1000 nmolar of estradiol.
CA 0224324~ 1998-07-16 Brief DescriPtion of the Drawinqs Various other objects, features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood when considered in coniunction with the accompany-in~ drawings, in which lilce reference characters designate the same or similar parts throughout the several views, and wherein:
Figure 1: Figure 1 shows the effects of sodium nitroprusside (SNP) (103M) on contractions of the rat detrusor muscle after stimulating the muscle with methylcholine (MC at 10-6M
and 1o-5M).
Figure 2: Data similar to Figure 1 is demonstrated in Figure 2.
Figure 3: Effects of DETA/N0 ~diethylenetriamine/N0) a nitric oxide donor compound on spontaneous contractions of the rat detrusor muscle.
, 1~ Detailed Descrir~tion of the Invention - In the experiments whose results are shown in Figure ~, rat blad-der detrusor muscle was obtained from ovariectomized and normal non-pre~nant animals~ The tissues were suspended in muscle baths to re-cord in vitro contractility and drugs were added to the baths to estimate their effects on the mechanical events. In the experiments shown in Fig~lres 1 and 2, methylcholine ~MC at 1 o-6M and 1 o-5M) was added to precontract the bladder samples, then the nitric oxide donor sodium nitroprusside (SNP at 10-3 M) was added to the bath.- SNP caused an immediato and significant decrease in contractility. The relaxation response was transient which is typical of SNP for this preparation.
Similar data was obtained from 16 other strips of tissues suspended in v;tro and treated with SNP.
In the results shown in Figure 3, tissues were contracting spon-taneously in vifro. When DETA/N0, a nitric oxide donor compound, was added to the muscle bath, spontaneous contractions abruptly dis-appeared and did not reappear during the recording period, about 30 minutes. Similar results were obtained from tissues from 16 rats.
Additionally, tissues from ovariectomized rats treated with estrogen showed more pronounced effects than untreated ovariectomized rats (n=8).
CA 0224324~ l998-07-l6 It can be concluded from these results that nitric oxide has a pro-found relaxation effect on the rat detrusor muscle. Since L-arginine is the substrate for nitric oxide one can deduce that nitric oxide substrates will also relax detrusor muscle. Further, since the effects of nitric oxide are much greater after treating rats with estrogen it can be concluded that estrogen plus a nitric oxide donor or a nitric oxide substrate may have greater effects when an nitric oxide substrate or donor are com-bined with estrogen. Furthermore, since estrogen and progesterone often act synergistically one can infer that estrogen and/or progesterone combinations would be useful. Relaxation of the detrusor muscle with nitric oxide donors indicates that nitric oxide may be involved in detru-sor relaxation during the filling phase of bladder function. Therefore, nitric oxide donors and/or substrates alone or in combination with ster-oids will prove effective for urinary incontinence. Furthermore, since the bladder is innervated by adrenergic and cholinergic nerves combina-tions with alpha adrenergic agonists, beta-receptor blocking agents, cholinergic-blocking compounds or cholinergic stimulating drugs will be useful to treat incontinence.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indi-cated, all parts and percentages are by weight.
The entire disclosures of all applications, patents and publica-tions, cited above and below, if any, are hereby incorporated by reference .
CA 02243245 l998-07-l6 EXAMPLES
ExamPle 1: Treatment of urinary iricontinence To a nonpregnant human female (ca 60 years; 50 - 90 kg) dis-playing the signs of menopause or postmenopausal symptoms, including amenorrhea, and urinary incontinence, administer L-arginine 0.5 to 20 g of L-arginine per os daily in three divided doses until the symptoms are ameliorated. Thereafter, administer 0.5 to 5 9 of L-arginine daily.
Example 2: Treatment of urinary incontinence To a female comparable to and displaying the same symptoms as Example 1, administer daily 5 - 10 mg of nitroglycerine transdermally.
ExamPle 3: Treatment of ur;nary ;ncontinence To a female comparable to and dlsplaying the same symptoms as Example 1, administer daily 2 x 2.5 mg of nitroglycerine orally.
ExamPle 4: Treatment of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 0.5 to 20 g of L-arginine in combination wi~h estrogen (e.g.r estradiol valerate) 1 - 2 mg daily.
Ex;amPle 5: Tre~ e.lt of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 2 x 5 mg nitroglycerine transdermally in combination with a partial estrogen agonist (e.g., raloxifen) 100 mg daily.
Example 6: Treatment of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 0.5 to 20 g o~ L-arginine in com~ination wil:h a partial estrogen agonist le.g., raloxi~en) 100 mg daily.
CA 0224324~ l998-07-l6 ExamPle 7: Treatment of urinary incontinence To a female similar to and displaying the same symptoms as Example 1, administer daily 2 x 2-~ mg nitroglycerin with a progestin (e.g., norgestrel) 150 ,ug per day.
ExamPle 8: Treatment of urinary incontinerlce To a female comparable to and displaying the same symptoms as Example 1, administer ~-arginine 0.5 to 20 g daily and/or a nitric oxide donor (e.g., nitroglycerine, 2 x 2.5 mg) daily with or without one of the following, an estrogen (e.g., estradiol valerate) 1 - 2 mg daily, on a pro-gestin (e.g., norgestrel, at 150 mg per day). The latter sex steroids to be given either continuously with L-arginine and/or a nitric oxide-donor, or sequentially - the progestins taken for only 6 - 12 days per month.
Example 9: Treatrnent of urinary incontinence To a female comparable to and displaying the same symptoms of 1 ~i Example 1, administer L-arginine (0.5 to 20 g daily) and/or a nitric oxidedonor (e.g. nitroglycerine, 2 x 2.5 mg daily) with or without one or more of the following, an estrogen (e.g., estradiol valerate, 1 --2 mg daily) or a progesterone (e.g. norgestrel, at 150 mg per day~, an alpha-adrenergic agonist) (e.g. phenylpropanolamine, 25 to 100 mg daily), a beta-receptor blocking agent (e.g. propranolol 20 - 120 mg daily), a cholinergic receptor blocking compound (e.g. propantheline 30 - 120 mg daily) or a cholinergic stimulating drug (e.g. bethanecol 30 - 120 mg daily) .
The preceding examples can be repeated with similar success by substituting the.generically or specifically described reactants and/or operating cond;tions of this invention for those used in the preceding examples .
From the foregoing description, one skilled in the art can easily ascertain the essentiai characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
REFERENCES
1. Barbieri, R.L. The bladder in menopause: Lower urinary tract dysfunction during the climacteric. Curr. Problems Obstet. Gynecol.
Fertil. 1994; 17(6): 196-228.
2. Eli, G. and Bergman, A. Estrogen effects on the urethra:
beneficial effects in women with genuine stress incontinence. Obstet.
Gynecol. 1993; 48(7):509-517.
3. Sartori, M.G., Baracat, E.C., Girad, M.J., Gonccalves, W.J., Sartori, J.P., d~ Lima, G.R. Menopausal genulne stress urinary inconti-nence treated with conju~ated estrogens plus progestogens. Int. J.
Gynecol. Obstet. 1995; 49(2): 165-169.
4. Cardozo, L.D. and Kelleher, C.J. Sex hormones, the meno-pause and urinary problems. Gynecol. Endocrinol.1995; 9(1):75-84.
5. Cardozo, L. and Kelleher, C. Sex hormones and the female io~,ver urinary tract. Physiotherapy 1994; 80: 135-138.
6. Brandeis, G.H. and Resnick, N.M. Pharmacotherapy of urinary incontinence in the elderly. Drug Therapy 1992; 22:93-102.
7. Furchgott, R.F. and Zawadzki, J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288:373-376.
8. Moncada, S., Palmer, R.M.G. and Higgs, E.A. Nitric oxide-physiology, pathophysiology and pharmacology. Pharmacol. Rev. 1991;
43: 109-142.
43: 109-142.
9. Ignarro, L.J. Physiological significance of Nitric oxide.
Seminars in Perinatology 1991; 15:20-26.
Seminars in Perinatology 1991; 15:20-26.
10. Ehren, l., Adolfsson, J. and Wilund, N.P. Nitric oxide synthase activity in the human urogenital tract. Urol. Res. 1994;
22: 287-290.
22: 287-290.
11. Andersson, K.E. and Persson, K. Nitric oxide synthase and nitfic oxide mediated effects in lower urinary tract smooth muscles.
World J. Urol. 1994; 12:274-280.
World J. Urol. 1994; 12:274-280.
12. Smet, P.J., Edyvane, K.A-., Jonavicius, J., Marshall, V.R.
Distribution of NADPH-diaphorase-positive nerves supplying the human urinary bladder. J. Autonomic Nervous System 1994; 47: 109-113.
Distribution of NADPH-diaphorase-positive nerves supplying the human urinary bladder. J. Autonomic Nervous System 1994; 47: 109-113.
13. Lee, J.G., Wein, A.J., Levin, R.M. Comparative pharmacology of the ma!e and female rabbit bladder neck and urethra:
Involvement of nitric oxide. Pharmacology 14. Chwaiisz, K. and Garfield, R.E. Role of progesterone during pregnancy: Models of parturition and preeclampsia. Z. Geburtsh. u.
Perinat. 198: 170- 180.
Involvement of nitric oxide. Pharmacology 14. Chwaiisz, K. and Garfield, R.E. Role of progesterone during pregnancy: Models of parturition and preeclampsia. Z. Geburtsh. u.
Perinat. 198: 170- 180.
Claims (30)
1. A method of treating urinary incontinence symptoms in a female mammal, comprising administering to an afflicted female an effective amount of (a) a nitric oxide synthase substrate, a nitric oxide donor, or both, and, optionally, further administering an effective amount of (b) one or more of a progestin, an estrogen and a partial estrogen agonist.
2. The method of claim 1, wherein the mammal is a non-pregnant human female suffering from urinary incontinence.
3. The method of claim 1, wherein the mammal is a non-pregnant human female who has exhibited or is a candidate for hormone replacement therapy.
4. The method of claim 1, wherein the mammal is a non-pregnant female human and a nitric oxide synthase substrate is administered thereto.
5. The method of claim 1, wherein the mammal is a-pregnant or postpartum human female.
6. The method of claim 1, wherein the nitric oxide substrate is L-arginine.
7. The method of claim 1, wherein the mammal is a non-pregnant human female and a nitric oxide donor is administered hereto.
8. The method of claim 1, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerin, glyceryl trinitrate, SIN-1, isosorbid mononitrate or isosorbid dinitrate.
9. The method of claim 8, wherein the nitric oxide donor is administered transdermally.
10. The method of claim 8, wherein the nitric oxide donor is administered orally.
11. The method of claim 1, wherein the mammal is a non-pregnant human female and the nitric oxide substrate or donor is administered thereto in combination with an estrogen.
12. The method of claim 11, wherein the estrogen is estradiol valerate, conjugated equine estrogens, 17.beta.-estradiol, estrone or estriol.
13. The method of claim 1, wherein the mammal is a non-pregnant human female and the nitric oxide substrate or donor is administered thereto in combination with a partial estrogen agonist.
14. The method of claim 13, wherein the partial estrogen agonist is raloxifen, centchroman or tamoxifen.
15. The method of claim 1, wherein the mammal is a non-pregnant human female and the nitric oxide substrate or donor is administeried thereto in combination with a progestin.
16. The method of claim 15, wherein the progestin is progesterone, dydrogesterone, medroxyprogesterone, norethisterone, levonorgestrel, norgestrel, gestodene or drospirenone.
17. The method of claim 1, wherein the mammal is a non-pregnant human female and concurrently a hormone replacement amount of an estrogen or a progestin is administered thereto continuously.
18. The method of claim 1, wherein the mammal is a non-pregnant human female and concurrently hormone replacement amounts of an estrogen and a progestin are administered sequentially.
19. The method of claim 1, wherein the mammal is a human female and the nitric oxide substrate or donor is administered thereto in further combination with one or more of an alpha-adrenergic agonist, a beta-receptor blocking agent, a cholinergic-blocking compound or a cholinergic stimulating drug.
20. The method of claim 19, where in the mammal is administered estrogen and/or progestin with an alpha-adrenergic agonist, a beta-receptor blocking agent, a cholinergic-blocking compound or a cholinergic stimulating drug.
21. The method of claim 1, wherein the amount of a nitric oxide synthase substrate, a nitric oxide donor, or both is effective to raise the blood level of circulating L-arginine to at least about 50 - 5000 µmolar above the normally 50 - 1000 µmolar circulating levels or raise nitric oxide donor levels to about 10 nM to 100 µM.
22. A pharmaceutical composition comprising an admixture of effective amounts of (a) a nitric oxide synthesis substrate, a nitric oxide donor or both, and (c) one or more of an alpha-adrenergic agonist, a beta-receptor blocking agent, a cholinergic blocking compound or a cholinergic stimulating drug, and, optionally, (b) an estrogen, a progestin or both.
23. The composition of claim 22, wherein (a) comprises a nitric oxide synthesis substrate.
24. The composition of claim 23, wherein the nitric oxide synthesis substrate is L-arginine.
25. The composition of claim 22, wherein (a) comprises a nitric oxide donor.
26. The composition of claim 25, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerin, glyceryl trinitrate, SIN-1, isosorbid mononitrate or isosorbid dinitrate.
27. The composition of claim 22, wherein (b) comprises an estrogen, which is estradiol valerate.
28. The composition of claim 22, wherein (b) comprises a progestin which is levonorgestrel.
29. The composition of claim 22, wherein the amounts of (a), (c) and optionally (b) are effective to ameliorate the symptoms of urinary incontinence in a menopausal or postmenopausal female mammal.
30. The composition of claim 22, wherein the effective amount of (a) comprises an amount of the nitric oxide synthase substrate, nitric oxide donor or both effective to raise the blood level of circulating L-arginine to at least about 50 - 5000 µmolar above the normally 50 - 1000 µmolar circulating levels or raise the nitric oxide donor levels toabout 10 nM to 100 µmolar, and the effective amount of (b) comprises an amount of estrogen equivalent to 1 - 2 mg of estradiol, an amount of progestin bioequivalent to 50 - 300 mg of injected progesterone, or both.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/588,586 | 1996-01-18 | ||
| US08/588,586 US5789442A (en) | 1996-01-18 | 1996-01-18 | Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors alone or in combination with estrogen or progesterone and/or other agents |
| PCT/US1997/000795 WO1997025984A1 (en) | 1996-01-18 | 1997-01-21 | Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2243245A1 true CA2243245A1 (en) | 1997-07-24 |
Family
ID=29422851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2243245 Abandoned CA2243245A1 (en) | 1996-01-18 | 1997-01-21 | Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2243245A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6647888B1 (en) | 1999-05-06 | 2003-11-18 | Anthony Joseph Cesaroni | Oxidizer package for propellant system for rockets |
-
1997
- 1997-01-21 CA CA 2243245 patent/CA2243245A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6647888B1 (en) | 1999-05-06 | 2003-11-18 | Anthony Joseph Cesaroni | Oxidizer package for propellant system for rockets |
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