HK1032911A - Combination effective for the treatment of impotence - Google Patents

Description

Combination therapy for impotence

no marking

The present invention relates to the treatment of impotence comprising co-administration of (1) an alpha adrenergic receptor antagonist and (2) an agent capable of elevating the level of cyclic guanosine 3 ', 5' -monophosphate (cGMP). This combination therapy is particularly suitable for the treatment of patients with impotence or erectile dysfunction.

Impotence refers to the inability to obtain and/or maintain an adequate erection while penetrating the vagina and/or intercourse. Impotence is therefore also referred to as "erectile insufficiency" or "erectile dysfunction". Approximately 1000-1200 million American men aged 18-75 years suffer from chronic impotence, most over 55 years.

When certain tissues, particularly the corpus cavernosum of the central part of the penis become engorged, the penis begins to erect gradually, thereby causing it to become hard and leading to further erection. Impotence may be due to psychological (psychogenic) factors, to physiological abnormalities (organic) or to a combination of both. Thus, erectile dysfunction in some males is not significantly impaired physically or by organs, but only by anxiety or depression. In other cases, erectile dysfunction is associated with atherosclerosis of the blood arteries supplying the penis. In other cases, erectile dysfunction is due to venous leakage or abnormal drainage, which prevents adequate pressure necessary to achieve or maintain an erection due to venous leakage from the penis. In other cases, the dysfunction is associated with a neural pathway, or is a result of a nerve injury due to trauma or pelvic injury. Impotence is typically caused by a variety of factors.

Alpha-adrenergic receptors (also referred to herein as alpha-adrenergic receptors or alpha-receptors) are located at specific protein recognition sites in the peripheral and central nervous systems and throughout other tissues of the body. Neurotransmitters such as norepinephrine can control many physiological functions by acting on these receptors, thereby transmitting information between cells or affecting biochemical processes within cells. Over the last 40 years, a number of agents have been developed that can modify the activity of norepinephrine at the alpha-receptor.

Drugs active at the α -adrenergic receptor can be divided into two broad classes, agonists and antagonists. Agonists exemplified by clonidine and naphazoline hydrochloride activate the receptor system in the same way as endogenous neurotransmitters (norepinephrine and epinephrine). Antagonists, represented by phenoxybenzamine and prazosin, do not activate receptors but block the action of endogenous neurotransmitters.

Over the past several years, different types of alpha-adrenergic receptors have been discovered, including alpha-adrenergic receptors and alpha-adrenergic receptors₂-adrenergic receptors. These receptor types are now further divided into subtypes 1A, 1B, 1H, 1L, 1N, 2A, 2B and 2C.

α 2-adrenergic receptors are located at nerve endings and act at least in part upon neurotransmitter release. Is known to beCan reduce the activity of sympathetic nervous system and increase the activity of parasympathetic nervous system, especially vagus nerve. In addition, α 2-adrenergic receptors from other tissues in the body control platelet aggregation, lipolysis, and metabolism. It has been found that₂Adrenergic receptors have a wide range of therapeutic effects including reversal of sensory loss (US5, 636, 204), treatment of glaucoma (US5, 590, 202), treatment of cognitive dysfunction such as endogenous depression, age-related memory decline, Alzheimer's disease (US5, 498, 623), and treatment of a variety of other neurodegenerative disorders (US5, 281, 607).

Known as alpha₁Adrenergic receptors can mediate contraction of arterial and venous smooth muscle. Alpha is alpha₁Adrenergic receptor antagonists are widely used in therapy as first-line drugs of hypertension and, more recently, in the treatment of symptomatic relief of Benign Prostatic Hyperplasia (BPH) (see Kenny et al, exp. opin. invest. drug (1995)4(10), pp 915-923). Some have a₁Compounds with adrenergic receptor antagonistic activity, such as phentolamine and chloropriazolone, are used for the treatment of impotence, although the mechanism by which they promote erectile function is not fully understood. It is believed that these compounds exert their effect at least in part by blocking the action of noradrenaline, which, if not blocked, can cause contraction of the smooth muscle of the corpus cavernosum, thereby allowing venous blood to leave the penis and cause the organ to de-swell and soften. Such compounds are typically administered topically by intracavernosal injection, but are often associated with complications such as priapism (prolonged erection with pain), pain and infection at the site of injection, and tissue fibrosis after prolonged use. In addition to these obvious discomforts, there is also the problem of spontaneous (erectile) loss of function.

Alpha-adrenergic receptors indirectly mediate decreased mid-smooth muscle contraction of the corpus cavernosum by centrally acting sympatholytic activity-reducing agents such as chloropriazolone and certain centrally active alpha₂-an adrenergic receptor agonist and a method of treatment,for example clonidine, or directly on smooth muscle cells, for example papaverine.

Formulations that can elevate cGMP levels are also well known and can act by any of several mechanisms. Formulations that can selectively inhibit enzymes include primarily cGMP disruptions, such as cGMP phosphodiesterase (cGMP PDE) as one example. Other phosphodiesterases also hydrolyze cGMP, and therefore inhibitors of these enzymes, including compounds like ciclopirox, zaprinast, and xanthine derivatives (e.g., caffeine, theophylline, and theobromine), can affect cGMP levels. Other compounds that increase cGMP levels may act by different mechanisms, including activation of soluble or membrane-bound guanylate cyclases, either directly as in the case of anterior chamber natriuretic peptides (atrinatriestricepeptides) or indirectly. Other compounds increase cellular cGMP levels by modulating cellular agonists. Other types of cGMP-increasing agents include muscarinic agonists, which increase cGMP levels without altering phosphodiesterase activity. Some prostaglandins (e.g., PGE1) are also known to be cGMP enhancers, Kanba et al, J.neurochem, Vo1.57, No. 6, 1991.

Cyclic guanosine 3 ', 5' -monophosphate phosphodiesterase (cGMP PDE) is generally known to be useful as a cardiovascular agent for the treatment of angina, hypertension and congestive heart failure. Recently, it has been discovered that inhibitors of cGMPPDE are effective in treating impotence and, importantly, must be administered orally. See PCT/EP94/01580, published in W094/28902. It is believed that the therapeutic effect of such compounds can be demonstrated by inhibiting phosphodiesterase and obtaining high levels of cGMP, which in turn relaxes and expands the cavernous cells and prevents the outflow of blood from the penis.

The present invention provides a method of treating impotence, in particular human impotence (also referred to herein in the art as "male erectile dysfunction"), which comprises co-administering to a patient in need of such treatment an effective amount of:

(1) a compound selected from the group consisting of alpha-adrenergic antagonists (also referred to herein as alpha-adrenergic antagonists), and

(2) compounds that can increase cGMP levels (also referred to herein as cGMP increasing agents).

It is to be understood that the compounds or formulations (e.g., alpha adrenergic antagonists and/or cGMP enhancers) of (1) or (2) above, and of the appended claims, should at any time encompass all active forms of such formulations, including their free forms (e.g., free acid or base forms), as well as all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, stereoisomers (e.g., diastereomers and enantiomers), and the like. Any active metabolic form of an alpha adrenergic antagonist or cGMP-enhancer is also included therein.

The alpha-adrenergic antagonist can be directed against alpha₁-or a₂-adrenergic receptors may or may not be selective, at alpha₁-and α₂Antagonistic activity was shown at the receptors. Non-selective antagonists are preferred. For alpha₁Antagonists with selectivity for adrenergic receptors are more preferred. At a known value of₁Among the adrenergic receptor subtypes, antagonists of the 1A, 1B, 1D, 1H, 1N, and 1L receptors are equally preferred.

As cGMP enhancers, cGMP PDE inhibitors are preferred. cGMP PDE inhibitors selective for cGMP PDEs other than cyclic guanosine 3 ', 5' -monophosphate phosphodiesterase (cGMP PDEs) and/or inhibitors selective for cGMP PDEv isozymes are preferred. cGMP PDE inhibitors as disclosed in WO/94/28902 international patent application are particularly preferred in US patent 5, 250, 534, 5, 346, 901, 5, 272, 147 and in addition to US patents, each of which is incorporated herein by reference.

Preferably, as used herein, the α -adrenergic antagonist and the cGMP PDE enhancer are "synergistic" in the sense that the effect of the simultaneous administration of the compounds selected from (1) and (2) as defined above is greater than the effect of the simple compounds. Thus, the combined effect of the two therapeutic agents is greater than the combined effect of the single agent. The advantages of this synergy are: it allows the amount of each therapeutic agent typically administered to be less than if the combined effects were obtained by adding the effects together. Thus, such treatment may be effective in cases where a single component (at a dose which is considered to be the maximum dose) is used, but the patient is still unable to respond adequately. In addition, when these ingredients are administered at low doses in connection with the additive effect of the combination, side effects such as priapism or pain at the injection site can be minimized or in many cases even avoided. The following published experiments can demonstrate such synergy.

This synergistic effect of the preferred combination is given as a further feature of the present invention and therefore, the present invention provides a method for obtaining a level of synergistic efficacy of impotence treatment comprising co-administering to a mammal in need of treatment the following compounds:

(1) an amount of a first compound selected from the group consisting of alpha-adrenergic antagonists; and

(2) an amount of a second compound selected from the group consisting of a compound that increases cGMP levels; wherein the amount of the first compound alone and the amount of the second compound alone are not sufficient to achieve a synergistic level of efficacy in the treatment of impotence, but wherein the combined therapeutic effect of the compositions comprising said amounts of the first and second compounds is greater than the sum of the levels of efficacy in the treatment of impotence achieved when the amounts of the first and second compounds are used alone.

Further preferred combinations include those that can be used "as needed" rather than over a long term. Such preferred combinations include those that modulate the sexual response in order to allow the patient to respond to sexual stimuli (e.g., vision), as opposed to those that would be effective in causing an erection in the absence of sexual stimuli.

Further preferred combinations include those "fast acting" combinations, which means that the time from administration to the point at which the sexual response can be modulated is less than about two hours, preferably less than about 1 hour, more preferably half an hour or less, and most preferably 10 to 15 minutes.

As used herein and in the appended claims, "coadministered" (e.g., in reference to alpha)₁A combination of an antagonist and a cGMP PDE inhibitor) are: the various components may be administered together as a composition if the route of administration of each component is the same. The present invention therefore further provides a composition comprising:

(1) a first compound selected from the group consisting of alpha adrenergic antagonists;

(2) a second compound capable of increasing the level of cGMP; and

(3) a pharmaceutically acceptable carrier. Preferably the composition is synergistic. As a further feature provided by the present invention, such synergistic compositions comprise:

(1) an amount of a first compound selected from the group consisting of alpha-adrenergic antagonists;

(2) an amount of a second compound selected from the group consisting of a compound that increases cGMP levels; wherein the amount of the first compound alone and the amount of the second compound alone are not sufficient to achieve a synergistic level of efficacy for the treatment of impotence, but wherein the effect of the composition comprising said amounts of the first and second compounds is greater than the sum of the levels of efficacy for the treatment of impotence achieved when the amounts of the first and second compounds are used alone; and pharmaceutically acceptable diluents and carriers.

As part of the same treatment plan or regimen, "co-administration" also includes the administration of compounds (1) and (2), respectively, which is expected to be administered each separately at different times and by different routes, as is recommended in some cases. Thus, the two compounds are not intended to be administered at the same time. In a preferred embodiment, the timing of administration is arranged so that the peak effect of the pharmacokinetics of one compound exactly coincides with the peak effect of the pharmacokinetics of the other compound. If co-administration is carried out separately, it is preferred to administer compounds (1) and (2) in oral dosage form.

"combination" here means that the compound selected from (1) and the compound selected from (2) are administered together, i.e. as a composition or separately, e.g. by different routes of administration.

The invention further provides a method of treating impotence, in particular human impotence, which comprises administering to a male human in need of such treatment an effective amount of doxazosin or a pharmaceutically acceptable salt thereof. Doxazosin may be administered as the only active ingredient, i.e. it need not be administered with an alpha-antagonist or any other active compound, although it may do so. Doxazosin is administered in a daily dose of 0.01 to 50mg, preferably 0.5 to 10mg, usually orally or by other routes as described herein, and when a composition, it contains doxazosin and a pharmaceutically acceptable carrier as described herein. Such compositions may be used to treat female sexual dysfunction, as described further below.

The compositions of the present invention are also useful for treating sexual dysfunction in female mammals, including humans. The composition may therefore be used to treat female sexual dysfunction, including orgasmic dysfunction associated with clitoral dysfunction. In the case of use in male mammals, compositions which have a synergistic effect, can be used as desired and can modulate the female sexual response are preferred. Preferred compounds, compositions and combinations for treating female sexual dysfunction (e.g., combinations of compounds for separate administration) are the same as disclosed herein for treating male erectile dysfunction.

The method for treating female sexual dysfunction is the same as the method for treating impotence or erectile dysfunction in a male animal provided herein.

Since one aspect of the present invention relates to the use of a combination of compounds for the treatment of impotence or female sexual dysfunction, the above compounds may be co-administered by separate administration. The invention also relates to combining separate pharmaceutical ingredients in a pharmaceutical kit. The kit comprises two separate pharmaceutical components: (1) a composition comprising a compound selected from the group consisting of alpha adrenergic receptor antagonists plus a pharmaceutically acceptable carrier or diluent; and (2) compositions comprising a compound selected from cGMP level increasing agents, plus a pharmaceutically acceptable carrier or diluent. (1) The amounts of (1) and (2) should be: when co-administered by separate administration, it may treat and/or ameliorate impotence or female sexual dysfunction conditions. The pharmaceutical kit also includes a container for holding separate compositions, such as separate vials or foil packets, wherein each separate space contains a plurality of doses (e.g., tablets) comprising either (1) or (2) dosage forms. In addition, in addition to dividing (packaging) the dosage forms containing the active ingredient, the pharmaceutical cassettes may contain separate compartments, each containing a full dose, which in turn may contain separate dosage forms. An example of this type of pharmaceutical pack is a blister pack wherein each individual blister contains two (or more) tablets comprising pharmaceutical composition (1), one (or more) tablet(s), and a second (or more) tablet(s) containing pharmaceutical composition (2). Typically, the pharmaceutical kit contains instructions for administration of the individual components. This form of kit is particularly advantageous where the individual components are to be administered in different dosage forms (e.g. oral and parenteral) or where different dosage intervals are required, or where the individual components of the combination are required by the attending physician. Thus, in the context of the present invention, a pharmaceutical kit comprises the following ingredients:

(1) a therapeutically effective dose of a composition comprising a compound selected from the group consisting of an alpha adrenergic receptor antagonist in a first dosage form together with a pharmaceutically acceptable carrier or diluent;

(2) a therapeutically effective dose of a composition comprising a compound selected from the group consisting of compounds that elevate cGMP levels in a second dosage form together with a pharmaceutically acceptable carrier or diluent; and

(3) a container containing said first and second dosage forms.

An example of a medicament cartridge mentioned above is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms, such as tablets, capsules and the like. Blister packs are usually made from a sheet of relatively rigid material covered with a foil of transparent plastics material. During the packaging process, the plastic foil forms depressions. The size and shape of the depressions are the same as those of tablets and capsules. Next, the tablet or capsule is placed in the depression and a thin sheet of relatively hard material is sealed against the plastic foil at the surface of the foil, which is in the opposite direction to the depression formation. As a result, the tablet or capsule is enclosed in the depression between the plastic foil and the sheet. Preferably, the strength of the sheet is such that manual pressure at the depressions causes the tablets or capsules to be transferred from the blister pack, thereby forming an opening in the sheet corresponding to the location of the depressions. The tablet or capsule can be transferred out of the opening.

It may be desirable to provide a memory aid on the medication box, for example in the form of a number accompanying a tablet or capsule that corresponds to the number of days in the treatment regimen and (prompts) that such a designated tablet or capsule should be ingested during that period. Another example of such a memory aid is a calendar printed on the card, such as "first week, monday, tuesday,. et al, second week, monday, tuesday,. et al. Other variations of memory assistance are apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a given day. The daily dose of the first compound may also consist of one tablet or capsule, while the daily dose of the second compound may also consist of several tablets or capsules, and vice versa. Memory aids can reflect this.

The combinations used in the present invention may optionally also contain other pharmaceutical ingredients as part of the combination, as long as they do not interfere with or adversely affect the action of the α -antagonist/cGMP-enhancer combination.

Preferred combinations are cGMP PDE inhibitors and selective alpha₂-an antagonist.

More preferred combinations are cGMP PDE inhibitors and non-selective alpha-antagonists.

More preferred combinations are cGMP PDE inhibitors and selective alpha₁-an antagonist.

Preferred combinations further comprise (1) in order from lower to higher, α₂-antagonists, non-selective alpha-antagonists or selective alpha₁-an antagonist; and (2) for cGMP PDE_vIsozymes are selective cGMP PDE inhibitors. The targeting of cGMP PDE is disclosed and described in PCT/EP94/01580 published in accordance with WO/94/28902_vIsozymes are selective compounds which are specifically assigned to the united states and are incorporated herein by reference.

Preferred cGMP PDE inhibitors include sildenafil and pharmaceutically acceptable salts thereof, which have the following structure:and compounds having the structure and pharmaceutically acceptable salts thereof.A second compound is disclosed in U.S. Pat. Nos. 5,272,147 and 5,426,207, both of which are incorporated herein by reference.

A preferred pharmaceutically acceptable salt of sildenafil for use in the present invention is the citrate salt, which is disclosed in pending U.S. patent application 08/944, 546, filed 10, 7, 1997 and incorporated herein by reference.

Also preferred are the compounds disclosed in PCT/EP95/00183, published as WO/95/19978 (particularly in the United states of America), which are incorporated herein by reference, and the compounds and salts and solvates thereof having the following structureWherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6-alkyl radical, C_2-6-alkenyl radical, C_2-6-alkinyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; r²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom on the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen; and R is³Represents hydrogen or C_1-3-alkyl, or R¹And R³Together the generations represent a 3-or 4-membered alkyl or alkenyl chain.

Preferred subgroups of the compounds of formula Ia and their salts and solvates (also disclosed in WO/95/19978) include compounds of the formulaWherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6Alkyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; and R is²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom in the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen.

Particular compounds in formula (i) are: (6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione.

Preferred alpha-antagonists include doxazosin, terazosin, abanoquine and prazosin and pharmaceutically acceptable salts thereof (particularly doxazosin mesylate, terazosin hydrochloride and prazosin hydrochloride) which are selective for the alpha 1-adrenergic receptor. Preferred specific combinations include any of the above compounds in combination with sildenafil or a pharmaceutically acceptable salt thereof, especially the citrate salt. Most preferred is the combination of sildenafil citrate with doxazosin mesylate or abanoquine mesylate.

Examples of other alpha-antagonists include alfuzosin, indapamide, naftopidil, phentolamine, tamsulosin, haloperidol, piprozole, phenoxybenzamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof. Rovoxate is also useful. Among these compounds, phenoxybenzamine, phentolamine, haloperidol and piprozole are reported to be non-selective, and rauwolfine, imipramine, eloxagliflon and yohimbine are reported to be para-alpha₂The receptors being selective, other specific compounds being selective for alpha₁The receptor is selective.

Has been reported to be on alpha₁Other α -antagonists whose receptors are selective include:

recordati 15/2739 having the structure:SNAP 1069 having the structure:SNAP 5089 having the structure:RS 17053 having the structure:SL 89．0591, having the structure:

specific combinations of an alpha-antagonist and a cGMP-enhancing agent for use in the present invention include any combination of an adrenergic antagonist and sildenafil. Sildenafil, especially sildenafil citrate, with alpha₁Combinations of selective antagonists (including any of the combinations mentioned herein before) are preferred.

The cGMP PDE inhibitors used in the present invention as cGMP enhancers may be selected from those compounds known in the art or subsequently discovered and/or presented below. Suitable cGMP PDE inhibitors include those disclosed in any of the following US patents, all of which are incorporated herein by reference:

5-substituted pyrazolo [4, 3-d ] pyrimidin-7-ones as disclosed in US 4, 666, 908;

US 4, 634, 706; 4,783, 532; 5,498, 819; 5,532, 369; a griseovic acid derivative as disclosed in any one of 5,556, 975 and 5, 616, 600;

phenyl purinones disclosed in US 4, 885, 301;

phenylpyridone as disclosed in US5, 254, 571;

fused pyrimidine derivatives as disclosed in US5, 047, 404;

condensed pyrimidine derivatives disclosed in US5, 075, 310;

pyrimidopyrimidine derivatives disclosed in US5, 162, 316;

purine compounds disclosed in US5, 073, 559;

quinazoline derivatives disclosed in US5, 147, 875;

phenyl pyrimidone derivatives disclosed in US5, 118, 686;

imidazoquinoxalinone derivatives or aza congeners thereof as disclosed in US5, 055, 465 and 5, 166, 344;

phenyl pyrimidinone derivatives disclosed in US5, 290, 933;

4-aminoquinazoline derivatives as disclosed in US5, 436, 233 and 5, 439, 895;

4, 5-dihydro-4-oxo-pyrrolo [1, 2-d ] quinoxaline derivatives disclosed in US5, 405, 847;

polycycloguanine derivatives disclosed in US5, 393, 755;

nitrogen-containing heterocyclic compounds disclosed in US5, 576, 322;

quinazoline derivatives disclosed in US 4, 060, 615; and

6-heterocyclic pyrazolo [3, 4-d ] pyrimidin-4-ones as disclosed in U.S. Pat. No. 5,294,612.

Other disclosed cGMP PDE inhibitors include the following compounds, all of which are incorporated herein by reference:

european Patent Application (EPA), publication No. 0428268;

european patent application 0442204;

international patent application, publication No. WO 94/19351;

japanese patent application, 5-222000;

european journal of pharmacology, 251, (1994), 1: and

international patent application, publication No. WO 94/22855;

in addition to the specific designations above, α -antagonists and salts thereof are widely disclosed in the patent literature, including US patents 4, 188, 390, 4, 026, 894, 3, 511, 836, 4, 513, 007, 3, 527, 761, 3, 997, 666, 2, 503, 059, 4, 703, 063, 3, 381, 009, 4, 252, 721 and 2, 599, 000. All of which are incorporated herein by reference.

Thus, the resulting alpha-antagonist compounds and their suitability for use in the present invention can be determined using a number of conventional in vitro assays. Suitable assays include those disclosed in US5, 599, 810, in which the rabbit aorta is used to determine alpha₁-adrenergic receptor antagonist activity and alpha is measured using the left anterior chamber of a Dutch pig₂In US5, 340, 814, the cerebral cortex membranes of rats were used to determine alpha₁And alpha₂-the activity of an antagonist. Both of the above patents are incorporated herein by reference.

The cGMP PDE inhibitory activity of a compound can also be determined by standard assays known in the art, for example as disclosed in US5, 250, 534, which is also incorporated herein by reference. Compounds that are selective for cGMP PDE inhibitors over cAMP PDEs are preferred. Methods for determining such compounds are given in US5, 250, 534. Particularly preferred is for cGMP PDE_vIsozymes are selective compounds, as disclosed in the aforementioned PCT/EP94/01580 published as WO/94/28902.

As disclosed above, the individual compounds of the combination used in the present invention are usually administered separately, and each compound may take its conventional and known route, and in some cases, the route of administration may be different. In preferred embodiments, the timing of administration is generally specified so that the α -antagonist and the cGMP-enhancer are consistent or nearly consistent in the time to achieve their maximum pharmacokinetic effect. The route of administration may be by any route known in the art, such as orally, parenterally by local injection via the cavernous body or in the urethra, or by transdermal application of the active ingredient in a gel or other such formulation which may be applied topically to the penis. Each compound may be formulated according to methods known in the art with pharmaceutically acceptable carriers or diluents, for example as tablets, capsules, lozenges, troches, suspensions, solutions or suspensions for oral administration, parenterally in a suitable vehicle for injection, or as lotions, ointments or creams for topical application. In a preferred embodiment, the cGMP-enhancer and the α -antagonist are co-administered orally, either together or separately.

The exact dosage of each component administered will, of course, vary depending upon the particular compound employed, the subject being treated, the severity of the sexual impotence or female disorder, the mode of administration and the judgment of the attending physician, and the like. Thus, the dosages given below are only used as a guide due to patient-to-patient variability, and the physician can adjust the dosage of the compound to achieve the therapeutic effect the physician deems appropriate for the patient, male or female. The physician must balance various factors, such as the age of the patient and the presence of other diseases or conditions (e.g., cardiovascular disease), in view of the degree of treatment required. Generally, the cGMP booster is administered in an amount ranging from 0.5 to 200mg, preferably from 10 to 125mg, more preferably from 25 to 100mg per day. The amount of alpha-antagonist administered is in the range of 0.01-50 mg, preferably 0.5-10 mg per day. If the cGMPD enhancer is a prostaglandin, it is typically administered by intracavernosal injection in an amount of 1ng to 100 ug per day, or via the urethra in an amount of 100 ug to 2mg per day. Typically, the volume of the injected volume does not exceed 1 ml. The carrier and diluent are typically sterile physiological saline or other physiologically acceptable salt solutions. Oral administration of prostaglandins is also convenient. See journal of urology, 83 (10): 1655-1661(1992).

As previously disclosed, the combination of a cGMP PDE elevating agent and an alpha adrenergic receptor antagonist can be administered as a composition. The compounds of the invention may thus be administered in any conventional form, for example oral, parenteral, rectal or transdermal, together with a pharmaceutically acceptable carrier or diluent.

For oral administration, the pharmaceutical compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, carbonic acid and calcium phosphate may be employed together with various disintegrants such as starch, preferably potato or tapioca starch and certain complex silicates, together with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful in the preparation of tablets. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules; in this regard, preferred materials also include lactose or milk sugar and high molecular weight polyethylene glycols. When oral administration using aqueous suspensions and/or suspensions is desired, the compounds of the invention may be combined with various sweetening, flavoring, coloring, emulsifying and/or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

For parenteral administration, sesame or peanut oily solutions or aqueous propylene glycol solutions and sterile aqueous solutions of the corresponding water-soluble salts may be used. Such aqueous solutions may be suitably buffered, if desired, by first making the diluent isotonic with sufficient saline and glucose. These aqueous solutions are particularly suitable for administration by intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this connection, the sterile aqueous medium employed can be readily obtained according to standard techniques well known to the expert in the field.

For transdermal (e.g., topical) administration, dilute sterile or partially sterile aqueous solutions (typically at concentrations of about 0.1% to 0.5%) or solutions similar to the parenteral solutions described above are preferred.

Methods for preparing various pharmaceutical compositions using certain amounts of active ingredients are known or will become apparent to those skilled in the art in light of the present disclosure. Examples of methods for preparing pharmaceutical compositions can be found in Remington's pharmaceutical sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The combination of an alpha-antagonist and a cGMP raising agent (e.g., a cGMP PDE inhibitor) can be tested in beagle dogs or monkeys. The following description is of monkeys, but is readily recognized by experts in the field: this experiment is equally applicable to beagle dogs.

Mature male monkeys weighing 4-8kg, typically Cercopithecusaethiops (green monkey) or Macaca fascicularis (cynomologous) were used. Animals were anesthetized with diazepam (2.5 mg), chlorthalidone chloride (20 μ g/kg, i.m. provided appropriate amounts), and an appropriate compound dissolved in normal saline (0.3 ml) was administered intracavernosally. The animal was supine, the penis extended, and a rubber bandage wrapped around the base root as a tourniquet was held in place for 3 minutes after injection. The solution was injected into one of the sponges through a 27G needle and after 5, 10, 25, 30, 60 and 180 minutes, the enlargement (volume increase) and firmness of the penis were assessed visually and by the condition of the heartbeat. To determine the domain effect, a series of animals were used to perform a coverage experiment on the appropriate dose range of the test compound using an injectable solution. Thereby determining the domain effect of the resulting compound.

Combinations of α -antagonists with cGMP-enhancing agents (e.g., cGMP PDE inhibitors) can be tested in human and animal models by clinical (typically oral) methods. A number of male patients were given each component alone at different times in amounts that produced little or no response, typically less than 50%, and then measured according to firm and swollen Rigiscan clinical evaluation parameters (see kaneko et al, J.Urol.136, 1026-1029 (1986); and 0gric et al, J.Urol.154, 1356-1359(1995)) along with an International erectile function index (IIEF) questionnaire to assess patient and partner satisfaction. By separately administering each component is meant that one component is administered first, and after an appropriate period of time, the second component is administered after the first component has been depleted. After depletion of each of the components administered separately, co-administration of the components is carried out in such a way that the two components co-manipulate the pharmacokinetics, preferably in such a way that the peak effect of the kinetics is due to coincidence (of the two components peaks). The effect of co-administration was evaluated according to the above-mentioned regiscan parameters and IIEF questionnaire, thereby providing a basis for comparing the effect of co-administration with the effect of single administration.

Claims (126)

1. A method of treating impotence comprising co-administering to a patient in need of such treatment an effective amount of:

(1) a compound selected from alpha-adrenergic antagonists, and

(2) a compound that can increase cGMP levels.

2. The method as defined in claim 1 wherein said cGMP elevating agent is a cGMP PDE inhibitor.

3. The method as defined in claim 1 wherein said cGMP increasing agent is a prostaglandin.

4. A method as defined in claim 2, wherein said cGM PDE inhibitor is selective for the cGMP PDEv isozyme.

5. The method as defined in claim 4 wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.

6. A method as defined in claim 5, wherein said salt is citrate.

7. The method as defined in claim 2 wherein said cGMP PDE inhibitor has the following structure

8. The method as defined in claim 2 wherein said cGMP PDE inhibitor and salts and solvates thereof has the structureWherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6-alkyl radical, C_2-6-alkenyl radical, C_2-6-alkinyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; r²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom on the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms andany one or two heteroatoms selected from oxygen, sulfur and nitrogen; and R is³Represents hydrogen or C_1-3-alkyl, or R¹And R³Together the generations represent a 3-or 4-membered alkyl or alkenyl chain.

9. The method as defined in claim 2 wherein said compound, and salts and solvates thereof, has the structureWherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6Alkyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; and R is²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom in the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen.

10. The method as defined in claim 1, wherein said alpha adrenergic antagonist is non-selective.

11. The method as defined in claim 1 wherein said α -adrenergic antagonist is a selective α₁-an antagonist.

12. The method as defined in claim 1 wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, mopidamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

13. The method as defined in claim 12 wherein said alpha adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof.

14. The method as defined in claim 13, wherein said alpha adrenergic antagonist is selected from the group consisting of doxazosin, abanoquine, or a pharmaceutically acceptable salt of both.

15. The method as defined in claim 14 wherein said alpha adrenergic antagonist is doxazosin mesylate or carbanoquine mesylate.

16. The method as defined in claim 1 wherein said first compound is doxazosin, abanoquine, or a pharmaceutically acceptable salt thereof and said second compound is sildenafil or a pharmaceutically acceptable salt thereof.

17. A method as defined in claim 16, wherein said first compound is doxazosin mesylate and said second compound is sildenafil citrate.

18. A method as defined in claim 16, wherein said first compound is abanoquine mesylate and said second compound is sildenafil citrate.

19. The method as defined in claim 1, comprising co-administration

(a) cGMP PDE inhibitors and selective alpha₂-an adrenergic antagonist;

(b) a cGMP PDE inhibitor and a non-selective alpha-adrenergic antagonist; or

(c) cGMP PDE inhibitors and selective alpha₁-adrenergic antagonists.

20. The method as defined in claim 19 wherein said cGMP PDE inhibitor is selective for cGMPPDEv isozyme.

21. The method as defined in claim 19 wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.

22. A method as defined in claim 21, wherein said salt is citrate.

23. The method as defined in claim 19 wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, mopidamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

24. The method as defined in claim 23 wherein said method comprises co-administering (1) an alpha-adrenergic antagonist selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof; (2) sildenafil or a pharmaceutically acceptable salt thereof.

25. The method as defined in claim 24, wherein said alpha adrenergic antagonist is doxazosin, abanoquine, or a pharmaceutically acceptable salt of both.

26. A method as defined in claim 25, wherein said antagonist is doxazosin mesylate or abanoquine mesylate.

27. A method as defined in claim 24, wherein the sildenafil salt is citrate.

28. The method as defined in claim 1 wherein (1) and (2) are both administered orally.

29. The method as defined in claim 1 wherein (1) and (2) are administered together in a composition.

30. The method as defined in claim 1 wherein (1) and (2) are administered separately.

31. A composition comprising:

(1) a first compound selected from an alpha-adrenergic receptor antagonist;

(2) a second compound that increases cGMP levels; and

(3) a pharmaceutically acceptable carrier.

32. The composition as defined in claim 31, wherein said cGMP elevating agent is a cGMP PDE inhibitor.

33. The composition as defined in claim 31, wherein said cGMP PDE enhancer is a prostaglandin.

34. The composition as defined in claim 32, wherein said cGMP PDE inhibitor is selective for the cGMP PDEv isozyme.

35. The composition as defined in claim 32 wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.

36. The composition as defined in claim 35, wherein said salt is citrate.

37. The composition as defined in claim 32, wherein said cGMP PDE inhibitor or a pharmaceutically acceptable salt thereof has the structure.

38. The method as defined in claim 32 wherein said cGMP PDE inhibitor or salts and solvates thereof has the structure,wherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6-alkyl radical, C_2-6-alkenyl radical, C_2-6-alkinyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; r²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom on the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen; and R is³Represents hydrogen or C_1-3-alkyl, or R¹And R³Together the generations represent a 3-or 4-membered alkyl or alkenyl chain.

39. The method as defined in claim 32 wherein said cGMP PDE inhibitor or salts and solvates thereof has the structure,wherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, and is selected from the group consisting of,C_1-6alkyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; and R is²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom in the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen.

40. The composition as defined in claim 31, wherein said first compound is an alpha adrenergic antagonist which is non-selective.

41. The composition as defined in claim 31, wherein said first compound is an alpha-adrenergic antagonist that is selective for alpha₁-an antagonist.

42. The composition as defined in claim 31, wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, mopidamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

43. The composition as defined in claim 42, wherein said alpha adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof.

44. The method as defined in claim 43, wherein said alpha adrenergic antagonist is selected from the group consisting of doxazosin, abanoquine, or a pharmaceutically acceptable salt of both.

45. The method as defined in claim 44, wherein said alpha adrenergic antagonist is doxazosin mesylate or carbanoquine mesylate.

46. The composition as defined in claim 31, wherein said first compound is doxazosin, abanoquine, or a pharmaceutically acceptable salt thereof, and said second compound is sildenafil or a pharmaceutically acceptable salt thereof.

47. A composition as defined in claim 46, wherein said first compound is doxazosin mesylate and said second compound is sildenafil citrate.

48. A composition as defined in claim 46, wherein said first compound is abanoquine mesylate and said second compound is sildenafil citrate.

49. The composition as defined in claim 31, wherein (1) and (2) are selected from the group consisting of:

(a) (1) is optional alpha₂-an adrenergic antagonist and (2) is a cGMP PDE inhibitor,

(b) (1) a non-selective alpha-adrenergic antagonist and (2) a cGMP PDE inhibitor, and

(c) (1) is optional alpha₁-an adrenergic antagonist and (2) is a cGMP PDE inhibitor.

50. The composition as defined in claim 49, wherein said cGMP PDE inhibitor is directed against cGMP PDE_vIsozymes are selective.

51. The composition as defined in claim 49, wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, mopidamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzylamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

52. The composition as defined in claim 49, comprising (1) an α -adrenergic antagonist selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof; (2) sildenafil or a pharmaceutically acceptable salt thereof.

53. The composition as defined in claim 52, wherein said alpha adrenergic antagonist is (1) abacoquinol, doxazosin, or a pharmaceutically acceptable salt of both, and (2) sildenafil citrate.

54. The composition as defined in claim 53, wherein said alpha adrenergic antagonist (1) is doxazosin mesylate.

55. The composition as defined in claim 53, wherein said alpha adrenergic antagonist (1) is abanoquine mesylate.

56. The composition as defined in claim 31, which is administered orally.

57. A method for obtaining a level of synergy of impotence treatment, comprising co-administering to a mammal in need of such treatment

(1) An amount of a first compound selected from the group consisting of alpha-adrenergic antagonists; and

(2) an amount of a second compound selected from the group consisting of a compound that increases cGMP levels; wherein the amount of the first compound alone and the amount of the second compound alone are not sufficient to achieve a synergistic level of efficacy in the treatment of impotence, but wherein the combined therapeutic effect of the compositions comprising said amounts of the first and second compounds is greater than the sum of the levels of efficacy in the treatment of impotence achieved when the amounts of the first and second compounds are used alone.

58. The method as defined in claim 57, wherein said cGMP enhancer is a cGMP PDE inhibitor.

59. The method as defined in claim 57, wherein said cGMP enhancer is a prostaglandin.

60. The method as defined in claim 58 wherein said cGMP PDE inhibitor is selective for cGMPDEV isozyme.

61. The method as defined in claim 58 wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.

62. A method as defined in claim 61, wherein said salt is citrate.

63. The method as defined in claim 58 wherein said cGMP PDE inhibitor or pharmaceutically acceptable salt thereof has the structure

64. The method as defined in claim 58 wherein said cGMP PDE inhibitor and salts and solvates thereof has the structureWherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6-alkyl radical, C_2-6-alkenyl radical, C_2-6-alkinyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; r²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom on the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen; and R is³Represents hydrogen or C_1-3-alkyl, or R¹And R³Together the generations represent a 3-or 4-membered alkyl or alkenyl chain.

65. The method as defined in claim 32 wherein said cGMP PDE inhibitor or salts and solvates thereof has the structure,wherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6Alkyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; and R is²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom in the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen.

66. The composition as defined in claim 57, wherein said first compound is an alpha adrenergic antagonist which is non-selective.

67. The composition as defined in claim 57, wherein said first compound is an alpha adrenergic antagonist which is selective for alpha₁-adrenergic antagonists.

68. The method as defined in claim 57, wherein said first compound is an α -adrenergic antagonist selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, indapamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

69. The method as defined in claim 68, wherein said alpha adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof.

70. The method as defined in claim 69 comprising (1) an α -adrenergic antagonist selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof; (2) sildenafil or a pharmaceutically acceptable salt thereof.

71. The method as defined in claim 70 wherein said alpha adrenergic antagonist is (1) abacoquinol, doxazosin, or a pharmaceutically acceptable salt of both, and (2) sildenafil citrate.

72. A method as defined in claim 71, wherein (1) is doxazosin mesylate.

73. A composition as defined in claim 71, wherein (1) is abanoquine mesylate.

74. The method as defined in claim 57, wherein (1) and (2) are selected from the group consisting of:

(a) (1) is optional alpha₂-an adrenergic antagonist and (2) is a cGMP PDE inhibitor,

(b) (1) a non-selective alpha-adrenergic antagonist and (2) a cGMP PDE inhibitor, and

(c) (1) is optional alpha₁-an adrenergic antagonist and (2) is a cGMP PDE inhibitor.

75. The method as defined in claim 74 wherein said cGMP PDE inhibitor is directed to cGMPP PD_vIsozymes are selective.

76. The method as defined in claim 74, comprising (1) an α -adrenergic antagonist selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof; and (2) sildenafil or a pharmaceutically acceptable salt thereof.

77. The method defined in claim 76 wherein α₁The adrenergic antagonist is doxazosin, abanoquine or pharmaceutically acceptable salts of the doxazosin and the abanoquine.

78. A method as defined in claim 57, wherein both (1) and (2) are administered orally.

79. The method as defined in claim 57 wherein (1) and (2) are administered together as a composition.

80. The method as defined in claim 57, wherein (1) and (2) are administered separately.

81. A composition comprising:

(1) an amount of a first compound selected from the group consisting of alpha-adrenergic antagonists;

(2) an amount of a second compound selected from the group consisting of a compound that increases cGMP levels; wherein the amount of the first compound alone and the amount of the second compound alone are not sufficient to achieve a synergistic level of efficacy in the treatment of impotence, but wherein the therapeutic effect of the composition comprising said amounts of said first and second compounds is greater than the sum of the levels of efficacy in the treatment of impotence achieved when the amounts of said first and second compounds are used alone; the composition further comprises a pharmaceutically acceptable diluent or carrier.

82. The composition as defined in claim 81, wherein said cGMP enhancer is a cGMP PDE inhibitor.

83. The composition as defined in claim 81, wherein said cGMP enhancer is a prostaglandin.

84. The composition as defined in claim 82, wherein said cGMP PDE inhibitor is directed against cGMP PDE_vIsozymes are selective.

85. The composition as defined in claim 84, wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.

86. The composition as defined in claim 85, wherein said salt is citrate.

87. The composition as defined in claim 82, wherein said cGMP PDE inhibitor or a pharmaceutically acceptable salt thereof has the structure.

88. The method as defined in claim 82 wherein said cGMP PDE inhibitor or salts and solvates thereof has the structure,wherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6-alkyl radical, C_2-6-alkenyl radical, C_2-6-alkinyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; r²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom on the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen; and R is³Represents hydrogen or C_1-3-alkyl, or R¹And R³Together the generations represent a 3-or 4-membered alkyl or alkenyl chain.

89. The method as defined in claim 82 wherein said cGMP PDE inhibitor or salts and solvates thereof has the structure,wherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6Alkyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; and R is²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring passing through a carbon atom of the phenyl ringThe atoms are attached to the rest of the molecule, wherein the fused A ring is a 5-or 6-membered ring, which may be saturated or partially or fully unsaturated, and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen.

90. The composition as defined in claim 81, wherein said first compound is an alpha adrenergic antagonist which is non-selective.

91. The composition as defined in claim 81, wherein said first compound is an alpha adrenergic antagonist which is selective for alpha₁-adrenergic antagonists.

92. The composition as defined in claim 81, wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, mopidamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzylamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

93. The composition as defined in claim 92, wherein said alpha adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof.

94. The composition as defined in claim 93, wherein said alpha adrenergic antagonist is selected from the group consisting of doxazosin, abanoquine, or a pharmaceutically acceptable salt of both.

95. The composition as defined in claim 94, wherein said alpha adrenergic antagonist is doxazosin mesylate or carbanoquine mesylate.

96. The composition as defined in claim 81, wherein said first compound is doxazosin, abanoquine, or a pharmaceutically acceptable salt thereof, and said second compound is sildenafil or a pharmaceutically acceptable salt thereof.

97. The composition as defined in claim 96, wherein said first compound is doxazosin mesylate and said second compound is sildenafil citrate.

98. The composition as defined in claim 96, wherein said first compound is abanoquine mesylate and said second compound is sildenafil citrate.

99. The composition as defined in claim 81, wherein (1) and (2) are selected from the group consisting of:

(a) (1) is optional alpha₂-an adrenergic antagonist and (2) is a cGMP PDE inhibitor,

(b) (1) a non-selective alpha-adrenergic antagonist and (2) a cGMP PDE inhibitor, and

(c) (1) is optional alpha₁-an adrenergic antagonist and (2) is a cGMP PDE inhibitor.

100. The composition as defined in claim 99, wherein said cGMP PDE inhibitor is directed to cGMP PDE_vIsozymes are selective.

101. The composition as defined in claim 99, wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, mopidamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzylamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

102. The composition as defined in claim 99, comprising (1) an α -adrenergic antagonist selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof; (2) sildenafil or a pharmaceutically acceptable salt thereof.

103. The composition as defined in claim 102, wherein said α -adrenergic antagonist is (1) abacoquinol, doxazosin, or a pharmaceutically acceptable salt of both, and (2) sildenafil citrate. .

104. The method as defined in claim 103 wherein said α -adrenergic antagonist (1) is doxazosin mesylate.

105. The composition as defined in claim 103, wherein said α -adrenergic antagonist (1) is abanoquine mesylate.

106. A composition as defined in claim 81, which is administered orally.

107. A medicament cartridge comprising

(1) A therapeutically effective amount of a first composition comprising an α -adrenergic antagonist compound and a pharmaceutically acceptable carrier or diluent in a first dosage form;

(2) a therapeutically effective dose of a second composition comprising a compound selected from the group consisting of cGMP level increasing compounds and a pharmaceutically acceptable carrier or diluent in a second dosage form; and

(3) a container filled with said first and second dosage forms.

108. The pharmaceutical kit as defined in claim 107 wherein the second composition comprises a cGMP elevating agent which is a cGMP PDE inhibitor.

109. The pharmaceutical kit as defined in claim 108 wherein said cGMP PDE inhibitor is directed against cGMP PDE_vIsozymes are selective.

110. The kit as defined in claim 109 wherein said cGMP PDE inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.

111. The pharmaceutical kit as defined in claim 110 wherein said salt is citrate.

112. The drug cassette as defined in claim 108 wherein said cGMP PDE inhibitor or a pharmaceutically acceptable salt thereof has the structure.

113. The drug cassette as defined in claim 108 wherein said cGMP PDE inhibitor or salts and solvates thereof has the structure,wherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6-alkyl radical, C_2-6-alkenyl radical, C_2-6-alkinyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; r²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom in the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains a carbon atomAnd optionally one or two heteroatoms selected from oxygen, sulfur and nitrogen; and R is³Represents hydrogen or C_1-3-alkyl, or R¹And R³Together the generations represent a 3-or 4-membered alkyl or alkenyl chain.

114. The drug cassette as defined in claim 108 wherein said cGMP PDE inhibitor or salts and solvates thereof has the structure,wherein: r⁰Represents hydrogen, halogen or C_1-6-an alkyl group; r¹Represents hydrogen, C_1-6Alkyl, halo C_1-6-alkyl radical, C_3-8-cycloalkyl radical, C_3-8-cycloalkyl group C_1-3Alkyl, aryl C_1-3-alkyl or heteroaryl C_1-3-an alkyl group; and R is²Represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring,the bicyclic ring is attached to the remainder of the molecule through a carbon atom in the phenyl ring, wherein the fused A ring is a 5-or 6-membered ring which may be saturated or partially or fully unsaturated and contains carbon atoms and any one or two heteroatoms selected from oxygen, sulfur and nitrogen.

115. The pharmaceutical kit as defined in claim 107 wherein said alpha adrenergic antagonist is non-selective.

116. The pharmaceutical kit as defined in claim 107 wherein said α -adrenergic antagonist is a selective α₁-adrenergic antagonists.

117. The kit as defined in claim 107 wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, alfuzosin, mopidamide, naftopidil, phentolamine, tamsulosin, haloperidol, phenoxybenzamine, idazoxan, eloxan, yohimbine, and pharmaceutically acceptable salts thereof.

118. The kit as defined in claim 117 wherein said α -adrenergic antagonist is selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof.

119. The kit as defined in claim 107 wherein (1) is a β -adrenergic antagonist selected from the group consisting of doxazosin, terazosin, abanoquine, prazosin, and pharmaceutically acceptable salts thereof; and (2) sildenafil or a pharmaceutically acceptable salt thereof.

120. The pharmaceutical kit as defined in claim 119 wherein said α is₁-the adrenergic antagonist is doxazosin or a pharmaceutically acceptable salt thereof.

121. The pharmaceutical kit as defined in claim 119 wherein the sildenafil salt is citrate.

122. The pharmaceutical kit as defined in claim 119 wherein (1) and (2) are both administered orally.

123. A pharmaceutical kit as defined in claim 107 which is suitable for the treatment of male erectile dysfunction or female sexual dysfunction.

124. A method of treating female sexual dysfunction comprising co-administering to a patient in need of such treatment an effective amount of:

(1) a compound selected from alpha-adrenergic antagonists, and

(2) a compound that can increase cGMP levels.

125. A method for achieving a level of synergistic efficacy in the treatment of female sexual dysfunction comprising co-administering to a mammal in need of such treatment the following compounds:

(1) an amount of a first compound selected from the group consisting of alpha-adrenergic antagonists; and

(2) an amount of a second compound selected from the group consisting of a compound that increases cGMP levels; wherein the amount of the first compound alone and the amount of the second compound alone are not sufficient to achieve a synergistic level of therapeutic efficacy in the treatment of female sexual dysfunction, and wherein the combined therapeutic effect of a composition comprising said amounts of the first and second compounds is greater than the sum of the levels of therapeutic efficacy in the treatment of female sexual dysfunction achieved when the amounts of the first and second compounds are used alone.

126. A method of treating male erectile dysfunction or female sexual dysfunction comprising administering to a mammal in need of such treatment an effective amount of doxazosin or a pharmaceutically acceptable salt thereof.