Patent Application: US-78049510-A

Abstract:
methods for treatment of sexual dysfunction in men and women using combination of phosphodiesterase type 5 inhibitors and 1 - deprenyl or propargylamine compounds are described . methods of reducing the dosage and preventing the side effects of pde type5 inhibitors are also described . the methods comprise administering a therapeutically effect amount of 1 - deprenyl or propargylamine compounds inhibitors ) in combination with pde inhibitors . stimulation of nitric oxide production and vasodilation by 1 - deprenyl and propargylamine compounds augments the actions of pde inhibitors or other drugs and methods used in the treatment of sexual dysfunction . the composition described here enhances the actions of pde inhibitors primarily by increasing the generation of cyclic gmp by stimulating the nitric oxide pathway and secondarily by providing several additional benefits such as enhanced dopamine activity . methods of enhancing the efficacy of various pde inhibitors in the treatment of a number of disorders other than sexual dysfunction are also disclosed .

Description:
the present invention is based on the discovery that a selective group of compounds , 1 - deprenyl and propargylamine compounds ( monoamine oxidase [ mao ] inhibitors ), acts synergistically with type 5 phosphodiesterase inhibitors to induce vasodilation and or prevent vasospasm . phosphodiesterase type 5 inhibitors potentiate the actions of nitric oxide ( no ) by elevating the levels of cgmp , and thus enhance blood flow and erectile function . we have previously shown that 1 - deprenyl and proprgylamine compounds stimulate the production of nitric oxide both in peripheral and cerebral tissues ( thomas , 2001 , 1998 ; u . s . pat . no . 6 , 432 , 991 ). mao inhibitors also elevate the levels of dopamine , a key mediator of sexual function in the brain . we show here that mao inhibitors augment the actions of pde5 inhibitors , reduce side effects , and enable the reduction of the dose of pde inhibitors . the flow chart , shown in fig1 , illustrates sites of actions of these compounds . it has been shown that 1 - deprenyl and other propargylamine derivatives induce , no production , vasodilation , and endothelial protection ( thomas , 2001 , 1998 ). these compounds will act synergistically with pde inhibitors . thus 1 - deprenyl like compounds may be useful in augmenting the effects of inhibitors of various classes of pde inhibitors . the beneficial actions of 1 - deprenyl and propargylamine compounds may also be mediated by the following actions — nitric oxide production , vasodilation , endothelial protection , smooth muscle relaxation , antioxidant action , free radical scavenging , antiapoptotic action , stimulation of antioxidant enzymes , anti - inflammatory activity , monoamine oxidase inhibitor , enhanced dopamine activity , inhibition of phosphodiesterase , enhancement of monoamine activity , neuroprotection , antidepressant , antidiabetic , etc . ( thomas , 2001 , 1998 ). in addition 1 - deprenyl may enhance sexual function by elevating dopamine levels in the brain through mao - b inhibition . the synergestic effect of type 5 pde inhibitors and 1 - deprenyl or propargylamine compounds can be utilized in a number of conditions . in one preferred embodiment , combinations of 1 - deprenyl and one or more pde5 inhibitors are administered to a male subject to treat erectile dysfunction and other sexual disorders . in another preferred embodiment , combinations of 1 - deprenyl and pde5 inhibitors are administered to a female subject to treat sexual dysfunction . in another preferred embodiment , combinations of 1 - deprenyl and pde5 inhibitors are administered to a subject to prevent or reduce vasospasm of a coronary artery or bypass graft . in another preferred embodiment , combinations of 1 - deprenyl and pde5 inhibitors are administered to produce vasodilation . in another preferred embodiment , combinations of 1 - deprenyl and pde5 inhibitors are administered to a subject to prevent or treat conditions such as : sexual dysfunction in hypogonadal men by combining testosterone and pde inhibitor . sexual dysfunction in men and women by combination therapy with antioxidants , vitamin e , arginine , apomorphine , beta blocker , or alpha adrenergic blockers . monoamine oxidase inhibitors contemplated in the invention include 1 - deprenyl ( selegiline ), r - deprenyl , desmethyl selegiline , clorgyline , pargyline , iproniazid , nialamide , phenelzine , tranylcypromine , quinacrine , hydrazine , carboxamide , ro 16 - 6491 , ro 41 - 1049 , propargylamines ( eg . rasagiline , lazabemide ), n - propargylamine compounds , n - methyl propargylamine , and n - methyl - n -( 2 - pentyl )- propargylamine . other mao a and b inhibitors , both natural and synthetic are also contemplated . chemical modifications , derivatives and metabolites of mao inhibitors , both natural and synthetic are also contemplated in the invention . compounds of the invention with one or more asymmetric carbon atoms may exist as enantiomers , diastereomers or as racemic mixtures , it is to be understood that the present invention anticipates and includes within its scope such isomers and mixtures . phosphodiesterase inhibitors contemplated in the invention include type 5 phosphodiesterase inhibitors such as , but not limited to , sildenafil , tadalafil , vardenafil , avanafil , zaprinast , dipyridamole , propentofylline , papverine , ibmx , pyrazolopyrimidinones , griseolic acid derivatives , 2 - phenylpurinones , phenylpyridone derivatives , pyrimidines , purines , quinazolines , phenylpyrimidinones , imidazoquinoxalinones , phenylpyridones , 4 - bromo - 5 -( pyridylmethylamino )- 6 -[ 3 -( 4 - chlorophenyl ) propoxy ]- 3 ( 2h ) pyridazinone , 1 -[ 4 -[( 1 , 3 - benzodiozol - 5 - 9pyridylmethylarnino )- 6 - chloro - 2 - quinazolinyl ]- 4 - piperidine - carboxylic acid , (+)- cis - 5 , 6a , 7 , 9 , 9 , 9a - hexahydro - 2 - [ 4 -( trifloromethyl )- phenylmethyl - 5 - methyl cyclopent - 4 , 5 ] imidazo [ 2 . 1 - b ] purin - 4 ( 3h ) one , furazlocillin , cis - 2 - hexyl - 5 - methyl - 3 , 4 , 5 , 6a , 7 , 8 , 9 , 9a - octahydrocyclopent [ 4 , 5 ] imidazo [ 2 , 1 - b ] purin - 4 - one , 3 - acetyl - 1 -( 2 - chlorobenzyl )- 2 - propylindole - 6 - carboxylate , 4 - bromo - 5 -) 3 - pyridylmethylamino )- 6 -( 3 -( 4 - chlorophenyl ) propoxy )- 3 ( 2h ) pyridazinone , 1 - methyl - 5 -( 5morpholinoacetyl - 2 - n - propoxyphenyl )- 3 - n - propyl - 1 , 6 - dihydro - 7 h - pyrazolo ( 4 , 3 - d ) pyrimidin - 7 - one , 1 -[ 4 [( 1 , 3 - benzodioxol - 5 - methyl ) amino ]- 6 - chloro - 2 - quinazolinyl ] 4 - piperic carboxylic acid . salts , derivatives and metabolites of phosphodiesterase 5 inhibitors are also included . other type 5 pde inhibitors are disclosed in pct publication nos . wo 94 / 28902 , wo 96 / 16644 , u . s . pat . no . 6 , 338 , 862 and u . s . pat . no . 6 , 476 , 037 . the optimal doses mao inhibitor in a pharmaceutical composition is in the amounts of 0 . 1 to 100 - mg / kg body weight and the doses of mao inhibitors in the pharmaceutical composition may be in the amounts of 0 . 1 - 50 . 0 mg / kg . depending on the application , the optimal doses of pde5 inhibitors will vary from 0 . 1 mg to 500 mg . it is also contemplated that compounds of the invention will also enhance the actions of other pde inhibitors , more specifically type i , ii , iii , iv , vi , and vii . it is also contemplated that compounds of the invention will enhance the effects of other modalities of treatment for erectile dysfunction . more specifically these modalities include psychotherapy , surgical methods , implants , and vacuum methods . according to this invention , one or more of pde5 inhibitors are administered in conjunction with 1 - deprenyl or propargylamine compounds to an individual prone to erectile dysfunction and or other conditions listed previously . while this invention is described in terms of application to human subjects , veterinary applications are contemplated within the scope of this invention . the pde inhibitor and 1 - deprenyl can be administered simultaneously or sequentially . both pde inhibitor and 1 - deprenyl can be administered by the same modality ( in the same preparation ) or they can be administered in different formulations and / or by different modalities . the pde inhibitors , and or 1 - deprenyl may be administered in the form of salts , esters , amides , prodrugs , derivatives and may be prepared using standard procedures known to art . type 5 pde inhibitors and 1 - deprenyl may be administered as parenteral , topical , or oral administration such as by aerosol or transdermally , for prophylactic and / or therapeutic treatment of erectile dysfunction and other conditions . the pharmacological compositions can be administered in a variety of unit dosage forms or kits depending upon the method of administration . suitable unit dosage forms include , but are not limited to powders , tablets , capsules , injectibles , lozenges , creams , suspensions , suppositories , etc . the concentration of active ingredients in the formulation can vary and will be based on the nature and extent of the disease , body weight , or fluid volumes in accordance with the needs of the subject . the following examples illustrate various actions of mao inhibitors which enhance the biological actions of phosphodiesterase inhibitors , but do not limit the scope of the invention in any way . further aspects of the invention , based on the disclosure above and the following examples , will be apparent to the person of ordinary skill in the art . fig1 illustrates the enhanced relaxation of rabbit corpus cavernosa by 1 - deprenyl in a dose dependent manner the phosphodiesterase 5 inhibitor sildenafil had no detectable effect on dilation . low concentrations of 1 - deprenyl stimulated the relaxation of corpus cavernosa and would thus enhance erectile function . fig2 demonstrates that 1 - deprenyl enhances the dilation of corpus cavernosa by sildenafil . the inhibition of this effect by hemoglobin ( an agent that traps nitric oxide ), indicates that the effect of 1 - deprenyl is mediated by nitric oxide . fig3 demonstrates that 1 - deprenyl enhances the dilation of corpus cavernosa by sildenafil . the inhibition of this effect by methylene blue ( an agent that inhibits cgmp formation ), indicates that the effect of 1 - deprenyl is mediated by increased production of cgmp . rabbits were treated orally with 1 mg / kg of 1 - deprenyl . the relaxation of isolated corpus cavernosa was measured as described under methods . l - deprenyl treated animal showed significantly enhanced relaxation inhibition of 1 - deprenyl effect by methylene blue ( fig4 ) indicates that cgmp mediates this action . the phosphodiesterase 5 inhibitor dipyridamole produced minimal dilation of rabbit cavernosa , the effect of dipyridamole was enhanced by 1 - deprenyl ( fig5 ). this illustrates that 1 - deprenyl is capable of enhancing the actions of different phosphodiesterase inhibitors . vascular dysfunction in diabetic state increases the risk for erectile dysfunction . corpora cavernosa smooth muscle were isolated from 8 week diabetic rabbits . diabetes was induced in rabbits using alloxan . these animals showed a decreased vasodilatory response ( fig6 ). addition of 1 - deprenyl enhanced the dilation of corpus cavernosa from diabetic animals by sildenafil . thus 1 - deprenyl - like compounds will be effective in treating vascular dysfunction in diabetes . oxidized ldl accelerates atherosclerosis and contributes to the pathology of ed . fig7 and 8 show that 1 - deprenyl inhibits human ldl oxidation . so 1 - deprenyl and other mao inhibitors will be effective in the prevention and treatment of ed and other vascular disorders . platelet aggregation has a major role in the development of atherosclerosis and thrombosis , contributing to endothelial dysfunction and ed . fig9 shows that 1 - deprenyl inhibited the aggregation of human platelets in a dose - dependent manner inhibition of platelet inhibition will ameliorate ed and other vascular disorders . leukocyte rolling and migration is a measure of inflammatory reaction , which is an early event in atherosclerosis and ed . the anti - inflammatory action of estrogen was potentiated by 1 - deprenyl as shown in fig1 . thus 1 - deprenyl will retard the development and progression of ed and other vascular disorders . the results of these examples clearly indicate that , under the conditions tested , the monoamine oxidase inhibitor compounds like 1 - deprenyl produce dilation of corpus cavernosa and also enhance the effect of phosphodiesterase 5 inhibitors . these actions of mao inhibitors are mediated through increased production of nitric oxide and cgmp . other actions of mao inhibitors which contribute to this effect are also described . therapeutic methods of using mao inhibitors and phosphodiesterase inhibitors for the treatment of erectile dysfunction , other male sexual disorders , female sexual disorders , and a variety of vascular , cerebral and peripheral disorders are disclosed . the ratio of mao inhibitors and phosphodiesterase inhibitors used for these applications can be varied depending on the nature and severity of the disorder , and the affected tissue or organ . abrams d . et al . 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( 2000 ). efficacy , safety and patient acceptance of sildenaf citrate as a treatment for erectile dysfunction . j . urol . 164 : 1192 - 1196 . mitka m . ( 2003 ) researchers seek new uses for sildenafil . jama 289 : 2784 - 27 moreira s g . et al . ( 2000 ) side - effect profile of sildenafil citrate ( viagra ) in clinical practice . urology 56 : 474 - 476 . nih concensus development panel on impotence ( 1993 ). nih concensus confer e : impotence . jama , 270 : 83 - 90 . poison ( 1996 ) cyclic nucleotide phosphodiesterases and vascular smooth muscle annual review of pharmacol . 26 : s13 - s20 . porst h . ( 1996 ) the rationale for prostaglandin e1 in erectile failure : a survey of worldwide experience . j . urol . 155 : 802 - 8 15 . porst h . 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( 2003 ). central mechanisms of erectile dysfunction : what a clinician may want to know . int . j . impot res . suppl . 2 : s3 - s6 . sung b - j . et al . ( 2003 ) structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules . nature 425 : 98 - 102 . thomas , t . ( 2002 ) methods of treatment using mao - a and mao - b inhibitors such as 1 - deprenyl . u . s . pat . no . 6 , 432 , 991 thomas , t . ( 2000 ) monoamine oxidase - b inhibitors in the treatment of alzheimer &# 39 ; s disease . neurobiol . aging . 21 : 343 - 348 . thomas t ( 2001 ) a role for estrogen in the primary prevention of alzheimer &# 39 ; s disease . climacteric . 4 : 102 - 109 . thomas t , et al . ( 2002 ) inhibition of ldl oxidation by the neuroprotective drug 1 - deprenyl . neurol . res . 24 : 169 - 173 . thomas t . et al . ( 1998 ) l - deprenyl : nitric oxide production and dilation of cerebral blood vessels . neuroreport . 9 : 1 - 6 . thomas t . et al . 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( 2002 ) suppressive effect of phosphodiesterase type 4 inhibitors at cultured microglial cells : comparison with other types of camp - elevating agents . neuropharmacology 42 : 262 - 269 . new zealand white rabbits ( body weight 3 . 0 kg ) were injected intravenously with alloxan ( via the lateral ear vein ) at a standard dose of 65 mg / kg . urine was monitored over the duration of diabetes for glucose , ketone bodies and proteins . after 6 months of alloxan treatment , rabbits ( together with age matched controls ) were killed by cervical dislocation and penises were excised and placed in dmem pre - gassed with 95 % oxygen and 5 % carbon dioxide . epidermal and connective tissue , urethra and corpus spongiosum were carefully excised from the penis . the corpora cavernosa was then cut longitudinally into two equal segments and then transversely into segments ( approx . 2 mm × 2 mm × 10 mm ) strips of corpus cavernosum were studied in 10 . 0 ml organ chambers for isometric tension measurement . the strips were tied with a silk thread to a wire connected to a force transducer on one end and fixed with silk ties to a metallic support on the other end . the organ chambers contained physiologic salt solution composed of nacl 2 , 118 . 3 mm ; kcl , 4 . 7 mm ; mgso 4 , 0 . 6 mm ; kh 2 po 4 , 1 . 2 mm ; cl 2 , 2 . 5 mm ; nahco 3 , 25 mm : calcium edta , 0 . 026 mm and glucose 11 . 1 mm /. the solution was gassed with 95 % oxygen and 5 % carbon dioxide . the temperature was maintained at 37 ° c . to obtain optimal resting isometric tension for contraction , the strips were stepwise stretched for a period of approximately two hours . resting tension was adjusted to the optimal isometric tension for contraction for each group by determining the tension at which contraction to phenylephrine ( 1 × 10 m ) was maximal . after the initial equilibration in the organ bath , the tissues were optimally stretched and contracted with phenylephrine . once a steady contraction was obtained , the tissues were relaxed by the addition of the phosphodiesterase inhibitors , sildenafil and dipyridamol or 1 - deprenyl . in some studies the phosphodiesterase inhibitors were added prior to contraction with phenylephrine and then 1 - deprenyl was added . the results were expressed as percent of phenylephrine induced contraction . the penile segments in triplicate was placed in 200 μl of dmem buffer 37 ° c . and gassed with 95 % air and 5 % carbon dioxide and equilibrated for an hour with occasional removal of the buffer ( 3 - 4 times ) and replacement with fresh buffer . the various drugs were added to the buffer and the incubations were continued for another 10 min . the reactions were stopped by the addition of 200 μl of 1 mol / l perchloric acid and the tissues were sonicated for 60 sec . after centrifugation at 1000 × g for 15 minutes , the supernatants were removed and neutralized with 1 mol / l k 3 po 4 . aliquots were taken and then acetylated with triethylamine / acetic anhydride ( 1 : 2 , v / v ). after appropriate dilution with phosphate buffer , the cgmp concentrations were measured by radioimmunoassay . having now fully described the invention , it will be appreciated by those skilled in the art that the same can be performed within a wide range of equivalent parameters , concentrations and conditions without departing from the spirit and scope of the invention and without undue experimentation . while the invention has been described in detail with respect to particular preferred embodiments , it should be understood that such description is presented by way of illustration and not limitation . many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof , and the invention includes all such modifications . all references cited herein , including journal articles or abstracts , published or corresponding u . s . or foreign applications , or any other references are entirely incorporated by reference herein , including all data , tables , figures , and text presented in the cited references . additionally , the entire contents of the references cited within the references cited herein are also entirely incorporated be references . reference to known methods , steps , or conventional methods , is not in any way an admission that any aspect , description or embodiment of the present invention is disclosed , taught or suggested in the relevant art . the foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can , by applying knowledge within the skill of the art ( including the contents of the references cited herein ), readily modify and / or adapt for various applications such specific embodiments , without undue experimentation , without departing from the general concept of the present invention . therefore , such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments , based on the teaching and guidance presented herein . it is to be understood that the phraseology or terminology herein is for the purpose of description and not limitation , such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance presented herein , in combination with knowledge of one of ordinary skill in the skill in the art .