Patent Document:

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 ( e . g . 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 - 9pyridylmethylamino )- 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 , 6 a , 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 - 7h - 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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( 2001 ) dopamine and sexual function . eur . eurol . 40 : 601 - 608 . goldstein i ( 2000 ) oral phentolamine : an alpha - 1 , alpha - 2 adrenergic antagonist for the treatment of erectile dysfunction . int . j . impot . res . 1 : s75 - 80 . gonzalez - cadavid n f . and rajfer j . ( 2000 ) therapeutic stimulation of penile nitric oxide synthase and related pathways . drugs of today . 36 : 163 - 174 . gretarsdottir s , thorieifsson g , reynisdottir s th , et al , ( 2003 ) the gene encoding for phosphodiesterase 4d confers risk of ischemic stroke . nature 35 : 131 - 138 . grootendorst d c , rabe k f . ( 2002 ) selective phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease . curr . opin . allergy clin . immunol . 2 : 6 1 - 67 . hedlund p . et al . ( 2000 ) cholinergic nerves in human corpus cavernosum and sponigiosum contain nitric oxide synthase and heme oxygenase . j . urol . 164 : 868 - 875 . jackson et al . ( 1999 ) effects of sildenafil citrate on human hemodynamics . am . j . cardiol . 83 : 13c - 20c . jones o m et al . (( 2002 ) phosphodiesterase inhibitors cause relaxation of the internal anal sphincter in vitro . dis . colon rectum 45 : 530 - 536 . knoll j . ( 1989 ) striatal dopamine , sexual activity and life span . longevity of rats treated with deprenyl . life sci . 45 : 525 - 53 1 . lue t f ( 2000 ) erectile dysfunction . n . engi . j . med . 342 : 1802 - 18 13 . maas r . et al ( 2003 ) the pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function . vascular medicine 7 : 2 13 - 225 . martin c . et al ( 2002 ). airway relaxant and anti - inflammatory properties of pde4 inhibitor with low affinity for the high - affinity rolipram binding site . naunyn schmiedebergs arch pharmacol . 365 : 284 - 289 . mcmahon c g . et al . ( 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 . ( 1996 ) the rationale for prostaglandin e1 in erectile failure : a survey of worldwide experience . j . urol . 155 : 802 - 815 . rajfer et al ( 1992 ). nitric oxide is a mediator of relaxation of the corpus cavernosum in response to noradrenegic , noncholinergic neurotransmission . nejm 326 : 90 - 94 rhoden , e l . et al ( 2002 ) the relationship of serum testosterone to erectile function in normal aging men . j . urol . 167 : 1745 - 1748 . rosen r c . ( 2001 ) psychogenic erectile dysfunction . classification and management . urol . clin . north am . 28 : 269 - 2 78 . sebkhi a . et al . ( 2003 ) phosphodiesterase type 5 as a target for the treatment of hypoxia - induced pulmonary hypertension . 107 : 3230 . seftel , a d . ( 2003 ) erectile dysfunction in the elderly : epidemiology and approaches to treatment . j . urol . 169 : 1999 - 2007 . stief c g . ( 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 . ( 1998 ) l - deprenyl protects vascular endothelium from amyloid - beta toxicity and stimulates production of nitric oxide . in alzheimer &# 39 ; s disease and related disorders ( ed . iqbal k . et al .) pp 493 - 5 00 , john wiley and sons ltd . tomlinson j and wright d . ( 2004 ) impact of erectile dysfunction and its subsequent treatment with sildenafil : qualitative study . brit . med . j . 328 : 1037 . trophy , t j ; page c . ( 2000 ) phosphodiesterases : the journey towards therapeutics . trends in pharmacol . sci . 21 : 157 - 169 . utkan , t . et al ( 2001 ) effects of specific phosphodiesterase inhibitors on alloxan - induced diabetic rabbit cavernous tissue in vitro . int . j . impot . res . 13 : 24 - 30 . zang b et al . ( 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 .

Classification Label: 0