Administration of active agents, including 5-HT receptor agonists and antagonists, to treat premature ejaculation

Abstract

A method is provided for delaying the onset of ejaculation in an individual. The method preferably involves administration of an antidepressant drug, a serotonin agonist or antagonist, an adrenergic agonist or antagonist, an adrenergic neurone blocker, or a derivative analog thereof, within the context of an effective dosing regimen. The preferred mode of administration is transurethral; however, the selected active agent may also be delivered via intracavernosal injection or using alternative routes. Pharmaceutical formulations and kits are provided as well.

1 . A method for delaying the onset of ejaculation in a human individual, comprising administering to the individual an effective amount of a pharmaceutical formulation containing an active agent comprising a serotonin agonist, a serotonin antagonist, or a combination thereof, wherein the active agent is effective to delay the onset of ejaculation by the individual during sexual intercourse.  
     
     
         2 . The method of    claim 1   , wherein the formulation is administered transurethrally.  
     
     
         3 . The method of    claim 1   , wherein the formulation is administered by intracavernosal injection.  
     
     
         4 . The method of    claim 1   , wherein the formulation is administered transdermally.  
     
     
         5 . The method of    claim 1   , wherein the formulation is administered topically.  
     
     
         6 . The method of    claim 1   , wherein the formulation is administered orally.  
     
     
         7 . The method of    claim 1   , wherein the formulation is administered parenterally.  
     
     
         8 . The method of    claim 1   , wherein the formulation is administered buccally.  
     
     
         9 . The method of    claim 1   , wherein the formulation is administered nasally.  
     
     
         10 . The method of    claim 1   , wherein the agent is a serotonin agonist.  
     
     
         11 . The method of    claim 10   , wherein the serotonin agonist is a 5-HT 4  agonist.  
     
     
         12 . The method of    claim 10   , wherein the serotonin agonist is selected from the group consisting of 2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone, D-lysergic acid diethylamide, ergot alkaloids, 8-hydroxy-(2-N,N-dipropylamino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride, mezacopride, and combinations thereof.  
     
     
         13 . The method of    claim 1   , wherein the agent is a serotonin antagonist.  
     
     
         14 . The method of    claim 13   , wherein the serotonin antagonist is a 5-HT 3  antagonist.  
     
     
         15 . The method of    claim 13   , wherein the serotonin antagonist is selected from the group consisting of ondansetron, granisetron, metoclopramide, tropisetron, dolasetron, tri-methobenzamide, methysergide, risperidone, ketanserin, ritanserin, clozapine, amitriptyline, k(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol, azatadine, cyproheptadine, fenclonine, dexfenfluramnine, fenfluramine, chlorpromazine, mianserin, and combinations thereof.  
     
     
         16 . The method of    claim 1   , wherein a predetermined dose of the agent is administered to the individual one to four times in a twenty-four hour period.  
     
     
         17 . The method of    claim 1   , wherein the pharmaceutical formulation further comprises a vasoactive agent.  
     
     
         18 . The method of    claim 2   , wherein the pharmaceutical formulation comprises a urethral suppository.  
     
     
         19 . The method of    claim 18   , wherein the urethral suppository contains a pharmacologically acceptable carrier selected from the group consisting of polyethylene glycol and derivatives thereof.  
     
     
         20 . The method of    claim 19   , wherein the urethral suppository further includes a solubilizing compound for increasing the solubility of the agent in the carrier.  
     
     
         21 . The method of    claim 1   , wherein the individual suffers from premature ejaculation.  
     
     
         22 . A method for delaying the onset of ejaculation in an individual, comprising administering to the individual an effective amount of a pharmaceutical formulation containing an active agent comprising: a 5-HT 1 A, 5-HT 1 B, 5-HT 1 E, 5-HT 1 F, 5-HT 2 , 5-HT 3  or 5-HT 4  agonist; a serotonin antagonist; or a combination thereof, wherein the active agent is effective to delay the onset of ejaculation by the individual during sexual intercourse.  
     
     
         23 . A pharmaceutical formulation for delaying the onset of ejaculation in a male individual, comprising a urethral dosage form of an active agent comprising a serotonin agonist, a serotonin antagonist, or a combination thereof, and a pharmaceutically acceptable carrier or excipient.  
     
     
         24 . The formulation of    claim 23   , wherein the agent is a serotonin agonist.  
     
     
         25 . The formulation of    claim 24   , wherein the serotonin agonist is a 5-HT 4  agonist.  
     
     
         26 . The formulation of    claim 24   , wherein the serotonin agonist is selected from the group consisting of 2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone, D-lysergic acid diethylamide, ergot alkaloids, 8-hydroxy-(2-N,N-dipropylamino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan, m-chlorophenyl-piperazine, trazodone, zacopride, mezacopride and combinations thereof.  
     
     
         27 . The formulation of    claim 23   , wherein the agent is a serotonin antagonist.  
     
     
         28 . The formulation of    claim 27   , wherein the serotonin antagonist is a 5-HT 3  antagonist.  
     
     
         29 . The formulation of    claim 27   , wherein the serotonin antagonist is selected from the group consisting of ondansetron, granisetron, metoclopramide, tropisetron, dolasetron, trimethobenzamide, methysergide, risperidone, ketanserin, ritanserin, clozapine, amitriptyline, R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol, azatadine, cyproheptadine, fenclonine, dexfenfluramine, fenfluramine, chlorpromazine, mianserin, and combinations thereof.  
     
     
         30 . The formulation of    claim 23   , further comprising a vasoactive agent.  
     
     
         31 . A kit for delaying the onset of ejaculation in an individual, comprising: a pharmaceutical formulation containing an active agent comprising a serotonin agonist, a serotonin antagonist, or mixtures thereof, a drug delivery means for administering the formulation; a container for housing the formulation and drug delivery means; and instructions for using the drug delivery means for administering the formulation to treat premature ejaculation.  
     
     
         32 . The kit of    claim 31   , wherein the drug delivery means comprises a transurethral drug delivery device.  
     
     
         33 . The kit of    claim 31   , further including a flexible, adjustable venous flow control (VFC) device and instructions for using the VFC device.  
     
     
         34 . A method for delaying the onset of ejaculation in a male individual, comprising locally administering to the individual an effective amount of a pharmaceutical formulation containing a pharmacologically active agent of a type and in an amount effective to delay the onset of ejaculation by the individual during sexual intercourse, wherein the agent is selected from the group consisting of antidepressants, serotonin agonists, serotonin antagonists, adrenergic agonists, adrenergic antagonists, adrenergic neurone blockers, and derivatives and analogs thereof.  
     
     
         35 . The method of    claim 34   , wherein the agent is an antidepressant.  
     
     
         36 . The method of    claim 35   , wherein the antidepressant is selected from the group consisting of amesergide, amineptine, amitriptyline, amoxapine, benactyzine, brofaromine, bupropion, butriptyline, cianopramine, citalopram, clomipramine, clorgyline, clovoxamnine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, etoperidone, femoxetine, fezolamine, fluoxetine, fluvoxamine, ifoxetine, imipramine, iprindole, isocarboxazid, levoprotiline, lofepramine, maprotiline, medifoxamine, melitracen, metapramine, methylphenidate, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nialamide, nomifensine, nortriptyline, opipramol, oxaflozane, oxaprotiline, oxitriptan, paroxetine, phenelzine, pirlindole, propizepine, protriptyline, quinupramine, rolipram, selegiline, sertraline, setiptiline, sibutramine, teniloxazine, tianeptine, tofenacin, toloxatone, tranylcypromine, trazodone, trimipramine, tryptophan, venlafaxine, viloxazine, viqualine, zimeldine, and combinations thereof.  
     
     
         37 . The method of    claim 34   , wherein the agent is a serotonin agonist.  
     
     
         38 . The method of    claim 37   , wherein the serotonin agonist is a 5-HT 4  agonist.  
     
     
         39 . The method of    claim 37   , wherein the serotonin agonist is selected from the group consisting of 2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone, lysergic acid diethylamide, ergot alkaloids, 8-hydroxy-(2-N,N-dipropylamino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride, mezacopride, and combinations thereof.  
     
     
         40 . The method of    claim 37   , wherein the agent is a serotonin antagonist.  
     
     
         41 . The method of    claim 40   , wherein the serotonin agonist is a 5-HT 4  agonist.  
     
     
         42 . The method of    claim 40   , wherein the serotonin antagonist is selected from the group consisting of ondansetron, granisetron, metoclopramide, tropisetron, dolasetron, trimethobenzamide, methysergide, risperidone, ketanserin, ritanserin, clozapine, amitryptiline, R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol, azatadine, cyproheptadine, fenclonine, dexfenfluramine, fenfluramine, chlorpromazine, mianserin, and combinations thereof.  
     
     
         43 . The method of    claim 34   , wherein the agent is an adrenergic agonist.  
     
     
         44 . The method of    claim 43   , wherein the adrenergic agonist is selected from the group consisting of methoxamine, methpentermine, metaraminol, mitodrine, clonidine, apraclonidine, guanfacine, guanabenz, methyldopa, amphetamine, methamphetamine, epinephrine, norepinephrine, ethylnorepinephrine, phenylephrine, ephedrine, pseudoephedrine, methylphenidate, pemoline, naphazoline, tetrahydrozoline, oxymetazoline, xylometazoline, phenylpropanolamine, phenylethylamine, dopamine, dobutamine, colterol, isoproterenol, isotharine, metaproterenol, terbutaline, metaraminol, tyramine, hydroxyamphetamine, ritodrine, prenalterol, albuterol, isoetharine, pirbuterol, bitolterol, fenoterol, formoterol, procaterol, salmeterol, mephenterine, propylhexedrine, and combinations thereof.  
     
     
         45 . The method of    claim 34   , wherein the agent is an adrenergic antagonist.  
     
     
         46 . The method of    claim 45   , wherein the adrenergic antagonist is selected from the group consisting of phenoxybenzamine, phentolamine, tolazoline, prazosin, terazosin, doxazosin, trimazosin, yohimbine, ergot alkaloids, labetalol, ketanserin, urapidil, alfuzosin, bunazosin, tamsulosin, chlorpromazine, haloperidol, phenothiazines, butyrophenones, propranolol, nadolol, timolol, pindolol, metoprolol, atenolol, esmolol, acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, carvedilol, medroxalol, naftopidil, bucindolol, levobunolol, metipranolol, bisoprolol, nebivolol, betaxolol, carteolol, celiprolol, sotalol, propafenone, indoramin, and combinations thereof.  
     
     
         47 . The method of    claim 34   , wherein the agent is an adrenergic neurone blocker.  
     
     
         48 . The method of    claim 47   , wherein the adrenergic neurone blocker is selected from the group consisting of bethanidine, debrisoquine, guabenxan, guanadrel, guanazodine, guanethidine, guanoclor, guanoxan, and combinations thereof.  
     
     
         49 . The method of    claim 34   , wherein a predetermined dose of the agent is administered to the male individual one to four times in a twenty-four hour period.  
     
     
         50 . The method of    claim 34   , wherein the pharmaceutical formulation further comprises a vasoactive agent.  
     
     
         51 . The method of    claim 34   , wherein the pharmaceutical formulation comprises a urethral suppository.  
     
     
         52 . The method of    claim 51   , wherein the urethral suppository contains a pharmacologically acceptable carrier selected from the group consisting of polyethylene glycol and derivatives thereof.