Apomorphine-induced penile tumescence in impotent patients — preliminary findings

Lal, Samarthji; Laryea, E; Thavundayil, Joseph; Nair, N.P.V.; Negrete, Juan Carlos; Ackman, Douglas; Blundell, Peter E.; Gardiner, Robert

doi:10.1016/0278-5846(87)90066-2

Cited by 98 publications

(30 citation statements)

References 29 publications

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“…The coordination of several neural events is required to release endogenous mediators (i.e., nitric oxide) at the level of the penile smooth muscle to induce relaxation, whereas a disruption of this series of events can lead to erectile dysfunction (ED) (1,2). Traditionally, drugs used for the treatment of ED have had a peripheral site of action, including phosphodiesterase (PDE)-5 inhibitors like sildenafil, but the recent demonstration that apomorphine can facilitate penile erection in ED patients has introduced a new approach to treatment, because apomorphine acts on central dopaminergic systems (3,4). Dopamine is the main catecholamine in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward, hormonal regulation; abnormalities in dopaminergic neurotransmission have been implicated in Parkinson's disease, schizophrenia, attention-deficit disorder, depression, and drug abuse, among other disorders (5,6).…”

mentioning

confidence: 99%

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Brioni

Moreland

Cowart

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

107

105

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Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D4 receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D 4 receptor agonist that activates human dopamine D 4 receptors with an EC50 of 12.4 nM and 61% efficacy, with no effect on dopamine D 1, D2, D3, or D5 receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction. P enile erection is the result of a complex series of integrated neuronal and vascular events that leads to accumulation of blood in the penis to achieve rigidity. The coordination of several neural events is required to release endogenous mediators (i.e., nitric oxide) at the level of the penile smooth muscle to induce relaxation, whereas a disruption of this series of events can lead to erectile dysfunction (ED) (1, 2). Traditionally, drugs used for the treatment of ED have had a peripheral site of action, including phosphodiesterase (PDE)-5 inhibitors like sildenafil, but the recent demonstration that apomorphine can facilitate penile erection in ED patients has introduced a new approach to treatment, because apomorphine acts on central dopaminergic systems (3,4). Dopamine is the main catecholamine in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward, hormonal regulation; abnormalities in dopaminergic neurotransmission have been implicated in Parkinson's disease, schizophrenia, attention-deficit disorder, depression, and drug abuse, among other disorders (5, 6). The regional distribution of the receptor subtypes, the recent generation of knock-out animals, and the availability of a large number of dopaminergic agents have aided researchers in clarifying the biological role of the dopamine receptors. Dopamine receptors in mammalian tissues have been classified as D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 , and D 4 ) based on their binding properties and their ability to activate or inhibit forskolin-induced adenylate cyclase activity, a classification supported by the cloning of the different subtypes during the last decade (7,8).Within the D 2 -like family, the D 2 receptor is highly expressed...

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mentioning

confidence: 99%

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Brioni

Moreland

Cowart

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

107

105

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“…Cet effet pro6rectile apparait sans aucune autre stimulation, et amplifie les effets pro~rectiles d'une stimulation sexuelle visuelle [28]. Les essais cliniques utilisant l'apomorpbine d61ivr6e par vole sublinguale d6crivent un effet pro6rectile du produit chez des patients souffrant de dysfonctions ~rectiles [60,61,76,77,119].…”

Section: Recents Developpements Dans L'utilisation De L'apomorphiunclassified

“…Des 6tudes r6alis6es chez le chien et le rat rdv~lent que l'apomorphine n'a pas d' effet sur le poids des organes g6nitaux, ni sur la mobilit6 et le nombre des spermatozoides, ni sur l'index de fertilit~ [138]. Chez l'homme les effets pro~rectiles de la bromocriptine ne sont pas d6finitivement av6r6s : le produit est sans effet selon certains auteurs [26], ou bien am61iore l'obtention d'une 6rection [76,77]. La L-DOPA augmente de 50% la fr6quence des 6rections nocturnes et la dur6e totale des 6rections pendant le sommeil [64].…”

Section: Recents Developpements Dans L'utilisation De L'apomorphiunclassified

Apomorphine, systèmes dopaminergiques centraux et contrôle de l’érection

Rampin

2002

Androl.

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Au cours des dernieres ann~es, les nombreuses donnees fondamentales ~lucidant les mecanismes Iocaux de I'~rection ont permis de proposer des traitements des dysfonctions ~rectiles par des m~dicaments a action p~ripherique. Ces produits permettent soit de provoquer une erection, ils sont alors efficaces seuls, soit de potentialiser une ~rec-tion.Dans un environnement sexuellement stimulant, I'~rection est provoquee par une modification de I'equilibre des effets antierectiles du syst~me sympathique et des effets pro~rectiles du syst~me parasympathique. Les voies sympathiques et parasympathiques naissent de la moelle ~pini~re. Le syst~-me nerveux central agit sur la moelle (~pini~re pour contr61er et modifier cet equilibre sympathiqueparasympathique. La dopamine est un neurom~dia-teur du syst~me nerveux central agissant sur le comportement sexuel et sur les noyaux centaux contr61ant le tractus g~nital chez le m&le. Les taux de dopamine augmentent dans plusieurs noyaux centraux (amygdale, aire preoptique mediane) pendant I'activit~ sexuelle chez le rat. Les agonistes dopaminergiques a action centrale comme I'apomorphine (agoniste DI/D2) provoquent I'~rection chez I'homme, le singe et le rat. Chez le rat, les effets proerectiles de I'apomorphine sont dus ~ sa fixation sur des recepteurs de type D2 dans le noyau paraventriculaire de I'hypothalamus (PVN), et seraient regul(~s par la testosterone. Des investigations cliniques r~centes ont mis en avant les avantages de I'utilisation de I'apomorphine pour traiter les patients souffrant de dysfonctions ~rec-tiles. Une molecule a action centrale comme I'apomorphine pourrait r~organiser I'~quilibre sympathique-parasympathique, conduisant & un recrutement adapte des voies nerveuses vers le p~nis. Mots-cl#,s : apomorphine, dopamine, erection, ejaculation, dysfonction 6rectile, c o m p o r t e m e n t sexuel.

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“…1 Another class of agents activates central mechanisms involved in penile erection. 8 Another class will utilize prostaglandin E1 administered via topical administration. 9 It is likely that phentolamine mesylate will achieve widespread use as an oral alpha-1 and alpha-2 blocking agent for the treatment of erectile dysfunction.…”

Section: Clinical Trialsmentioning

confidence: 99%

Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction

Goldstein

2000

Int J Impot Res

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Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high af®nity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30±40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are suf®cient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1±5 and 15) from screening to the end of treatment was signi®cantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satis®ed or very satis®ed compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts. The correction of erectile dysfunction or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. All trends of response were the same regardless of any concomitant medication. There were no severe adverse events. At 40 mg, 7.7% experienced rhinitis and fewer than 3.1% experienced any other side effect of treatment. Phentolamine is safe, well tolerated and ef®cacious for the treatment of erectile dysfunction.

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Apomorphine-induced penile tumescence in impotent patients — preliminary findings

Cited by 98 publications

References 29 publications

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Apomorphine, systèmes dopaminergiques centraux et contrôle de l’érection

Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction

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Apomorphine-induced penile tumescence in impotent patients — preliminary findings

Cited by 98 publications

References 29 publications

Activation of dopamine D 4 receptors by ABT-724 induces penile erection in rats

Activation of dopamine D 4 receptors by ABT-724 induces penile erection in rats

Apomorphine, systèmes dopaminergiques centraux et contrôle de l’érection

Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction

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Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats