Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction

Goldenberg, Marvin M.

doi:10.1016/s0149-2918(98)80103-3

Cited by 108 publications

(81 citation statements)

References 24 publications

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“…Furthermore, the safety and pharmacokinetics of these drugs have already been assessed. Examples of such repositioning include the use of anticancer drugs zidovudine (AZT), decitabine, and gemcitabine for HIV (human immunodeficiency virus) treatment (8) and of the erectile dysfunction drug sildenafil, which was originally developed for antihypertension treatment (9).…”

mentioning

confidence: 99%

Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy

Perwitasari

Yan

Johnson

et al. 2013

Antimicrob Agents Chemother

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Influenza A virus infection is a major global health concern causing significant mortality, morbidity, and economic loss. Antiviral chemotherapeutics that target influenza A virus are available; however, rapid emergence of drug-resistant strains has been reported. Consequently, there is a burgeoning need to identify novel anti-influenza A drugs, particularly those that target host gene products required for virus replication, to reduce the likelihood of drug resistance. In this study, a small interfering RNA (siRNA) screen was performed to identify host druggable gene targets for anti-influenza A virus therapy. The host organic anion transporter-3 gene (OAT3), a member of the SLC22 family of transporters, was validated as being required to support influenza A virus replication. Probenecid, a prototypical uricosuric agent and chemical inhibitor of organic anion transporters known to target OAT3, was shown to be effective in limiting influenza A virus infection in vitro (50% inhibitory concentration [IC 50 ] of 5.0 ؋ 10 ؊5 to 5.0 ؋ 10 ؊4 M; P < 0.005) and in vivo (P < 0.05). Probenecid is widely used for treatment of gout and related hyperuricemic disorders, has been extensively studied for pharmacokinetics and safety, and represents an excellent candidate for drug repositioning as a novel anti-influenza A chemotherapeutic.

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mentioning

confidence: 99%

Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy

Perwitasari

Yan

Johnson

et al. 2013

Antimicrob Agents Chemother

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“…The central role of this pathway is demonstrated by the phosphodiesterase type 5 inhibitor sildenafil as today's most successful therapy for the treatment of erectile dysfunction. However, as some side effects and limitations on use have been reported, 21,22 there is increasing interest in alternative therapeutic measures. As the predominant intracellular receptor of NO, sGC is a promising therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Role of the soluble guanylyl cyclase α1-subunit in mice corpus cavernosum smooth muscle relaxation

et al. 2007

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Soluble guanylyl cyclase (sGC) is the major effector molecule for nitric oxide (NO) and as such an interesting therapeutic target for the treatment of erectile dysfunction. To assess the functional importance of the sGCa 1 b 1 isoform in corpus cavernosum (CC) relaxation, CC from male sGCa 1 À/À and wild-type mice were mounted in organ baths for isometric tension recording. The relaxation to endogenous NO (from acetylcholine, bradykinin and electrical field stimulation) was nearly abolished in the sGCa 1 À/À CC. In the sGCa 1 À/À mice, the relaxing influence of exogenous NO (from sodium nitroprusside and NO gas), BAY 41-2272 (NO-independent sGC stimulator) and T-1032 (phosphodiesterase type 5 inhibitor) were also significantly decreased. The remaining exogenous NO-induced relaxation seen in the sGCa 1 À/À mice was significantly decreased by the sGC-inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The specificity of the impairment of the sGC-related responses was demonstrated by the unaltered relaxations seen with forskolin (adenylyl cyclase activator) and 8-pCPT-cGMP (cGMP analog). In conclusion, the sGCa 1 b 1 isoform is involved in corporal smooth muscle relaxation in response to NO and NO-independent sGC stimulators. The fact that there is still some effect of exogenous NO in the sGCa 1 À/À mice suggests the contribution of (an) additional pathway(s).

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“…8 The clinical performance of the first oral PDE5 inhibitor, sildenafil, provided unequivocal proof that it is very efficacious in treating patients with mild to moderate erectile dysfunction. [9][10][11] Since the successful launch of sildenafil, vardenafil and tadalafil have also entered the market 12 and several other potent and selective PDE5 inhibitors have been reported in the literature. 13 We have previously reported a novel series of PDE5 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction

et al. 2006

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Phosphodiesterase 5 (PDE5) inhibitors are efficacious in treating patients with erectile dysfunction. New PDE5 inhibitors with different selectivity and pharmacokinetic profiles have been vigorously pursued. Here we report two novel, potent, and selective PDE5 inhibitors, JNJ-10280205 and JNJ-10287069, with K i values of 0.05 and 0.12 nM, respectively. Both compounds displayed superior selectivity against PDE1-4 and -6 when compared to sildenafil. In the anesthetized dogs, JNJ-10280205 and JNJ-10287069 exhibited similar efficacy as sildenafil in enhancing erectile functions, with no significant effect on cardiovascular parameters. Pharmacokinetic studies showed that JNJ-10287069 had better oral bioavailability than JNJ-10280205 in several animal species. In vitro study suggested that cytochrome P450 (CYP) 3A4 played a major role in the metabolism of both compounds. The compounds inhibited some of the CYP450 enzymes and the human ether-a-go-go (HERG) channel at much higher concentrations than that required to inhibit PDE5, thus, no cross inhibition would be expected at therapeutic doses. Both compounds are suitable clinical candidates.

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Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction

Cited by 108 publications

References 24 publications

Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy

Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy

Role of the soluble guanylyl cyclase α1-subunit in mice corpus cavernosum smooth muscle relaxation

JNJ-10280205 and JNJ-10287069: novel PDE5 inhibitors as clinical candidates for erectile dysfunction

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