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M Maggi - One of the best experts on this subject based on the ideXlab platform.
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hypogonadal men nonresponders to the PDE5 Inhibitor tadalafil benefit from normalization of testosterone levels with a 1 hydroalcoholic testosterone gel in the treatment of erectile dysfunction tadtest study
The Journal of Sexual Medicine, 2011Co-Authors: Jacques Buvat, Francesco Montorsi, M Maggi, Hartmut Porst, Antti Kaipia, Marie Helene Colson, Beatrice Cuzin, Ignacio Moncada, Antonio Martinmorales, Aksam YassinAbstract:ABSTRACT Introduction Addition of testosterone (T) may improve the action of phosphodiesterase type 5 Inhibitors (PDE5‐Is) in patients with erectile dysfunction not responding to PDE5‐Is with low or low‐normal T levels. Aims To confirm this add‐on effect of T in men optimally treated with PDE5‐Is and to specify the baseline T levels at which such an effect becomes significant. Methods A multicenter, multinational, double‐blind, placebo‐controlled study of 173 men, 45–80 years, nonresponders to treatment with different PDE5‐Is, with baseline total T levels ≤4 ng/mL or bioavailable T ≤ 1 ng/mL. Men were first treated with tadalafil 10 mg once a day (OAD) for 4 weeks; if not successful, they were randomized in a double‐blind, placebo‐controlled design to receive placebo or a 1% hydroalcoholic T gel (50 mg/5 g gel), to be increased to 10 mg T if results were clinically unsatisfactory. Main Outcomes Measures Mean change from baseline in the Erectile Function Domain Score of the International Index of Erectile Function and rate of successful intercourses (Sexual Encounter Profile 3 question). Results Erectile function progressively improved over a period of at least 12 weeks in both the placebo and T treatment groups. In the overall population with a mean baseline T level of 3.37 ± 1.48 ng/mL, no additional effect of T administration to men optimally treated with PDE5‐Is was encountered. The differences between the T and placebo groups were significant for both criteria only in the men with baseline T ≤3 ng/mL. Conclusions The maximal beneficial effects of OAD dosing with 10 mg tadalafil may occur only after as many as 12 weeks. Furthermore, addition of T to this PDE5‐I regimen is beneficial, but only in hypogonadal men with baseline T levels ≤3 ng/mL. Buvat J, Montorsi F, Maggi M, Porst H, Kaipia A, Colson MH, Cuzin B, Moncada I, Martin‐Morales A, Yassin A, Meuleman E, Eardley I, Dean JD, and Shabsigh R. Hypogonadal men nonresponders to the PDE5 Inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study).
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:OBJECTIVES: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. METHODS: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). RESULTS: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression (p<0.05), and ES response at all stimulation frequencies (p<0.001). T supplementation completely restored PDE5 expression, erectile response to ES and responsiveness to PDE5 Inhibitor. Both acute and chronic tadalafil treatment were ineffective in ameliorating the ES response in castrated rats. Injection of increasing concentrations of SNP in castrated rats resulted in a statistically significant increase in ICP/MAP ratio as that observed in intact rats. In addition, tadalafil did not amplify the SNP effect in castrated rats at all the doses tested (0.06-6 nmoles). CONCLUSIONS: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:Abstract Objectives: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. Methods: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). Results: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression ( p p Conclusions: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.
Xinhua Zhang - One of the best experts on this subject based on the ideXlab platform.
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:OBJECTIVES: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. METHODS: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). RESULTS: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression (p<0.05), and ES response at all stimulation frequencies (p<0.001). T supplementation completely restored PDE5 expression, erectile response to ES and responsiveness to PDE5 Inhibitor. Both acute and chronic tadalafil treatment were ineffective in ameliorating the ES response in castrated rats. Injection of increasing concentrations of SNP in castrated rats resulted in a statistically significant increase in ICP/MAP ratio as that observed in intact rats. In addition, tadalafil did not amplify the SNP effect in castrated rats at all the doses tested (0.06-6 nmoles). CONCLUSIONS: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:Abstract Objectives: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. Methods: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). Results: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression ( p p Conclusions: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.
Richard Labaudiniere - One of the best experts on this subject based on the ideXlab platform.
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the discovery of tadalafil a novel and highly selective PDE5 Inhibitor 2 2 3 6 7 12 12a hexahydropyrazino 1 2 1 6 pyrido 3 4 b indole 1 4 dione analogues
Journal of Medicinal Chemistry, 2003Co-Authors: Alain Claudemarie Daugan, Pascal Grondin, Cecile Ruault, Annecharlotte Le Monnier De Gouville, Herve Coste, Jean Michel Linget, Jorge Kirilovsky, Francois Hyafil, Richard LabaudiniereAbstract:Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 Inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 Inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 Inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 Inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 Inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1−4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil...
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the discovery of tadalafil a novel and highly selective PDE5 Inhibitor 1 5 6 11 11a tetrahydro 1h imidazo 1 5 1 6 pyrido 3 4 b indole 1 3 2h dione analogues
Journal of Medicinal Chemistry, 2003Co-Authors: Alain Claudemarie Daugan, Pascal Grondin, Cecile Ruault, Annecharlotte Le Monnier De Gouville, Herve Coste, Jorge Kirilovsky, Francois Hyafil, Richard LabaudiniereAbstract:Starting from ethyl β-carboline-3-carboxylate (β-CCE), 1, a modest Inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-β-carboline derivatives has been identified as a novel chemical class of potent and selective PDE5 Inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compound 2 and of the aromatic ring on position 5 led to the identification of compound 6e, a highly potent and selective PDE5 Inhibitor, with greater selectivity for PDE5 vs PDE1−4 than sildenafil. Compound 6e demonstrated a long-lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.
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the discovery of tadalafil a novel and highly selective PDE5 Inhibitor 1 5 6 11 11a tetrahydro 1h imidazo 1 5 1 6 pyrido 3 4 b indole 1 3 2h dione analogues
Journal of Medicinal Chemistry, 2003Co-Authors: Alain Claudemarie Daugan, Pascal Grondin, Cecile Ruault, Annecharlotte Le Monnier De Gouville, Herve Coste, Jorge Kirilovsky, Francois Hyafil, Richard LabaudiniereAbstract:Starting from ethyl β-carboline-3-carboxylate (β-CCE), 1, a modest Inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-β-carboline derivatives has been identified as a novel chemical class of potent and selective PDE5 Inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compound 2 and of the aromatic ring on position 5 led to the identification of compound 6e, a highly potent and selective PDE5 Inhibitor, with greater selectivity for PDE5 vs PDE1−4 than sildenafil. Compound 6e demonstrated a long-lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.
Gianni Forti - One of the best experts on this subject based on the ideXlab platform.
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:OBJECTIVES: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. METHODS: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). RESULTS: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression (p<0.05), and ES response at all stimulation frequencies (p<0.001). T supplementation completely restored PDE5 expression, erectile response to ES and responsiveness to PDE5 Inhibitor. Both acute and chronic tadalafil treatment were ineffective in ameliorating the ES response in castrated rats. Injection of increasing concentrations of SNP in castrated rats resulted in a statistically significant increase in ICP/MAP ratio as that observed in intact rats. In addition, tadalafil did not amplify the SNP effect in castrated rats at all the doses tested (0.06-6 nmoles). CONCLUSIONS: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:Abstract Objectives: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. Methods: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). Results: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression ( p p Conclusions: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.
Michaela Luconi - One of the best experts on this subject based on the ideXlab platform.
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:OBJECTIVES: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. METHODS: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). RESULTS: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression (p<0.05), and ES response at all stimulation frequencies (p<0.001). T supplementation completely restored PDE5 expression, erectile response to ES and responsiveness to PDE5 Inhibitor. Both acute and chronic tadalafil treatment were ineffective in ameliorating the ES response in castrated rats. Injection of increasing concentrations of SNP in castrated rats resulted in a statistically significant increase in ICP/MAP ratio as that observed in intact rats. In addition, tadalafil did not amplify the SNP effect in castrated rats at all the doses tested (0.06-6 nmoles). CONCLUSIONS: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.
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testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum
European Urology, 2005Co-Authors: Xinhua Zhang, Annamaria Morelli, Michaela Luconi, Linda Vignozzi, Sandra Filippi, Mirca Marini, G B Vannelli, Rosa Mancina, Gianni Forti, M MaggiAbstract:Abstract Objectives: To investigate the effect of testosterone on PDE5 expression and PDE5 Inhibitor tadalafil in vivo responsiveness in a rat model. Methods: PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP). Results: Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression ( p p Conclusions: Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 Inhibitor, tadalafil, in the rat CC.