(brand name: tadalafil)


Bibliography and References. Review.
List of selected scientific articles (abstracts). Experimental and clinical data.

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Int J Clin Pract. 2005 Feb;59(2):143-9.
A 6-month study of the efficacy and safety of tadalafil in the treatment of erectile dysfunction: a randomised, double-blind, parallel-group, placebo-controlled study in Australian men.
McMahon CG, Stuckey BG, Lording DW, Wittert GA, Murphy A, Shin J, Sutherland PD, Palmer NR, Lowy MP, Jesudason DR, Fredlund P.
Australian Centre for Sexual Health, St Leonards, Sydney, New South Wales 2011, Australia.

The efficacy and safety of tadalafil for the treatment of erectile dysfunction (ED) were assessed in a 6-month, randomised, double-blind, placebo-controlled study. Australian men with mild, moderate or severe ED of organic, psychogenic or mixed aetiology were randomised to tadalafil 20 mg as needed (n = 93) or placebo (n = 47). Efficacy assessments included the international index of erectile function (IIEF) and the sexual encounter profile (SEP) diary. Tadalafil significantly improved erectile function compared with placebo (p < 0.001, all measures). At the end of the study, the mean per-patient proportion of successful sexual intercourse attempts (SEP question three) was 73.5% for patients treated with tadalafil and 26.8% for placebo-treated patients. Improved erections were reported by 78% of tadalafil-treated patients compared to 12.8% of placebo-treated patients. The most common treatment-emergent adverse events--headache and dyspepsia--were generally mild or moderate. Tadalafil was effective and well tolerated in Australian men with mild to severe ED.

J Androl. 2005 May-Jun;26(3):310-8.
Tadalafil Improved Erectile Function at Twenty-Four and Thirty-Six Hours After Dosing in Men With Erectile Dysfunction: US Trial.
Young JM, Feldman RA, Auerbach SM, Kaufman JM, Garcia CS, Shen W, Murphy AM, Beasley CM Jr, Hague JA, Ahuja S.
South Orange County Medical Research Center, 24301 Paseo de Valencia, Suite 100; Laguna Woods, CA 92653.

In a previous study assessing tadalafil for the treatment of erectile dysfunction (ED), tadalafil 20 mg was shown to improve erectile function for up to 36 hours vs placebo. This study sought to demonstrate the effectiveness of both 10- and 20-mg tadalafil vs placebo at 2 prespecified assigned times of 24 and 36 hours postdosing. This double-blind, placebo-controlled, parallel-group study randomized 483 men with ED into 6 groups according to a combination of treatment (placebo, tadalafil 10 or 20 mg) and assigned time (24 or 36 hours) for intercourse attempts. Patients were stratified by baseline ED severity based on Erectile Function Domain scores. The study had 4 phases: a 4-week run-in (no ED medication taken); a 2- to 4-week equilibration (dosing as needed); a 4- to 6-week assessment; and a 6-month open-label extension. During the assessment phase, men took a total of 4 doses of study medication, each dose separated by more than or equal to 7 days. Efficacy was measured as the mean per-patient percentage of successful intercourse attempts (Sexual Encounter Profile Diary Question 3: SEP3) during the assessment phase. Men taking either 10- or 20-mg tadalafil had a significant increase in SEP3 from baseline scores vs placebo at both 24 hours (P = .038 and <.001 for 10 and 20 mg, respectively) and 36 hours (P < .001 for both doses) postdose. The mean per-patient percentages of successful intercourse attempts for the 24-hour time point were 41.8%, 55.8%, and 67.3% for placebo and tadalafil 10 and 20 mg, respectively; for the 36-hour time point, the mean per-patient percentages were 32.8%, 56.2%, and 61.9% for placebo and tadalafil 10 and 20 mg, respectively. The most common treatment-emergent adverse events were headache, back pain, dyspepsia, and nasopharyngitis. Both 10- and 20-mg tadalafil improved erectile function for up to 36 hours postdosing in men with ED of varied severity.

Expert Opin Pharmacother. 2005 Jan;6(1):75-84.
Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction.
Doggrell SA.
Doggrell Biomedical Communications, 47 Caronia Crescent, Lynfield, Auckland, New Zealand.

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70years of age. In the first major trial of sildenafil in ED, at 24weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardena-fil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildena-fil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100mg) by men with ED, possibly because of its longer duration of action. Of the phosphodiesterase inhibitors, tadalafil may displace sild-enafil as the drug of choice among men with ED.

Clin Pharmacol Ther. 2005 Jan;77(1):63-75.
Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo.
Ring BJ, Patterson BE, Mitchell MI, Vandenbranden M, Gillespie J, Bedding AW, Jewell H, Payne CD, Forgue ST, Eckstein J, Wrighton SA, Phillips DL.
Eli Lilly and Company, Indianapolis, IN 46285, USA.

OBJECTIVES: Tadalafil was examined in vitro and in vivo for its ability to affect human cytochrome P450 (CYP) 3A-mediated metabolism. METHODS: Reversible and mechanism-based inhibition of CYP3A by tadalafil was examined in human liver microsomes. The ability of tadalafil to influence CYP3A activity was also examined in primary cultures of human hepatocytes. The effect of tadalafil on the pharmacokinetics of CYP3A probe substrates was evaluated in human volunteers before and after coadministration with either a single dose or multiple doses of tadalafil (10 or 20 mg). RESULTS: Negligible competitive inhibition of CYP3A was observed in vitro. Mechanism-based inhibition of CYP3A was detected, albeit with a low potency. In human hepatocytes, exposure to 1 micromol/L or greater of tadalafil resulted in increased CYP3A protein expression; however, as with a combined effect of induction and inhibition, a corresponding increase in CYP3A activity did not occur. The clinical pharmacokinetics of midazolam and lovastatin, probe substrates of CYP3A, were unaffected by up to 14 days of tadalafil administration (90% confidence intervals for the ratio of least squares means for the pharmacokinetic parameters of tadalafil were contained within the no-effect boundaries of 0.7 to 1.43). CONCLUSIONS: In vitro results suggested that tadalafil would have little effect on the pharmacokinetics of drugs metabolized by CYP3A. Clinical studies demonstrated that the pharmacokinetics of 2 different CYP3A substrates, midazolam and lovastatin, were virtually unchanged after tadalafil coadministration. Thus therapeutic concentrations of tadalafil do not produce clinically significant changes in the clearance of drugs metabolized by CYP3A.

Stroke. 2005 Mar;36(3):557-60. Epub 2005 Feb 03.
Effects of high altitude exposure on cerebral hemodynamics in normal subjects.
Van Osta A, Moraine JJ, Melot C, Mairbaurl H, Maggiorini M, Naeije R.
Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Belgium.

BACKGROUND AND PURPOSE: Acute mountain sickness (AMS) may be an early stage of high altitude cerebral edema. If so, AMS could result from an alteration of dynamic autoregulation of cerebral blood flow resulting in overperfusion of capillaries and vasogenic cerebral edema. METHODS: We measured middle cerebral artery blood flow velocity (Vmca) by transcranial Doppler and arterial blood pressure by finger plethysmography at 490 m and 20 hours after arrival at 4559 m in 35 volunteers who had been randomized to tadalafil, dexamethasone, or placebo in a study on the pharmacological prevention of high altitude pulmonary edema. A dynamic cerebral autoregulation index (ARI) was calculated from continuous recordings of Vmca and blood pressure during transiently induced hypotension. RESULTS: Altitude was associated with an increase in a cerebral-sensible AMS (AMS-C) score (P<0.001) and with a decrease in arterial oxygen saturation (Sao2), whereas average Vmca or ARI did not change. However, at altitude, the subjects with the lowest ARI combined with the lowest Sao2 presented with the highest AMS-C score (P<0.03). In addition, a stepwise multiple linear regression analysis on arterial Pco2, Sao2, and baseline or altitude ARI identified altitude ARI as the only significant predictor of the AMS-C score (P=0.01). The AMS-C score was lower in dexamethasone-treated subjects compared with high altitude pulmonary edema-susceptible untreated subjects. Neither tadalafil nor dexamethasone had any significant effect on Vmca or ARI. CONCLUSIONS: High altitude hypoxia is associated with impairment in the regulation of the cerebral circulation that might play a role in AMS pathogenesis.

Urology. 2005 Feb;65(2):353-9.
Efficacy, safety, and treatment satisfaction of tadalafil versus placebo in patients with erectile dysfunction evaluated at tertiary-care academic centers.
Carson C, Shabsigh R, Segal S, Murphy A, Fredlund P, Kuepfer C; Trial Evaluating the Activity of Tadalafil for Erectile Dysfunction-United States (TREATED-US) Study Group.
Division of Urology, University of North Carolina, Chapel Hill, North Carolina 27599-7235, USA.

OBJECTIVES: To determine the efficacy, safety, and treatment satisfaction of tadalafil 20 mg for erectile dysfunction (ED) in patients evaluated at tertiary-care academic centers. METHODS: In this randomized, double-blind, placebo-controlled trial, patients were randomly allocated to receive fixed-dose tadalafil 20 mg (n = 146) or placebo (n = 49) for 12 weeks. Efficacy was assessed by the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP), and Global Assessment Question (GAQ); patient and partner treatment satisfaction by the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and SEP; and safety by adverse events, laboratory values, and vital signs. RESULTS: Mean baseline IIEF erectile function (EF) domain was 12.98. Fifty-one percent of enrolled patients had severe baseline ED, and 82% had organic ED. Pre-existing, ED-associated comorbid conditions were common. When compared with patients treated with placebo, those receiving tadalafil reported significant improvement from baseline in the IIEF EF domain (P <0.001), successful penetration attempts (SEP question 2; P <0.001), successful intercourse (SEP question 3; P <0.001), and all secondary efficacy outcomes (P <0.001). Patients and their sexual partners were also significantly more satisfied with tadalafil treatment (P <0.001), including overall satisfaction (P <0.001) and length of time the treatment worked (P <0.001). Mild or moderate headache, dyspepsia, and myalgia were the most frequent treatment-emergent adverse events reported. CONCLUSIONS: Tadalafil significantly improved erectile function and patient and partner satisfaction and was well tolerated. These results were observed in a tertiary-care, academic center population with a high incidence of severe, organic ED, and comorbid medical conditions, factors known to compromise erectile function and treatment outcome.

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