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History of the development of tadalafil

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History of tadalafilThe Bothell, Washington-based pharmacologic research company ICOS Corporation was started in 1990, and it began the initial cardiovascular testing of a PDE5 inhibitor called IC351 in 1993. Meanwhile, sildenafil citrate (sildenafil) was discovered to cause improved erectile function as a side effect in a trial testing its efficacy for the treatment of angina pectoris in 1994. IC351 was patented that year, and phase I clinical trials began in 1995. Two years later, phase II clinical trials began on patients with ED.

The same year that the FDA approved sildenafil as the first PDE5 inhibitor for the treatment of ED, Eli Lilly and Company joined the ICOS Corporation to form Lilly ICOS LLC in 1998 to expand the marketing venture of the newest PDE5 inhibitor. Tadalafil was officially born in the year 2000 when a new drug application was put forth for IC351 with the generic name tadalafil and trade name Cialis.

In May 2002, the first reports regarding the efficacy and duration of action of tadalafil for ED were presented at the 97th Annual Meeting of the American Urological Association (AUA) in Orlando, Florida, USA. Brock and colleagues presented their initial data supporting the efficacy and safety of canadian tadalafil, and Porst and colleagues presented that tadalafil is efficacious for up to 36 hours. Brock’s data were published later that year in a landmark integrative analysis of five randomized controlled trials of tadalafil that ultimately led to the approval of the drug. Tadalafil was approved for use in Europe in late 2002, and on November 21, 2003, tadalafil was approved by the FDA for use in the United States.

Treatment strategies and effect on sexual behavior

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Tags: ED, tadalafil

sexual behavior

Although efficacy and safety are two important characteristics when choosing a pharmacological treatment for ED, the ideal therapy should be reliable during maintenance. Furthermore, beyond erection and penetration, intercourse success and overall satisfaction needs have to be considered. The primary goal in the treatment of ED should be the restoration of sexual life rather than merely the achievement of a penile erection.

An important characteristic of tadalafil is its prolonged period of responsiveness. In prescribing a therapy for ED, the long lasting effect of the drug may not be the most important issue. Tadalafil is unique to the PDE5 inhibitors available because of its efficacy up to 36 h after dosing. This should release from the need to plan sexual activities and therefore favor spontaneity.

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The clinical evidence: safety of tadalafil in ED

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Tags: ED, tadalafil

safety of tadalafilMost of the side effects reported in the clinical trials are dose-dependent and consistent with the vasodilatatory effect of PDE-5 inhibition. When tadalafil (Cialis) was administered on an on-demand basis headache and dyspepsia were the most frequent symptoms, followed by back pain, nasal congestion, myalgia, and flushing. Subgroup analyses have revealed no differences between incidences of adverse events in tadalafil-treated men over 65 years compared with the younger group. No relevant differences in the frequency and pattern of side-effects have been reported when tadalafil was schedully administered (eg, three times per week, or daily). The daily administration of tadalafil was well tolerated with headache, dyspepsia, facial flushing, nasal congestion, and backache as the most frequently reported adverse events. In the “eleven trials analysis”, adverse events leading to study discontinuation account for 3.2% of patients taking tadalafil 20 mg, 1.6% of patients taking tadalafil 10 mg and 1.3% of patients on placebo. Respectively, 51%, 58%, and 39% of the subjects experienced at least one or more unwanted symptoms. Side-effects were generally mild to moderate and decreased in frequency during continued treatment. While no significant laboratory or electrocardiographic changes were assessed, the most common treatment-emergent adverse events were headache (15%, 12%, 5% respectively), dyspepsia (8%, 7%, 1% respectively), back pain/myalgia (8%, 11%, 3% respectively), nasopharyngitis and nasal congestion (4%, 11%, 5% respectively), flushing (3%, 3%, 1% respectively), pain in limb (3%, 3%, 1% respectively).

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The clinical evidence: efficacy of tadalafil in ED

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Tags: ED, tadalafil

clinical evidence

The most important outcome for an ED therapy is the patient’s perception of success. When patients with ED experience a successful intercourse after treatment, they feel cured of their problem. Furthermore, they express the desire of unplanned, unpremeditated or spontaneous sexual intercourse. In this sense, one possible use of the self-administered questionnaire International Index of Erectile Function – Erectile Function domain (IIEF-EF) score is to ascertain whether patients return to normal erectile function after treatment, with scores of 26–30 representing the normal ranges. Integrated analysis of data from phase III trials demonstrated that tadalafil, at doses from 5 mg to 20 mg versus placebo, significantly improved erectile function (EF) by all measures. In particular, 50%–65% of patients, regardless of ED severity at baseline, returned to normal erectile function with almost 60%–90% of success rate at intercourse attempts during active treatment.

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A clinical pharmacological approach to the effective and safe use of tadalafil

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Tags: cGMP, tadalafil

clinical pharmacologicalThe mechanism of action leading to penile erection involves inhibition of PDE5, the major cyclic guanosine monophospate (cGMP) hydrolyzing enzyme located in the vascular smooth muscle cells of corpus cavernosum. Sexual stimulation triggers the release of the endothelium dependent relaxing factor nitric oxide (NO), stimulating through the protein kinase G the release of guanylyl cyclase with an increase of intracellular cGMP, thus causing a decrease in intracellular calcium and, ultimately, the relaxation of trabecular erectile tissues and the dilatation of the helicine artery of the penis. The increase in blood flow causes the engorgement of the sinusoidal spaces of the corpora cavernosa, the tunica albuginea compresses the subtunical venules that drain the corpora and reduces the venous outflow increasing penile blood pressure and causing erection. This mechanism acts primarily to maintain the tumescence phase, whereas neuronal-derived NO is mainly active in the induction of erectile function. Inhibiting PDE5 prolongs the effects of nerve stimulation. Tadalafil, like the PDE5 inhibitors sildenafil and vardenafil, competitively blocks the cGMP hydrolysis by PDE5, thereby fostering cGMP accumulation and the relaxation of vascular smooth muscle. Increased concentrations of cGMP produce higher PDE5 promoter activities. cGMP accumulation stimulates cGMP degradation, but the pharmacological PDE5 inhibition blocks this negative feedback process. Thus, with PDE5 inhibitors, erection develops in a physiologic manner and only with sexual stimulation.

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