Study Sildenafil

Sildenafil was the first oral treatment for ED and is the most extensively evaluated (35). Overall success rates in patients with cardiovascular disease of 80% or greater have been recorded with no evidence of tolerance, Patients with diabetes with or without additional risk factors, with their more complex, and extensive pathophysiology, have an average success rate of 60%. In randomized trials to date, open-label or outpatient monitoring studies the use of sildenafil is not associated with any excess risk of myocardial infarction, stroke, or mortality (38-40), In patients with stable angina pectoris there is no evidence of an ischemic effect due to coronary steal, and in one large, double-blind, placebo-controlled, exercise study sildenafil 100 mg increased exercise time and diminished ischemia (41), A study of the hemodynamic effects in men with severe CAD identified no adverse cardiovascular effects and a potentially beneficial effect on coronary blood flow reserve (42), Studies in patients with and without diabetes have demonstrated improved endothelial function acutely and after long-term oral dose administration, which may have implications beyond... 

In a pharmacological study, sildenafil 50 mg did not potentiate the inerease in bleeding time seen with aspirin 150 mg. No additional precautions therefore seem neeessary on eoneurrent use. 

Khan KM et al. (2005) A facile and improved synthesis of sildenafil (Viagra) analogs through solid support microwave irradiation possessing tyrosinase inhibitory potential, their conformational analysis and molecular dynamics simulation studies. Mol Divers 9(l-3) 15-26... 

Unless otherwise stated, general information applies to the entire class of phosphodiesterase inhibitors. Sildenafil is highlighted because it was the first to be marketed and is the most thoroughly studied. The newer agents tadalafil and vardenafil have different pharmacokinetic profiles (Table 83-3), drug-food interactions, and adverse effects. 

Adulteration, which can be accidental or deliberate, is another problem. Many herbal products have been found to contain prescription or OTC drugs and dangerous heavy metals. In 1998, for example, the California Department of Health reported that 32% of Asian herbal medicines sold in that state contained undeclared pharmaceuticals or heavy metals. A subsequent study of more than 500 Chinese herbal medicines found that about 10% of them contained undeclared drugs or toxic levels of metals. The FDA and other investigators have also detected sildenafil, colchicine, adrenal steroids, alprazolam, and other prescription drug ingredients in products claimed to contain only natural ingredients. 

One additional medication that has recently been studied is sildenafil, which is more commonly known by its trade name Viagra. Sildenafil is taken at doses from 50 to 100 mg per dose about 1-2 hours before sex. Sildenafil is sometimes effective but its expense and potential complications in patients with heart disease limit its usefulness. It can be quite useful in males who experience erectile dysfunction, though it does not improve delayed ejaculation. 

The safety and efficacy of combinations of sildenafil or vardenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. 

Many patients do consider these problems to be a nuisance rather than a reason to terminate SSRI therapy. Others find these problems intolerable. A wide range of treatments have been tried including dopamine agonists including bupropion, yohimbine, cyproheptadine, and sildenafil. Most of these treatments had only anecdotal and open label studies to support their usefulness. However, sildenafil was found to be superior to placebo in a double-blind study ( 445). 

Nurnberg HG, Gelenberg AJ, Fava M, et al. Sildenafil for SRI associated sexual dysfunction a three-center six weeks double blind placebo controlled study in 90 men. 40th Annual Meeting NCDEU, Boca Raton, Florida, 2000. 

The available case reports in the FDA AERS support the published literature that there are pharmacokinetic interactions between St. John s wort and CYP3A4 and/or p-glycoprotein substrates, such as cyclosporine, levonorgestrel/estradiol and sildenafil, and pharmacodynamic interactions with the SSRIs or MAOI. Subsequent clinical studies including those conducted via a CDER clinical pharmacology research cooperative agreement (14—16) provided mechanistic basis of many of these interactions (refer to Chapter 4). 

These drugs have also been studied for possible use in other conditions. Clinical studies show distinct benefit in some patients with pulmonary arterial hypertension, and possible benefit in systemic hypertension, cystic fibrosis, and benign prostatic hyperplasia. Preclinical studies suggest that sildenafil may be useful in preventing apoptosis and cardiac remodeling after ischemia and reperfusion. 

The E-factors of different types of chemical processes are shown in Table 13.4.32 In general, processes performed on a larger scale tend to involve fewer operations and form simpler products. Both facets help lead to lower E-factor values. Remarkably, oil refining generates approximately 10-fold more product than waste. In contrast, pharmaceutical processes can be less than 1% efficient based on waste production. The commercial process of sildenafil (13.73), highlighted in the Case Study below, has been optimized more extensively than the typical pharmaceutical synthesis. 

Tadalafil has also been extensively evaluated in patients with cardiovascular disease and has a similar safety and efficacy profile to sildenafil (45). Studies have shown no adverse effects on cardiac contraction, ventricular repolarization, or ischemic threshold. A similar hypotensive effect has been recorded with a dose of doxazosin 8 mg so caution is needed. As hypotension does not occur in the supine position and as tadalafil has a long half-life it is suggested that tadalafil is taken in the morning and doxazosin in the evening. There is no interaction of tadalafil with the selective a-adrenoceptor antagonist tamsulosin, which can, therefore, be prescribed as an alternative to doxazosin for symptomatic benign prostate hypertrophy (46). 

Since vardenafil has a very similar chemical structure to sildenafil, it is not surprising that it has a similar clinical profile. One study has reported no impairment of exercise ability in stable CAD patients receiving vardenafil 20 mg (49). Similar clinical efficiency for all three agents has been observed in patients with diabetes,... 

Gillies HC, Roblin D, Jackson G. Coronary and systemic haemodynamic effects of sildenafil citrate from basic science to clinical studies in patients with cardiovascular disease. Int J Cardiol 2002 86 131-141. 

Shabsigh R, Kaufman JM, Steidle C, et al. Randomised study of testosterone gel as adjunctive therapy to sildenafil in hypogo-nadal men with erectile dysfunction who do not response to sildenafil alone. J Urol 2004 172 658-663. 

Webb DJ, Freestone S, Allen MJ, et al. Sildenafil citrate and blood-pressure-lowering drngs results of dmg interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999 83 21C-28C. 

Another recent example is provided by the discovery of the use of sildenafil (Viagra Fig. 1.15), a phosphodiesterase type 5 (PDE5) inhibitor, as an efficacious, orally active agent for the treatment of erectile dysfunction [25,26]. Initially, this compound was brought to the clinic as an hypotensive and cardiotonic substance, but its usefulness in erectile dysfunction resulted unexpectedly from clinical observations made during a 10-day toleration study in Wales [27]. 

A more recent example is that of sildenafil which, as a result of observations made during Phase I studies in male volunteers, is now used to treat erectile dysfunction. Sildefanil had originally been designed as an analogue of zaprinast, and a more selective phosphodiesterase inhibitor (PDE5) for use as a cardiovascular agent (see Chapter 1-1). 

In a double-blind, placebo-controlled study in 90 patients with sexual dysfunction who were taking a variety of 5HT re-uptake inhibitor antidepressants, sildenafil (50-100 mg) produced improvement in all aspects of the sexual response in 54% of antidepressant-treated patients compared with a placebo response rate of 4.4% (NNT = 2) (6). This suggests that sildenafil is an effective treatment for antidepressant-induced sexual dysfunction. 

The main adverse effects reported in chnical studies were flushing, headache, dyspepsia, visual disturbances, and rhinitis, some of which show that vasodilatation is not confined to the corpora cavernosa. They were mUd, and only 1-2% of the patients discontinued sildenafil because of adverse effects. 

The adverse effects of a single dose of sildenafil 50 mg have been evaluated in a placebo-controlled study in 40 young healthy volunteers (3). The most commonly reported adverse effects with sildenafil and placebo respectively were flushing (75 and 0%), headache (50 and 5%), and dyspepsia (15 and 5%). This adverse effects profile was similar to that observed in chnical trials. Heart rate changed significantly, but blood pressure did not. 

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