Resumo de Novel Uses Of Sildenafil And Related Drugs (phosphodiesterase Enzyme Type V Inhibitors)

Novel uses of sildenafil and related drugs (phosphodiesterase enzyme type V inhibitors)The phosphodiesterase type 5 (PDE5) inhibitors like sildenafil and other similar drugs were developed for patients with erectile dysfunction (ED). These drugs have enjoyed considerable success in ED and are termed blockbusters as far as sales are concerned. Recent years have seen the emergence of these drugs as drugs that may be effective in a variety of other conditions as researchers seek new uses for sildenafil and related drugs.<1>
The current article looks at the novel, emerging indications for this group of interesting drugs.1. Acute pulmonary hypertension.The phosphodiesterase enzyme type III inhibitor milrinone produces pulmonary vasodilation but lacks selectivity. Sildenafil, a phosphodiesterase enzyme type V inhibitor, can also induce relaxation of the pulmonary vasculature; however, only the oral formulation is presently available. One study evaluated the effects of a new intravenous sildenafil analogue--UK 343-664--compared with milrinone during acute pulmonary hypertension in a porcine model of thromboxane-induced pulmonary hypertension.<2> After acute pulmonary hypertension, 24 adult swine were randomized to 3 groups. Group 1 (n = 9) received an intravenous dose of 500 micro gm of UK 343-664, group 2 (n = 8) received milrinone 50 mg/kg, and group 3 (n = 7) received 10 mL of normal saline solution. All agents were administered for more than 5 minutes. Data were recorded continuously for 30 minutes. Both milrinone and UK 343-664 partially reversed thromboxane-induced pulmonary hypertension, with a notable decrease in mean pulmonary artery pressure and pulmonary vascular resistance and a concomitant increase in cardiac output. In addition, milrinone improved right ventricular contractility but produced marked systemic vasodilatation.In contrast, the administration of UK 343-664 was associated with pulmonary vasodilatation, without appreciable changes in systemic arterial pressure or vascular resistance. It was concluded that: Milrinone and UK 343-664 were equally effective as pulmonary vasodilators; however, only UK 343-664 exhibited a high degree of pulmonary selectivity.The role of the NO (nitric oxide) axis and its therapeutic implications in pulmonary arterial hypertension has been evaluated.
Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature leading to vasoconstriction and remodeling of the pulmonary arteries. The resulting increase in the right ventricular after load leads to right ventricular failure and death. The treatment options are limited, expensive and associated with significant side effects. The nitric oxide (NO) pathway in the pulmonary circulation provides several targets for the development of new therapies for this disease. However, the NO pathway is modulated at multiple levels including transcription and expression of the NO synthase gene, regulation of the NO synthase activity, regulation of the production of cyclic guanomonophosphate (cGMP) by phosphodiesterases, postsynthetic oxidation of NO, etc. This makes the study of the role of the NO pathway very difficult, unless one uses multiple complementary techniques. Furthermore, there are significant differences between the pulmonary and the systemic circulation which make extrapolation of data from one circulation to the other very difficult. In addition, the role of NO in the development of pulmonary hypertension varies among different models of the disease. 2. Primary Pulmonary hypertension We conducted a Randomized, Placebo Controlled, Double blind, Cross-over study to evaluate the Efficacy and Safety of Oral Sildenafil Treatment in Severe Pulmonary Artery Hypertension. The primary end point of efficacy was improvement in walking capacity as judged by 6MWT after 6 weeks of treatment. The secondary end points included improvement in clinical condition, NYHA class, and exercise duration, and Mets achieved on modified Bruce exercise protocol and reduction in PAP as measured by Doppler echocardiography.Patients were randomized to receive one of either sildenafil or placebo. Adult patients were given 25 mg sildenafil on first day repeated after 6 hours and observed for 1 day. If there was no hypotension the patient was given 100 mg three times a day. In children weighing less than 30 kg an initial dose of 3.125 mg of sildenafil was given and maintained at 25 mg TDS. In older children weighing more than 30 kg initial dose of 6.25 mg was given and maintained at 50 mg thrice a day. The patients were given second dose only if there was no significant fall in BP. In 6 minute walk test the mean distance walked at baseline was 262+98.99 meters, which increased to 293.0+89.38 meters after placebo administration and increased to 358+96.51 meters after sildenafil administration. The increase in walking capacity with the use of sildenafil was highly significant. (p=0.0001). The mean pulmonary artery pressure at baseline was 98.8 + 20.5 mm Hg. After giving placebo for 6 weeks it was 94.8 + 16.5 and after giving drug for 6 weeks it was 78.3 + 15.3. There was a fall in pulmonary artery pressure from baseline to placebo which was not significant statistically (p=.189). There was highly significant fall in pulmonary artery pressure from baseline to drug (20.7%) and placebo to drug (17.4%) (p=.0001). 3. Eisenmenger?s syndromeEisenmenger?s syndrome (congenital systemic to pulmonary shunts) broadly resembles IPAH in terms of pathologic characteristics, clinical presentation, diagnostic modalities and therapeutic options. Same protocol was followed as in case of idiopathic pulmonary hypertension. The improvements in mean pulmonary artery pressure, 6 minute walk test, mean exercise duration, and NYHA class were similar to those observed in patients with idiopathic pulmonary hypertension.

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