18 Jul 2018 10:30
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Phosphodiesterase inhibitors are most commonly prescribed for the treatment of erectile dysfunction (ED) and work by selectively blocking PDE5, the enzyme necessary for the degradation of cGMP.4 The accumulation of cGMP in the corpus cavernosum of the penis results in the increased vasodilation necessary for an erection.4 Therefore when both nitrates and PDE5 inhibitors are administered closely together (within the past 24 hours for Fildena and vardenafil and within the past 36 hours for Fildena due to its longer half-life), the PDE5 inhibitor prevents the breakdown of NO mediated increases in cGMP. Drugs that inhibit PDE5, Fildena , Fildena and vardenafil , have been used as treatment for erectile dysfunction 13 These inhibitors increase the cGMP, smooth muscle relaxation and consequentally cause penis erection 6 during sexual stimulation. Beside the clinical application for erectile dysfunction and for pulmonary arterial hypertension, a growing body of research has confirmed putative beneficial effects of PDE5 inhibitors in CF. Recent studies conducted in F508del and in wild-type CFTR expressing Xenopus laevis oocytes and human bronchial epithelial cells have indicated that Fildena acts as a corrector and as a potentiator of the mutant and wild-type protein by distinct cGMP-independent and cGMP-dependent mechanisms respectively ( Leier et al., 2012 ). While in X. laevis oocytes, low (1.5 μmol/l) doses were required to rescue F508del-CFTR function and cell membrane localization, suprapharmacological doses roughly 120 times larger than those commonly used for the treatment of erectile dysfunction were needed to achieve the same correcting effects in human bronchial epithelial cells ( Leier et al., 2012 ). In this perspective, adverse drug effects including flushing, headache, and other cardiovascular effects could compromise the potential use of PDE5 inhibitors in CF.
Risks and uncertainties include, but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation in the United States and internationally; global trends toward healthcare cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. Oral PDE5 inhibitors, which mainly include Fildena, vardenafil and Fildena, are the first line drugs for treatment of erectile dysfunction 6 , 7 It's possible to use them to treat cardiovascular diseases such as pulmonary arterial hypertension and dilated cardiomyopathy because of its vasodilation effect and its influence on endothelial function of blood vessels all over the body 6 6. Numerous theoretical evidences support the use of PDE5 inhibitors in HF patients, and clinical trials have begun exploring their potential as an adjunct in the pharmacological management of HF 8 , 9 , 10 , 11 , 12 , 13 However, mixed results have been reported, possibly because of sample heterogeneity or methodological inconsistencies.
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