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The role of sildenafil in the treatment of stroke.
Curr Opin Investig Drugs. 2008 Jul; 9(7): 754-759
Bednar MM
The structural underpinning responsible for neuroplasticity and neurorestoration under physiological and pathophysiological conditions is only beginning to be elucidated. It is evident that life-long neurogenesis occurs in the human brain, with experimental data supporting its upregulation following an insult (eg, stroke) and/or in response to pharmacological therapy. Sildenafil, a PDE5 inhibitor currently marketed for the treatment of erectile dysfunction, enhances neurorestoration in rat models of stroke, as measured by neurogenesis, synaptogenesis and angiogenesis. This neurorestorative effect is associated with improved outcome despite no observed effect on brain infarct size. This neurorestorative effect has also been observed in both young and old animals, and is demonstrable even if therapy is initiated 1 week post-stroke. The extended therapeutic window and novel mechanism of action of neurorestorative therapies, such as sildenafil, warrant further investigation for the treatment of stroke.
Clin Drug Investig. 2008; 28(8): 479-485
Sekar V, Lefebvre E, De Marez T, De Pauw M, De Paepe E, Vangeneugden T, Hoetelmans RM
BACKGROUND AND OBJECTIVES: Darunavir (DRV, TMC114) is a novel protease inhibitor administered in combination with low-dose ritonavir (DRV/r) and is highly active against both wild-type and multidrug-resistant HIV-1 strains. Sildenafil is an oral therapy for erectile dysfunction. Concomitant administration of protease inhibitors and sildenafil increases sildenafil plasma concentrations. The potential for a pharmacokinetic drug interaction exists when sildenafil and DRV/r are co-administered, as these drugs are primarily metabolized by cytochrome P450 (CYP) 3A, and darunavir and ritonavir are CYP3A inhibitors. The primary objective of this open-label, crossover, phase I study was to assess the effect of multiple doses of DRV/r on the pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil. The secondary objective was to assess the short-term safety and tolerability of co-administration of sildenafil and DRV/r. METHODS: Sixteen HIV-negative healthy male subjects were randomized to one of two sequences. In two sessions each subject received treatments A and B. In treatment A, a single dose of sildenafil 100 mg was administered. In treatment B, the subjects received DRV/r 400/100 mg twice daily for 8 days and on day 7 a single dose of sildenafil 25 mg was co-administered. Full pharmacokinetic profiles of sildenafil, N-desmethyl sildenafil, darunavir and ritonavir were determined. Safety and tolerability were also assessed. RESULTS: Sildenafil exposure (area under the plasma concentration-time curve [AUC]) was comparable between the two treatments despite administration of a lower dose of sildenafil (25 mg) with DRV/r than when sildenafil (100 mg) was administered alone. When sildenafil 25 mg was co-administered with DRV/r, the sildenafil maximum plasma concentration (C(max)) was 38% lower compared with C(max) after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil C(max) and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUC(last)]) values decreased by approximately 95% when sildenafil 25 mg was co-administered with DRV/r compared with sildenafil 100 mg alone. Combined treatment with DRV/r and sildenafil was generally safe and well tolerated. CONCLUSION: Sildenafil exposure is increased in the presence of DRV/r. In this setting, a dose adjustment for sildenafil is warranted; no more than 25 mg of sildenafil is recommended over a 48-hour period when co-administered with DRV/r.
Urology. 2008 Jul 1;
McVary KT, Siegel RL, Carlsson M
OBJECTIVES: To evaluate the body mass index (BMI) and lower urinary tract symptom (LUTS) severity on treatment response to sildenafil in men with erectile dysfunction (ED) and moderate to severe LUTS associated with benign prostatic hyperplasia. METHODS: A post hoc analysis of data from a 12-week, double-blind, placebo-controlled study of sildenafil (50 mg once daily titrated to 100 mg once daily) was conducted. The BMI categories were obese (>/=30 kg/m(2)), overweight (>/=25 to
Treatment of Pulmonary Hypertension in Children with Chronic Lung Disease with Newer Oral Therapies.
Pediatr Cardiol. 2008 Jul 2;
Krishnan U, Krishnan S, Gewitz M
Chronic lung disease (CLD) is often complicated by chronic pulmonary vascular changes and pulmonary hypertension (PH) in young children. Current therapies for severe PH in such patients, including oxygen, inhaled nitric oxide, and parenteral prostacyclin, are often suboptimal, cumbersome, and expensive. Recently, oral endothelin receptor blockers and phosphodiesterase-5 inhibitors have been used successfully to control and reverse pulmonary vascular disease in idiopathic PH, but the use and efficacy of these agents in pediatric CLD have not been previously reported. We report a series of six children with CLD and severe PH treated with bosentan (six of six) and sildenafil (four of six). Vascular reactivity was assessed by cardiac catheterization prior to and after 6 months of therapy. Serial echocardiography was also used to assess response. Patients have been treated for 2.1-2.9 years (mean, 2.53 years). Response to therapy has included improvement in oxygenation, symptoms, echocardiographic parameters, and hemodynamics by cardiac catheterization. Transiently elevated liver enzymes were noted associated with viral respiratory infections in two subjects; no other adverse effects were noted. Three patients with large cardiac right-to-left shunts prior to therapy had subsequent shunt reversal, two of whom underwent shunt closure later. Oral therapy with bosentan alone or in combination with sildenafil improves PH in patients with CLD over a period of 3-4 years.
Cancer Res. 2008 Jul 1; 68(13): 5439-49
Serafini P, Mgebroff S, Noonan K, Borrello I
Tumor-induced T-cell tolerance is a major mechanism that facilitates tumor progression and limits the efficacy of immune therapeutic interventions. Regulatory T cells (Treg) play a central role in the induction of tolerance to tumor antigens, yet the precise mechanisms regulating its induction in vivo remain to be elucidated. Using the A20 B-cell lymphoma model, here we identify myeloid-derived suppressor cells (MDSC) as the tolerogenic antigen presenting cells capable of antigen uptake and presentation to tumor-specific Tregs. MDSC-mediated Treg induction requires arginase but is transforming growth factor-beta independent. In vitro and in vivo inhibition of MDSC function, respectively, with NOHA or sildenafil abrogates Treg proliferation and tumor-induced tolerance in antigen-specific T cells. These findings establish a role for MDSCs in antigen-specific tolerance induction through preferential antigen uptake mediating the recruitment and expansion of Tregs. Furthermore, therapeutic interventions, such as in vivo phosphodiesterase 5-inhibition, which effectively abrogate the immunosuppressive role of MDSCs and reduce Treg numbers, may play a critical role in delaying and/or reversing tolerance induction.
Eur J Pharmacol. 2008 Jun 19;
Toque HA, Teixeira CE, Lorenzetti R, Okuyama CE, Antunes E, De Nucci G
Nitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed (0.001-100 microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 microM) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in PDE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate.
Phosphodiesterase inhibitors for the treatment of pulmonary hypertension.
Eur Respir J. 2008 Jul; 32(1): 198-209
Wilkins MR, Wharton J, Grimminger F, Ghofrani HA
The pulmonary vascular bed is both a source of and target for a number of vasoactive factors. Among the most important for pulmonary vascular homeostasis are factors that utilise cyclic guanosine monophosphate (cGMP) as an intracellular second messenger. These include nitric oxide and the natriuretic peptide family (atrial, brain and C-type natriuretic peptides). In the search for therapeutic strategies that engage the cGMP signalling pathway for the treatment of pulmonary arterial hypertension (PAH), inhibition of cGMP metabolism by phosphodiesterase type 5 (PDE5)-targeted compounds has proven most successful to date. One PDE5 inhibitor, sildenafil, has been shown to improve pulmonary haemodynamics and exercise capacity in patients with PAH and is now an approved treatment. Others are under investigation. An interesting, although still tentative, observation is the potential of sildenafil to reduce pulmonary vascular resistance without adversely affecting ventilation-perfusion matching. Another is the expression of phosphodiesterase type 5 in the hypertrophied right ventricle. These data suggest that phosphodiesterase type 5 inhibitors may have effects that distinguish them from other treatments for pulmonary hypertension and merit further study.
Int J Gynaecol Obstet. 2008 Jun 25;
Cavalcanti AL, Bagnoli VR, Fonseca AM, Pastore RA, Cardoso EB, Paixão JS, Soares JM, Saad F, Baracat EC
OBJECTIVE: To analyze the effects of sildenafil citrate on clitoral blood flow and sexual response in postmenopausal women with orgasmic dysfunction. METHOD: In this randomized, double-blind, placebo-controlled trial 22 women received a 50-mg dose of sildenafil (n=11) or placebo (n=11) daily for 15 days. The Golombok Rust Inventory of Sexual Satisfaction (GRISS) was used for subjective evaluation of the sexual-response cycle. Clitoral blood flow was measured by color and pulse Doppler at baseline, after 1 hour of taking the first dose, and after 15 days of treatment. RESULTS: Blood flow was significantly more improved in the sildenafil than in the placebo group (P
Exp Mol Med. 2008 Jun 30; 40(3): 286-93
Kim KO, Park SY, Han CW, Chung HK, Ryu DH, Han JS
The purpose of this study was to identify the effect of sildenafil citrate on IL-1beta-induced nitric oxide (NO) synthesis and iNOS expression in human synovial sarcoma SW982 cells. IL-1? stimulated the cells to generate NO in both dose- and time-dependent manners. The IL-1beta-induced NO synthesis was inhibited by guanylate cyclase (GC) inhibitor, LY83583. When the cells were treated with 8-bromo-cGMP, a hydrolyzable analog of cGMP, NO synthesis was increased upto 5-fold without IL-1beta treatment suggesting that cGMP is an essential component for increasing the NO synthesis. Synoviocytes and chondrocytes contain strong cGMP phosphodiesterase (PDE) activity, which has biochemical features of PDE5. When SW982 cells were pretreated with sildenafil citrate (Viagra), a PDE5 specific inhibitor, sildenafil citrate significantly inhibited IL-1beta-induced NO synthesis and iNOS expressions. From this result, we noticed that PDE5 activity is required for IL-1?-induced NO synthesis and iNOS expressions in human synovial sarcoma cells, and sildenafil citrate may be able to suppress an inflammatory reaction of synovium through inhibition of NO synthesis and iNOS expression by cytokines.
Neurosci Lett. 2008 Jun 7;
Yoon MH, Kim WM, Lee HG, Kim YO, Huang LJ, An TH
Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50mul) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.