Development of a liquid chromatographic method for bioanalytical applications with sildenafil.

Sheu MT, Wu AB, Yeh GC, Hsia A, Ho HO.

Graduate Institute of Pharmaceutical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan, PR China.

An improved HPLC method was developed for the determination of sildenafil concentrations in plasma. Analysis of sildenafil in plasma samples was simplified by utilizing a one-step liquid-liquid extraction after alkaline treatment of only 1 ml of plasma. The lower limit of quantitation was 10 ng/ml with a coefficient of variation of less than 20%. A linear range was found to exist from 10 to 1000 ng/ml. This HPLC method was validated with precisions (coefficient of variation, C.V.) for inter- and intra-day runs of 0.41-11.15% and 0.36-8.05%, respectively, and accuracies (the relative error of the mean, REM) for inter- and intra-day runs of -8.72-6.81% and 0.41-11.15%, respectively. A bioavailability study of sildenafil was performed on one normal healthy male volunteer by analyzing sildenafil plasma concentrations with this validated HPLC method. Results demonstrated that this HPLC method is appropriate for applications to bioavailability studies of sildenafil. In addition, an example of the influence of the co-administration of grapefruit juice on sildenafil pharmacokinetics in a healthy volunteer is presented.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12798185&dopt=Abstract sildenafil Viagra online



Sildenafil, N-desmethyl-sildenafil and Zaprinast enhance photoreceptor response in the isolated rat retina.

Barabas P, Riedl Z, Kardos J.

Department of Neurochemistry, Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri ut 59-67, H 1025, Budapest, Hungary.

Here we report that the active component of Viagra, Sildenafil and the first metabolite, N-desmethyl-sildenafil (UK-103, 320) increased the amplitude of flash-evoked electroretinogram (ERG) of dark-adapted albino rat retina. Effects of Sildenafil and N-desmethyl-sildenafil were comparable to those of the known phosphodiesterase inhibitor, Zaprinast. The photoreceptor cell response was isolated by blocking the glial K(+) ion-buffering and the on-bipolar components of the ERG with the use of BaCl(2) (500 microM) and the specific type VI metabotropic glutamate receptor agonist, DL-2-amino-4-phosphonobutyric acid (25 microM), respectively. Zaprinast, Sildenafil and N-desmethyl-sildenafil (1 microM each) increased the amplitude of photoreceptor cell response either. Besides, Sildenafil was significantly more effective than N-desmethyl-sildenafil. These findings suggest an increased sensitivity of photoreceptor cells in the presence of Sildenafil and it is metabolite.

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Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome.

Shekerdemian LS, Ravn HB, Penny DJ.

Paediatric Intensive Care Unit, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia. lara.shekerdemian rch.org.au

There has been recent interest in the use of the phosphodiesterase-5 inhibitor sildenafil for treating pulmonary hypertension. We examined the interaction between inhaled nitric oxide (iNO) and i.v. sildenafil in 12 piglets with acute pulmonary hypertension and lung injury secondary to meconium aspiration. Six animals (controls) received no intervention after meconium instillation, and six received iNO (20 ppm) from 120 min, with the addition at 240 min of an i.v. sildenafil infusion (2 mg/kg over 2 h). Meconium instillation increased mean pulmonary artery (PA) pressure from 16.0 +/- 3.1 to 24.8 +/- 4.6 mm Hg (p < 0.01) and pulmonary vascular resistance (PVR) from 0.047 +/- 0.008 to 0.089 +/- 0.027 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.01). Oxygenation index increased from 3 +/- 0.8 to 8.3 +/- 3.0 (p < 0.01). There were no further changes beyond 120 min in controls. iNO reduced PA pressure and PVR to baseline values, without influencing oxygenation. The addition of sildenafil further reduced PA pressure, tended to increase the cardiac output, and reduced PVR from 0.049 +/- 0.02 to 0.028 +/- 0.01 mm Hg. ml(-1). min(-1). kg(-1) (p < 0.05). Sildenafil lowered the systemic blood pressure and systemic vascular resistance and produced profound arterial hypoxemia, reducing arterial Po(2) from 69 +/- 23 mm Hg to 49 +/- 15 mm Hg, despite substantial increases first in inspired oxygen fraction and subsequently in mean airway pressures. Consequently, the oxygenation index increased by 13.9 +/- 4.8 (p = 0.01). When given in addition to iNO, sildenafil at a dose of >0.5 mg/kg produced profound pulmonary vasodilation, but this was coupled with an unacceptable deterioration in oxygenation and systemic vasodilation in this model of pulmonary hypertension with acute parenchymal lung disease.

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Ocular adverse effects of sildenafil.

[No authors listed]

(1) Abnormal colour vision and brightness were two adverse effects of sildenafil observed during pre-marketing studies. Both effects are dose-dependent and reversible, and led to sildenafil being contraindicated in patients with hereditary degenerative retinal disturbances such as pigmentary retinitis. (2) Several cases of anterior ischaemic optic neuropathy have been reported since the marketing release of sildenafil. These are potentially serious adverse effects that can have permanent sequelae, such as a reduced field of vision.

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ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction.

Eisenhardt A, Sperling H, Hauck E, Porst H, Stief C, Rubben H, Muller N, Siffert W.

Department of Pharmacology, University Hospital Essen, Essen, Germany.

OBJECTIVES: To examine a potential association between the response to the phosphodiesterase-5 inhibitor sildenafil and angiotensin-converting enzyme (ACE), as well as NOS3 G894T genotypes in patients with erectile dysfunction (ED). An insertion/deletion (I/D) polymorphism in the gene encoding the ACE and a single nucleotide exchange polymorphism (G894T) in the gene NOS3 encoding endothelial nitric oxide synthase have been associated with cardiovascular disorders. METHODS: The response to sildenafil in 113 men with ED was monitored according to the patients' diaries. ACE and NOS3 genotypes were determined in patients with ED and in 108 healthy male blood donors. RESULTS: Genotype distributions of ACE and NOS3 polymorphisms in the patient group were similar to those of the healthy control group. Analysis of the response to sildenafil revealed that 15 of 20 individuals homozygous for the ACE II genotype showed a positive erectile response after sildenafil use and only 46 of 93 D allele (combined DD and DI genotypes) carriers had a positive response (positive erectile response, odds ratio 3.07, 95% confidence interval 1.03 to 9.13, P = 0.04; chi-square test). Analysis of NOS3 genotypes revealed that 30 of 52 individuals homozygous for the G894 allele had a sufficient response to sildenafil and only 4 of 12 patients homozygous for the 894T allele had a sufficient erection. CONCLUSIONS: It appears that patients with elevated ACE serum concentrations, as associated with the D allele of the ACE I/D polymorphism, are less likely to respond to sildenafil.

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Evaluation of the effects of sildenafil citrate (Viagra) on canine renal artery, carotid and aortic blood flow with the aid of color Doppler sonography.

Serhatlioglu S, Kiris A, Kocakoc E, Canpolat I, Bozgeyik Z, Han MC.

Department of Radiology, Faculty of Medicine, Firat University, Elazig, Turkey. sserhatlioglu firat.edu.tr

INTRODUCTION: Erectile dysfunction is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Oral use of sildenafil citrate has been proved to be effective in the treatment of erectile dysfunction. Although the effects of sildenafil citrate have been investigated in several studies, its effect on aortic, carotid and renal artery blood flow is unknown. The aim of this study was to investigate the early and late phase effects of sildenafil citrate on canine aortic, carotid and renal artery blood flow using color Doppler sonography (CDS). MATERIALS AND METHODS: A total of 6 healthy adult dogs was used in this study. With the aid of CDS peak systolic flow rate, end diastolic flow rate, resistivity index (RI) and pulsatility index in aortic, renal and carotid artery were determined before the administration of sildenafil citrate, 45-75 min after drug administration and after 15 days of drug administration. Data were statistically analyzed using Friedman and Wilcoxon rank tests. p < 0.05 was considered to be statistically significant. RESULTS AND CONCLUSIONS: Significant changes were determined in only 4 out of 28 parameters studied. The significantly changed parameters were as follows: a significant increase in the early and late phase of the postdrug peak of systolic aortic blood flow compared to values before drug administration, an increase in pre- and postdrug RI values of the aorta, a significant decrease in maximum velocity of the right carotid artery, and peak systolic maximum velocity of the left renal segmental artery after drug administration compared to their respective predrug basal values. The results from this study indicate that sildenafil citrate has no significant effects on aortic, renal and carotid artery blood flow rate either in the early or in the late phase. Since this study involved only 6 dogs there is a need for further clinical studies involving larger groups of subjects to conclude that this drug is safe with respect to the hemodynamic parameters evaluated in this study. Copyright 2003 S. Karger AG, Basel

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[Necessity for using evidence-based medicine in making clinical decisions based on the example of erectile dysfunction]

[Article in Russian]

Apolikhin OI, Abdullin II.

The choice of the method to treat erectile dysfunction is often not easy. The evidence-based approach to the critical appraisal of the medical literature could help us to find the best way. All the available information was critically assessed in order to find the answer to the question: Ds sildenafil effective in the treatment of erectile dysfunction in patients with diabetes mellitus? All sources of information have been analysed including medical text books and the sources from the university of Cochrane library. The result of the analysis was the following: sildenafil is effective with a B degree of significance in the treatment of erectile dysfunction in patients with diabetes mellitus. This allows us to recommend sildenafil for treatment of erectile dysfunction in men with diabetes mellitus. The above algorithm of the critical assessment of the primary medical literature can be used for preparing standards of urological diseases treatment.

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Sildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomy.

Schwartz EJ, Wong P, Graydon RJ.

Division of Urology, University of Connecticut Health Sciences Center, Farmington, USA.

PURPOSE: Early use of vasoactive agents has been shown to rehabilitate erectile function after nerve sparing radical retropubic prostatectomy (RRP). The loss of intracorporeal smooth muscle (SM) and an increase in intracorporeal fibrosis have been demonstrated in vasculogenic impotence and implicated in permanent post-RRP erectile dysfunction. We assessed the effect of sildenafil on SM content after RRP. MATERIALS AND METHODS: A total of 40 potent volunteers with prostate cancer underwent RRP and were divided into 2 treatment groups, namely 1-50 mg sildenafil and 2-100 mg sildenafil every other night for 6 months beginning the day of catheter removal. Percutaneous biopsy was performed using general anesthesia prior to incision for RRP. Another biopsy was performed using local anesthesia 6 months later. Volunteers were excluded prior to the second biopsy if they discontinued sildenafil. Biopsies were stained for SM and connective tissue, and analyzed by computer in at least 15 different fields. The paired Student t test was used for statistical analysis. RESULTS: A total of 11 patients in group 1 and 10 in group 2 underwent the second biopsy. In group 1 there was no statistically significant change in mean SM content preoperatively to postoperatively (51.52% and 52.67%, respectively). In group 2 there was a statistically significant increase in mean SM content 6 months after RRP (42.82% vs 56.85%, p <0.05). CONCLUSIONS: Early use of sildenafil after RRP may preserve intracorporeal SM content. At higher doses post-RRP sildenafil may increase SM content. The effect on the return of potency is not known but maintaining the pro-erectile ultrastructure is integral to rehabilitating post-RRP erectile function.

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