Fatal overdosage with sildenafil citrate (Sildenafil): first report and review of the literature.
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Cardiovascular Diseases↗
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Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells.
Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O(2)(*-)) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO). Since NO inhibits NADPH oxidase expression through a cyclic GMP-mediated mechanism, sildenafil, a type V phosphodiesterase inhibitor, may be therapeutically effective in ARDS through an augmentation of NO-mediated inhibition of NADPH oxidase. Therefore, the effect of sildenafil citrate and NO-donating sildenafil (NCX 911) on O(2)(*-) formation and gp91(phox) (active catalytic subunit of NADPH oxidase) expression was investigated in cultured porcine pulmonary artery endothelial cells (PAECs). PAECs were incubated with 10 nM TXA(2) analogue, 9,11-dideoxy-9alpha,11alpha-methanoepoxy-prostaglandin F(2alpha) (U46619) (+/-sildenafil or NCX 911), for 16 h and O(2)(*-) formation measured spectrophometrically and gp91(phox) using Western blotting. The role of the NO-cGMP axis was studied using morpholinosydnonimine hydrochloride (SIN-1), the diethylamine/NO complex (DETA-NONOate), the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo{4,3-a}quinoxalin-1-one (ODQ), and the protein kinase G inhibitor, 8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS). NO release was studied using a fluorescence assay and O(2)(*-)-NO interactions by measuring nitrites. After a 16-h incubation with 10 nM U46619, both NCX 911 and sildenafil elicited a concentration-dependent inhibition of O(2)(*-) formation and gp91(phox) expression, NCX 911 being more potent (IC(50); 0.26 nM) than sildenafil citrate (IC(50); 1.85 nM). These inhibitory effects were reversed by 1 microM ODQ and 10 microM Rp-8-Br-cGMPS. NCX 911 stimulated the formation of cGMP in PAECs and generated NO in a cell-free system to a greater degree than sildenafil citrate. The inhibitory effect of sildenafil was augmented by 1 muM SIN-1 and blocked partially by the eNOS inhibitor 10 microM N(5)-(1-iminoethyl)-ornithine (L-NIO). Acutely, sildenafil and NCX 911 also inhibited O(2)(*-) formation, again blocked by 1 microM ODQ. NCX 911 reacted with O(2)(*-) generated by xanthine oxidase, an effect that was inhibited by superoxide dismutase (500 U ml(-1)). Since O(2)(*-) formation plays contributory role in ARDS, both sildenafil citrate and NCX 911 may be indicated for treating ARDS through suppression of NADPH oxidase expression and therefore of O(2)(*-) formation and preservation of NO bioavailability.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Nasal obstruction as a common side-effect of sildenafil citrate.
Sildenafil citrate is an effective oral drug for erectile dysfunction. The main action of sildenafil is the enhancement of the effect of nitric oxide (NO) by inhibiting the cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase-5 (PDE-5), an enzyme responsible for degradation of cGMP. NO is also present in the nasal mucosa and is responsible for vasodilation causing congestion and nasal obstruction. The aim of this study was to detect the effect of sildenafil on nasal mucosa in terms of nasal obstruction. A total of 16 patients presented to urology clinic suffering from impotence and medicated with sildenafil were included in the study. Before and after oral administration of 50 mg sildenafil, in all of the patients the nasal patency was examined by active anterior rhinomanometry (a method of assessing nasal resistance) using air pressure of 150 Pascal. In addition, all patients were asked about their sensation of nasal patency to detect the symptomatic nasal obstruction. There was a significant decrease in nasal air flow values (cm(3)/s) (p < 0.05). Except for three cases, all patients indicated that they had the sensation of nasal obstruction after the use of sildenafil (p < 0.05). Nasal obstruction is a common complaint for the patients using Sildenafil.
Aged↗
Overall cardiovascular profile of sildenafil citrate.
Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.
3',5'-Cyclic-GMP Phosphodiesterases↗
Physicochemical properties of sildenafil citrate (Viagra) and sildenafil base.
Sildenafil citrate (Viagra) [I] and sildenafil base [II] are easily and unequivocally characterized by a set of physicochemical methods that include X-ray diffractometry, infrared spectroscopy, and thermal analysis. Monoclinic lattice constants: [I]: a = 26.98 A; b = 11.95 A; c = 16.68 A; beta = 106.97 degrees. [II]: a = 8.66 A; b = 34.27 A; c = 8.93 A; beta = 96.63 degrees. Both compounds decompose at 189.4 degrees C [I] and 251.9 degrees C [II]. Densities and refractive indices are given.
Citric Acid↗
Sildenafil citrate (Viagra).
Sildenafil citrate, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type V (PDE V), initially designated as compound 92-480-10 by Pfizer, was studied in the late 1980s as an antianginal. An unexpected side effect of the early clinical investigations was improved erectile function among the men studied. This serendipitous finding has transformed the field of erectile dysfunction therapy (1-3). The novelty of this compound is its oral route of delivery and efficacy across a broad range of etiologies.
Journal Article↗
Determination of sildenafil citrate in plasma by high-performance liquid chromatography and a case for the potential interaction of grapefruit juice with sildenafil citrate.
This study was designed to establish a simple and reliable assay method that could be routinely used in the clinical laboratory setting using liquid extraction and high-performance liquid chromatography (HPLC). In addition, a case of potential interaction of grapefruit juice with sildenafil citrate is presented. The peaks of sildenafil (measured as sildenafil salt) and internal standard were identified with an ultraviolet detector at 230 nm and detection limit at 10 ng/mL. In a single elderly male patient, grapefruit juice increased the Cmax of sildenafil by 42% (1067.7 ng/mL to 1517.0 ng/mL) although AUC was not significantly altered (4082.9 ng x h/mL to 4171.9 ng x h/mL) by grapefruit juice. Sildenafil could be determined in a simple and reliable method using HPLC with liquid extraction. This case indicated that grapefruit juice might increase the Cmax of sildenafil without significant change in AUC. A further study with an appropriate number of subjects is needed before determining the degree of interaction between grapefruit juice and sildenafil.
3',5'-Cyclic-GMP Phosphodiesterases↗
Algorithm for diagnosis and treatment of erectile dysfunction in the era of sildenafil citrate.
Since Viagra (sildenafil citrate) was released as a pharmaceutical agent for the treatment of erectile dysfunction, it has had a big impact on the work undertaken in our practice. I herewith present an algorithm for the diagnosis and treatment of erectile dysfunction in the era of sildenafil citrate.
Algorithms↗
Effect of sildenafil citrate on the cardiovascular system.
Sildenafil citrate is a drug commonly used to manage erectile dysfunction. It is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H -pyrazolo[4,3-d]pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6(O4)S). It is a highly selective inhibitor of cyclic guanine monophosphate-specific phosphodiesterase type 5. In late March through mid-November 1998, the US Food and Drug Administration (FDA) published a report on 130 confirmed deaths among men (mean age, 64 years) who received prescriptions for sildenafil citrate, a period during which >6 million outpatient prescriptions (representing about 50 million tablets) were dispensed. The US FDA recently reported that significant cardiovascular events, including sudden cardiac death, have occurred in men with erectile dysfunction who were taking sildenafil citrate. These reports have raised concerns that sildenafil citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively in both animal and clinical studies. According to extensive data available to date, sildenafil citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions are needed for patients with cardiovascular diseases. However, the only absolute contraindication for sildenafil citrate is the concurrent use of nitrates. This article is intended to review sildenafil citrate's cardiovascular effects, as well as current debates about its arrhythmogenic effects.
Adult↗
Sildenafil citrate (Viagra).
Sildenafil is the first of a series of orally active treatments for MED which has resulted in unprecedented demand for treatment and potentially high cost to the NHS. Further oral therapies are likely to follow in the next year or so. In clinical trials, sildenafil produced an erection (sufficient to achieve intercourse) lasting up to 4 h on around 70% of occasions. This was reduced to 50% in 'high-risk' groups (e.g. diabetics) and a placebo response in as many as 10-20% has been reported. Whether or not sildenafil should be prescribed at NHS expense has been more a matter for political, than clinical, debate. A clearer picture is now emerging with treatment available to those considered the 'most deserving' cases. The bigger picture is of impotence in large numbers of men with hypertension who are on antihypertensive therapy and have obvious small vessel disease. One option is to consign sildenafil to Schedule 10 (Black List) so that it is only available on private prescription. This would allay fears of the cost of treatment for those merely seeking to 'boost' already adequate sexual performance.
Administration, Oral↗
Sildenafil citrate significantly improves nocturnal penile erections in sildenafil non-responding patients with psychogenic erectile dysfunction.
Effects of sildenafil citrate on nocturnal penile tumescence and rigidity (NPTR) were evaluated among sildenafil non-responding patients with psychogenic erectile dysfunction. All patients (n=30), equally divided into groups I and II, completed four consecutive nights using the RigiScan Plus device. Sildenafil citrate (50 mg) was given in the third night in group I and in the fourth in group II, whereas a placebo was given in the remaining nights. Additional patients (n=12) receiving only a placebo served as a control group. Results of NPTR recordings revealed neither significant differences between the control and non-sildenafil nights of both test groups, nor between the corresponding values of both groups (P>0.05). On the other hand, when sildenafil citrate nights of groups I and II taken together were compared with placebo nights, a significant increase of total events duration (P<0.001), average rigidity of the tip (P<0.05) and base (P<0.01), and rigidity activity unit (RAU) and tumescence activity unit (TAU) of tip and base (P<0.001) was observed. These results suggest that performance anxiety may be responsible for failure of response during awakening.
Adult↗
Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits.
Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.
Acetophenones↗
Improved flap viability with site-specific delivery of sildenafil citrate using fibrin glue.
Sildenafil is a cyclic guanosine-specific phosphodiesterase type 5 (PD-5) inhibitor that is widely used for erectile dysfunction. Potent and competitive inhibition of PD-5 enhances levels of cyclic guanosine monophosphate (cGMP). Fibrin glue-apart from tissue fixation-has been used for slow release of drugs. In this study, local delivery of Sildenafil citrate with fibrin glue was accomplished to improve random flap survival. Fifty Wistar rats were randomized into 5 groups, and a standardized dorsal random-pattern skin flap was elevated in each rat. In Group I (n = 10), the base of the flap was divided, making it a "graft" control to study the graft effect. In Group II (n = 10), a thin Silastic sheet was used to separate the flap from the underlying vascular bed, and no pharmacologic treatment was given. In Group III (n = 10), only 0.5 mL of fibrin glue was applied to the flap donor site. In Group IV (n = 10), 2.5 mg of sildenafil citrate mixed in 0.5 mL of fibrin glue was applied to donor site of the flap, whereas 10 mg of sildenafil citrate mixed in 0.5 mL of fibrin glue was applied in Group V (n = 10). Area of flap survival was evaluated on postoperative seventh day. Total necrosis of all of the flaps was observed in "graft" control group (Group I). Sildenafil and fibrin glue groups (Group IV and V) resulted in a statistically significant decrease in flap necrosis compared with Groups II and III (P < 0.0001). A statistically significant difference could not be documented between Group II and Group III (P > 0.0001). The decrease in skin necrosis was statistically significant in Group V compared with Group IV (P < 0.0001). Histologic examination revealed significantly increased vascular density in Groups IV and V compared with Groups II and III (P < 0.0001), whereas a significant difference could not be documented between Groups IV and V (P > 0.0001) and between Groups II and III (P > 0.0001). In view of these results, topical sildenafil application seems to improve flap survival in random-pattern skin flaps in dose-dependent manner.
Animals↗
Histopathological effects of sildenafil citrate on rat corpus cavernosum.
Sildenafil citrate (Viagra) is widely used for the treatment of erectile dysfunction with various etiologies. The aim of the present study was the investigation of histopathological effects of sildenafil citrate on rat corpus cavernosum using tight and electron microscopical techniques. Twenty male rats were divided into two groups. The first group (n = 10) was used as a control and the second group (n = 10) was treated with sildenafil citrate. Penile tissue was collected, fixed with formalin and embedded in paraffin for light microscopy, or fixed with gluteraldehyde and osmium tetroxide and embedded in Epon for electron microscopy. Light microscopical analysis showed that the corpus cavernosum was elongated and the number of blood vessels was increased. The amount of connective tissue in the penis was increased and dense collagen and smooth muscle fibers were observed in treated rats. Electron microscopical analysis showed that stromal structures of the corpus cavernosum (collagen fibers and number of cellular elements) were increased in treated rats. Fibroblasts showed signs of activation and the number of other stromal cells was increased. Immature newly synthesized collagen fibers were observed and penetrated endothelial basement membranes. In addition, endothelial cells also showed signs of activation such as cytoplasmic granules in treated rats, whereas the surface area of blood vessels was increased and basement membranes were thickened. These histopathological changes due to treatment with sildenafil citrate indicate that prolonged use of sildenafil citrate may increase the risk of fibrosis in the penis.
Animals↗
Ocular safety of Viagra, (sildenafil citrate).
To date, sildenafil citrate (Viagra) gives every evidence of being a safe drug for the eye despite a series of expressed concerns. A review of how its ocular safety profile has been identified offers insights into the strengths and weaknesses of present systems and resources for judging the ocular safety of Viagra or, for that matter, of any new drug. Such insights include: The great value of careful, informed assessment of preclinical information gleaned from laboratory experiments. By and large, such assessments point the way toward appropriate clinical evaluation. For Viagra, early in its development it was noted that besides exerting a major inhibitory effect on the intended target, the vascular-associated enzyme phosphodiesterase 5 (PDE5), the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6, located in the retina. For this reason, preclinical evaluation of the drug included electroretinography plus postmortem histology. In addition, an extended eye examination was incorporated into clinical protocols. The often chaotic but invaluable information stream that becomes available once marketing approval has been gained and large populations begin to use a drug. False alarms, misattribution, and erroneous information are the order of the day. Nevertheless, as information accumulates, patterns of response clarify and the true nature of special susceptibility for subpopulations, if any, becomes apparent. A role for the astute clinician remains: Subtle changes or unusual risks for subpopulations can be missed entirely for long periods of time. A manifest need for improvement in evaluation of postmarketing side-effects. This need has led to the establishment of a new discipline: pharmacoepidemiology. In ophthalmology, the National Registry of Drug Induced Ocular Side-Effects maintains a constant and invaluable surveillance. Examples are supplied to illustrate each of these major points: Our presentation will include data gleaned from clinical trials plus postmarketing information on the incidence, duration, and type of color vision defects observed at different doses of Viagra.
3',5'-Cyclic-GMP Phosphodiesterases↗
Effects of sildenafil citrate (Viagra) combined with nitrate on the heart.
BACKGROUND: Sildenafil citrate (Viagra) is indicated for the treatment of erectile dysfunction. Large and sudden decreases in systemic blood pressure were reported in a substantial number of patients taking sildenafil citrate combined with nitroglycerin. We studied the effect of sildenafil citrate on the relationship between changes in systemic blood pressure and coronary blood flow. METHODS AND RESULTS: Healthy male beagles were used to assess systemic blood pressure, pulmonary arterial pressure, and flow in the left circumflex artery (in which a critical stenosis was established) and left anterior descending coronary artery. After measurement of the hemodynamic variables, 2 mg/kg sildenafil citrate was administered via a nasogastric tube. Hemodynamic changes were monitored for 1 hour. Subsequently, the acute effect of nitrate combined with sildenafil citrate was studied by the bolus injection of 0.2 mg isosorbide dinitrate before and after sildenafil citrate. Systemic blood and pulmonary arterial pressures and circumflex flow did not change during this study; however, left anterior descending coronary arterial flow increased from 16.0+/-5.8 to 24.6+/-8.7 mL/min 1 hour after administration of sildenafil citrate. The prolongation of systemic blood pressure decrease and the circumflex flow decrement induced by isosorbide dinitrate after sildenafil citrate were significantly larger and longer than those before sildenafil citrate. CONCLUSIONS: Sildenafil citrate had the effect of vasodilation in a normal coronary artery; however, a combined effect with nitrate resulted in large and protracted decreases in systemic blood pressure and coronary blood flow in vessels with critical stenosis.
Administration, Oral↗
Side-effect profile of sildenafil citrate (Viagra) in clinical practice.
OBJECTIVES: Sildenafil citrate (Viagra) has been shown to be an effective treatment for erectile dysfunction. Initial studies reported a high tolerability and low incidence of certain characteristic adverse reactions. We sought to evaluate the incidence of side effects of sildenafil citrate, independent of industry support and constraints, utilizing a heterogeneous cohort of patients from a university-based practice. METHODS: A prospective, open-label, flexible-dose study of 256 patients treated with sildenafil citrate for erectile dysfunction was performed at a single institution. The patients were questioned explicitly about the occurrence of headache, flushing, dyspepsia, nasal congestion, visual changes, and other side effects. RESULTS: The adverse reactions most commonly observed were flushing (30.8%), headache (25. 4%), nasal congestion (18.7%), and heartburn (10.5%). All events were short lived and mild in nature. In the present study, 31.6% of patients experienced one or more adverse events. However, no one withdrew from the study because of the severity of these events. There was a significant association between higher doses and the occurrence of side effects. CONCLUSIONS: The incidence of adverse events attributable to sildenafil citrate may be higher than initially reported, but an explanation may be the methodology of data collection and the industry-independent nature of this study. The side-effect profile is dose related and mild. Sildenafil citrate remains a safe and well-tolerated treatment for erectile dysfunction.
Adult↗
Effects of sildenafil citrate on hepatic function and regeneration in normal and alcohol-fed rats.
Sildenafil citrate is a potent inhibitor of specific phosphodiesterase-5, which mediates metabolism of intracellular second message -- cGMP. Sildenafil citrate has been widely used for erectile dysfunction in men. Moreover, it is known that men with liver diseases have higher rate of erectile dysfunction. Furthermore, it has been demonstrated that nitric oxide plays an important role in liver function and regeneration. The present study evaluates effects of sildenafil citrate on hepatic function and regeneration in normal and alcohol-fed rats. In normal rats sildenafil citrate has a trend to improve hepatic function after partial hepatectomy (PHx). Moreover, sildenafil citrate significantly reduces hepatic regenerative activity at the concentration of 5 mg/kg body weight. However, sildenafil had no effects on hepatic function and regeneration of alcohol-fed rats. In general, sildenafil citrate did not induce significant changes in hepatic function and regenerative activity after PHx in normal and alcohol-fed rats, except at concentration of 5 mg/kg sildenafil citrate significantly inhibit hepatic regeneration in normal rats.
3',5'-Cyclic-GMP Phosphodiesterases↗