Co-administration Of Sildenafil Research Articles

SILDENAFIL DECREASED TNF-α AND IL-6 LEVELS IN CD‐INDUCED ACUTE TOXICITY

Objective: This study aimed to evaluate the effects of sildenafil (SIL) on inflammation and histopathological changes in cadmium (Cd)-induced toxicity in female rats. Material and Method: Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF- α) levels were measured to assess the degree of inflammation. Histopathological changes in the liver, lungs and kidneys were also assessed. Result and Discussion: SIL significantly reduced the cellular release of TNF-α and IL-6, which have been implicated in the pathogenesis of Cd-induced tissue damage. When SIL was administered alone, it showed histopathological effects similar to the control group. However, it was found that co-administration of SIL with Cd prevented portal vein dilation and central vein enlargement in the liver, prevented necrosis in kidney tissue, but did not affect the lung. Although SIL has variable protective effects on tissues, our results are in support of the idea that the use of SIL in tissue damage management can be investigated for its efficacy in modulating oxidative stress-induced proinflammatory cytokine activation in vivo and ultimately help prevent Cd-induced tissue damage. Our study has shown that SIL can reduce Cd-induced acute toxicity in rats. SIL may be use as a protective agent against toxicity of heavy metals.

The combined uterorelaxant effect of sildenafil and terbutalin in the rat: The potential benefit of co-administration of low doses

AimsOur aims were to investigate the uterus relaxant effect of sildenafil alone and co-administered with β2-mimetic terbutaline in an isolated organ bath and to perform in vivo smooth muscle electromyographic studies in pregnant rats. The modifications in uterine cAMP/cGMP levels were also detected. Main methodsContractions of non-pregnant and 5/15/18/20/22-day pregnant uterine rings were measured in an isolated organ bath system in the presence of sildenafil alone or with terbutaline. The uterine levels of cAMP and cGMP were determined by commercial ELISA assays. The in vivo efficacy of the combination was measured by smooth muscle electromyography. Key findingsSildenafil reduced uterine contractions in vitro and in vivo; additionally, terbutaline significantly increased the uterorelaxant effect of sildenafil in the lower concentration or dose ranges. Terbutaline enhanced the cGMP level increasing effect of sildenafil. SignificanceThe co-administration of sildenafil and terbutaline could be a promising tocolytic combination to reduce maternal and foetal adverse events and increase efficacy.

Influence of methylxanthines isolated from Bancha green tea on the pharmacokinetics of sildenafil in rats.

Sildenafil is used to treat erectile dysfunction and pulmonary arterial hypertension and is metabolized in the liver mainly by CYP3A4, thus co-administration with drugs or herbal extracts that affect CYP3A4 activity may lead to drug-drug or drug-herb interactions, respectively. The aim of the present study was to evaluate the influence of single and multiple oral doses of methylxanthine fraction, isolated from Bancha green tea leaves on the pharmacokinetics of sildenafil in rats. Rats were given sildenafil alone as well as simultaneously with methylxanthines or ketoconazole. The plasma concentrations of sildenafil were measured with high-performance liquid chromatography method with ultraviolet detection. The pharmacokinetic parameters of sildenafil were calculated by non-compartmental analysis. Concomitant use of sildenafil with a single oral dose of methylxanthines resulted in a decrease in Cmax (p > 0.05), AUC0-t (p < 0.05) and AUC0-inf (p < 0.05), while the administration of sildenafil after methylxanthines pretreatment resulted in an increase in Cmax (p < 0.0001), AUC0-t (p < 0.0001) and AUC0-inf (p < 0.001) compared to the sildenafil group. After co-administration of sildenafil and ketoconazole, a significant increase in Cmax, AUC0-t and AUC0-inf was observedin both of the experiments. Drug-herb interactions were observed when sildenafil was co-administered with Bancha methylxanthines in rats. Further in vivo studies about the potential drug interactions between sildenafil and methylxanthines, especially caffeine, are needed to clarify mechanisms underlying the observed changes in sildenafil pharmacokinetics.

Comparison of sildenafil, fluoxetine and its co-administration against chronic constriction injury induced neuropathic pain in rats: An influential additive effect

ABSTRACTCurrent drug treatment available for neuropathic pain (NP) provides meager and partial pain relief due to incomplete efficacy and dose-dependent adverse effect. Hence, combination therapy can provide prolongation in analgesic effect with milder side effects. The present investigation aimed at observing the effects of sildenafil (SD) on Fluoxetine (FLX) in attenuation of chronic constriction injury (CCI) induced NP in rats. CCI was achieved in rats by placing four loose ligations around the sciatic nerve and rats were received respective treatments on SD and FLX till 14 days further behaviors parameters like heat hyperalgesia and allodynia, pin prick and acetone drop test were executed in order to access thermal, mechanical and cold allodynia, respectively, on a predetermined time interval. On the 21st day the animals were sacrificed for determination of total protein, myeloperoxidase activity in the adjoining muscular tissues while glutathione and TNF-α in the sciatic nerve. Co-administration of SD + FLX + CCI gave the pronounced effect that was superior over individual responses of SD and FLX in all behavioral as well as biochemical parameters. It was observed that attenuation in the altered behavioral pattern of CCI induced rats was modified prominently from 3rd day only in a group of rats treated with SD + FLX + CCI. The whole study was finally supported by histopathological results. Finally, it was concluded that SD produces an additive effect when given with FLX in attenuation of NP may be due to elevation in the level of intracellular concentrations of cyclic guanosine monophosphate which further causes downregulation of calcium channel.

Development and validation of an HPLC-UV method for simultaneous determination of sildenafil and tramadol in biological fluids: Application to drug-drug interaction study

The introduction of sildenafil (SDF) to treat erectile dysfunction has solved a widespread condition with negative on the quality of life. Recently, the co-administration of tramadol (TMD) with SDF to manage premature ejaculation has illegally increased and thus drug-drug interaction studies of these drugs became of great importance. Although certain biological functions have been altered upon co-administration of the two drugs, methods for their determination in vivo to understand their interactions have yet to be published. Herein, therefore, an HPLC method with photometric detection was developed for the determination of a binary mixture of TMD and SDF in rabbit plasma after oral administration. In this study, a reversed-phase chromatography was performed at room temperature on a C18 column with a mobile phase composed of 10 mM Na2HPO4 solution (pH 7.5): acetonitrile (45:55, v/v) at a flow rate of 0.8 mL min−1 using caffeine (CAF) as an internal standard. The detector was set at 220 nm. The total analysis time was 6 min. Calibration graphs were linear in the concentration ranges of 0.1–10 and 0.05–10 μg mL−1 with a detection limit of 0.05 and 0.02 μg mL−1 for TMD and SDF, respectively. The method was validated in terms of accuracy, precision, limit of detection and quantitation, recovery, and stability as per US FDA bioanalytical guidelines. In addition, the metabolites N-desmethylsildenafil (UK-103,320) and O-desmethyltramadol were quantified in rabbit plasma after 2 h of oral administration using LC–MS/MS. The simultaneous administration of TMD with SDF has affected peak plasma concentration (Cmax), Tmax, area under the concentration-time curve (AUC), and the elimination rate constant (Kel) of SDF. The present study is the first to give valuable insights into the drug-drug interaction and the pharmacokinetic implications associated with the co-administration of SDF and TMD.

Safety and Efficacy of the Coadministration of Sildenafil and Finasteride

Purpose The 5-alpha reductase inhibitors (5ARI) are one of the most commonly used medications for the treatment of benign prostatic hyperplasia (BPH). Phosphodiesterase type-5 inhibitors are also used to treat BPH. 5ARI is a drug with adverse effects of sexual dysfunction. In this study, we investigated the safety and efficacy of coadministration of finasteride and sildenafil on sexual function and lower urinary symptoms in patients with BPH. Materials and Methods We retrospectively reviewed the medical records of patients who were receiving finasteride and sildenafil daily regimens for treatment of BPH in 2 university hospitals. Patients with adverse effects, vital sign, physical exam, laboratory test, 5-item version of the international index of erectile function (IIEF-5), International Prostate Symptom Score (IPSS), quality of life (QoL) were analyzed. Results The number of patients analyzed in this study was 218. The mean age of the patients was 62.63±8.37 years and the mean duration of medication was 18.23±10.97 weeks. Significant changes were not observed in the vital signs measured before and after the drug administration. Compared with before treatment, improvement of lower urinary tract symptom (IPSS: 17.56±4.21 vs. 11.64±5.33, p<0.001) was observed and improvement of sexual function (IIEF-5: 9.44±5.21 vs. 12.73±6.81, p<0.001) was also confirmed. Conclusions Daily coadministration of finasteride and sildenafil for the treatment of BPH could be used safely, and improvement of lower urinary tract symptom as well as improvement of sexual function could be expected. Key Words: Erectile dysfunction; Prostatic hyperplasia; Lower urinary tract symptoms.

Evaluation of Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild-to-Moderate Hypertension.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open‐label, three‐period, single sequence study, patients with mild‐to‐moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (–5/–4/–4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.

Effect of sildenafil on the activity of some antidepressant drugs and electroconvulsive shock treatment in the forced swim test in mice

Sildenafil, a potent and selective inhibitor of phosphodiesterase type 5, is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. It is often taken by patients suffering from depression and receiving antidepressant drug treatment. However, its influence on the efficacy of antidepressant treatment was not sufficiently studied. Therefore, the aim of the present study was to investigate the influence of sildenafil on the anti-immobility action of several antidepressant drugs (i.e., sertraline, fluvoxamine, citalopram, maprotiline, trazodone, and agomelatine) as well as on antidepressant-like effect of electroconvulsive stimulations in the forced swim test in mice. The obtained results showed that acute sildenafil treatment enhanced the antidepressant-like activity of all of the studied drugs. The observed effects were not due to the increase in locomotor activity. The interactions between sildenafil and sertraline, maprotiline, and trazodone were pharmacodynamic in nature, as sildenafil did not affect concentrations of these drugs neither in serum nor in brain tissue. Increased concentrations of fluvoxamine, citalopram, and agomelatine in brain tissue evoked by sildenafil co-administration suggest that pharmacokinetic interactions between sildenafil and these drugs are very likely. Sildenafil injected acutely did not alter the antidepressant-like efficacy of electroconvulsive stimulations in mice, as assessed in the forced swim test. Interestingly, repeated (14 days) administration of sildenafil decreased the anti-immobility action of the electroconvulsive stimulations. In conclusion, the present study shows that sildenafil may alter the effectiveness of antidepressant treatment. Further studies are warranted to better characterize the influence of sildenafil on the activity of antidepressant drugs and electroconvulsive therapy.

Pharmacokinetic interaction between Kaempferia parviflora extract and sildenafil in rats.

Kaempferia parviflora (KP) is a plant widely used in Southeast Asia. Its major compounds are 3,5,7,3',4'-pentamethoxyflavone (PMF), 5,7,4'-trimethoxylflavone (TMF), and 5,7-dimethoxyflavone (DMF). This study investigated the effect of KP extract on the blood levels and pharmacokinetics of sildenafil co-administration in rats. Rats were randomly assigned to four groups. Groups 1, 2, and 3 were given sildenafil 20mg/kg daily for 9days. On days 4-9 of each treatment period, the treated rats received KP extract (250mg/kg) and vehicle (groups 2 and 3, respectively). Group 4 received KP extract only (250mg/kg daily for 9days). Daily blood concentrations of sildenafil, PMF, TMF, and DMF were determined by HPLC to evaluate the daily blood level interactions. Additional blood samples were collected at various times on the last day of treatment to evaluate the pharmacokinetic interactions. The KP extract decreased blood levels of sildenafil on the first day of co-administration by 95% but the percentage reduction was insignificant on subsequent days. When co-administered with KP extract, the area under the curve (AUC), maximum concentration (C max), and half-life (T 1/2) of sildenafil were decreased by 60-65, 40-52, and 32-54%, respectively, with the elimination rate constant (K e) increased by 37-77%. In addition, PMF, TMF, and DMF concentrations and their AUC, C max, T max, K e, and T 1/2 values were changed after co-administration of KP extract and sildenafil.

Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents

Type 2 diabetic men commonly experience erectile dysfunction for which phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) are often recommended. By preventing degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle, these inhibitors also enhance arterial vasorelaxant effects of nitric oxide donors (which stimulate cGMP synthesis). In the present work, we confirmed this enhancing effect after co-administration of sildenafil with nitroprusside to freshly-isolated rat tail arterial tissues. However, in the same tissues we also observed that sildenafil does not enhance but rather attenuates vasorelaxant effects of three commonly-used antidiabetic drugs, i.e. the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone. Indeed, sildenafil completely blocked vasorelaxant effects of low concentrations of these drugs. In addition, we found that this same novel anti-vasorelaxant interaction of sildenafil with these agents was abolished by either 1) omitting extracellular glucose or 2) inhibiting specific smooth muscle glycolytic pathways; pathways known to preferentially utilize extracellular glucose to fuel certain adenosine triphosphate (ATP)-dependent ion transporters: e.g. ATP-sensitive K channels, sarcoplasmic reticulum Ca-ATPase, plasma membrane Ca-ATPase and Na/K-ATPase. Accordingly, we suspect that altered activity of one or more of these ion transporters mediates the observed attenuating (anti-vasorelaxant) interaction of sildenafil with the antidiabetic drugs. The present results are relevant because hypertension is so common and difficult to control in Type 2 diabetes. The present data suggest that sildenafil might interfere with the known antihypertensive potential of metformin and the thiazolidinediones. However, they do not suggest that it will interact with them to cause life-threatening episodes of severe hypotension, as can occur when it is co-administered with nitrates.

Influence of sildenafil on the antidepressant activity of bupropion and venlafaxine in the forced swim test in mice

Recent studies highlight the involvement of the nitrergic system in the mechanism of action of antidepressant drugs. Sildenafil, a selective PDE5 inhibitor, was shown to abolish the anti-immobility effects of bupropion, venlafaxine and s-citalopram in mice. In this study we assessed the effects of sildenafil on the activity of bupropion and venlafaxine in the forced swim test in mice. Swim trials were conducted by placing mice in glass cylinders filled with water for 6min and the duration of the behavioral immobility during the last 4min of the test was evaluated. Locomotor activity was evaluated with photoresistor actimeters. Brain and serum concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 20mg/kg, but not 5 and 10mg/kg, significantly increased the anti-immobility action of bupropion (20mg/kg). The antidepressant activity of venlafaxine (2mg/kg) was potentiated by joint administration with sildenafil at doses of 10 and 20mg/kg. Since the combined treatments did not increase the locomotor activity, the antidepressant-like effects were not related to non-specific behavioral activation. Data from pharmacokinetic studies revealed that sildenafil increased bupropion and venlafaxine levels in serum without affecting their concentrations in the brain. The present study demonstrates the enhancement of anti-immobility action of bupropion and venlafaxine by sildenafil co-administration. The observed changes might have been partly due to pharmacokinetic interactions. However, mechanisms underlying the effects of sildenafil on the antidepressant activity of bupropion and venlafaxine should be carefully evaluated in further studies.

Sildenafil, a phosphodiesterase type 5 inhibitor, enhances the activity of two atypical antidepressant drugs, mianserin and tianeptine, in the forced swim test in mice

Sildenafil, a selective phosphodiesterase type 5 inhibitor, has recently been reported to abolish anti-immobility action of antidepressant drugs, i.e., bupropion, venlafaxine and S-citalopram, in the forced swim test in mice. The present study was designed to investigate the influence of sildenafil on the potential of two atypical antidepressants, namely mianserin and tianeptine. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. To evaluate the potential pharmocokinetic interaction, total brain concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 2.5 mg/kg did not affect the activity of mianserin (20 mg/kg) in the forced swim test. Interestingly, at higher doses (5 and 10 mg/kg), sildenafil significantly enhanced the anti-immobility action of mianserin. Likewise, sildenafil (5, 10 and 20 mg/kg) robustly augmented the antidepressant activity of tianeptine (30 mg/kg). Mianserin alone, as well as in a combination with sildenafil at the highest dose, caused a potent reduction in locomotor activity. However, the changes in motor activity did not interfere with the data obtained in the forced swim test. Sildenafil significantly increased the total brain tianeptine concentration. No alteration in mianserin level in the brain after sildenafil co-administration was observed. The present study suggests that sildenafil enhances the activity of mianserin and tianeptine in the forced swim test in mice. The changes in the antidepressant activity of mianserin evoked by sildenafil co-administration were related to pharmacodynamic interaction while the interaction between tianeptine and sildenafil was, at least in part, pharmacokinetic in nature.

Influence of sildenafil on the anticonvulsant action of selected antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice

The aim of the present study was to investigate the effect of sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, on threshold for clonic seizures in mice. In addition, the effects of sildenafil on the anticonvulsant activity of selected antiepileptic drugs (AEDs), i.e., clonazepam (CZP), valproate (VPA), phenobarbital (PB), ethosuximide (ETS) and tiagabine (TGB), were also evaluated. The subcutaneous pentylenetetrazole (PTZ) test was used to determine the effects of sildenafil on convulsive susceptibility and the anticonvulsant activity of the studied AEDs in mice, while the acute side effects of sildenafil and its combinations with the studied AEDs were evaluated in the chimney test, step-through passive-avoidance task and grip-strength test in mice. Total brain concentrations of AEDs were also determined. Sildenafil (5–40 mg/kg) did not influence the threshold for PTZ-induced clonic seizures in mice, but increased the anticonvulsant activity of ETS in this test without any significant changes in the total brain concentration. The activity of the remaining AEDs was not significantly changed by sildenafil. Neither sildenafil alone nor its combinations with the studied AEDs produced any changes in the motor coordination, long-term memory and muscular strength in mice. Co-administration of sildenafil with ETS in male epileptic patients with co-existing erectile dysfunctions might lead to the pharmacodynamic interactions that may be beneficial for the patients. Combinations of sildenafil with CZP, VPA, PB and TGB appear to be neutral in terms of their influence on seizures.

Inhaled NO and Sildenafil Combination in Cardiac Surgery Patients With Out-of-Proportion Pulmonary Hypertension

Background— The goal of this study was to examine the effects of coadministration of sildenafil and inhaled nitric oxide (iNO) in patients with out-of-proportion pulmonary hypertension who underwent cardiac valve replacement surgery. Methods and Results— Twenty consecutive cardiac surgery patients with out-of-proportion pulmonary hypertension were randomly assigned postoperatively into 2 groups: group A received 10 ppm of iNO followed by sildenafil (100 mg) orally 30 minutes later, and group B initially received sildenafil (100 mg) orally followed by 10 ppm of iNO 60 minutes later. Hemodynamic and gas exchange data were obtained at baseline, after administration of either iNO or sildenafil alone, and at 90 minutes from baseline. In group A, iNO resulted in a significant reduction in mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI) (by 9.6% and 20.8%, respectively). In group B, sildenafil administration also resulted in a significant decrease in mean arterial pressure, MPAP, pulmonary artery occlusive pressure, PVRI, and systemic vascular resistance index but also in the PaO 2 /inspired fraction of oxygen ratio (by 18.7%, 22.0%, 15.7%, 31.6%, 21.3%, and 14%, respectively). In both groups, the coadministration of the 2 drugs resulted in a significant further reduction of mean arterial pressure, MPAP, pulmonary artery occlusive pressure, systemic vascular resistance index, and PVRI, whereas cardiac index and mixed venous oxygen saturation remained unchanged. The hypoxemia after sildenafil administration in group B improved after the coadministration of iNO, and thus PaO 2 /inspired fraction of oxygen returned to values near baseline. Conclusion— In this study, the postoperative coadministration of iNO and oral sildenafil in patients with out-of-proportion pulmonary hypertension undergoing cardiac surgery is safe and results in an additive favorable effect on pulmonary arterial pressure and pulmonary vascular resistance, without systemic hypotension and ventilation/perfusion mismatch.

Pharmacokinetics of Bosentan in Routinely Treated Japanese Pediatric Patients with Pulmonary Arterial Hypertension

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.

Effect of sildenafil on the anticonvulsant action of classical and second‐generation antiepileptic drugs in maximal electroshock‐induced seizures in mice

The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second-generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step-through passive avoidance task, and grip-strength test. Total brain and free plasma concentrations of AEDs were also determined. Sildenafil raised the threshold for electroconvulsions in a dose-dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long-term memory in mice. Interestingly, sildenafil dose-dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long-term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.

The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects

AIMSThis study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers.METHODSHealthy subjects (18–60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period.RESULTSSildenafil exposure was slightly higher [AUC∞ geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (Emax+) and maximum negative (Emax–) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8–7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study.CONCLUSIONThe dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.

Pharmacokinetics and Safety of Ambrisentan in Combination With Sildenafil in Healthy Volunteers

The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ET(A)-selective, propanoic acid-based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC(0-infinity)) and maximum plasma concentration (C(max)) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC(0-infinity) and C(max) for sildenafil and N-desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20-mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N-desmethyl sildenafil. Ambrisentan C(max) was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC(0-infinity) (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil C(max) was increased slightly (113.4% [99.6%-129.1%]), and AUC(0-infinity) was unchanged (98.7% [91.2%-110.5%]) with ambrisentan coadministration. N-desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.

Effect of Repeated Doses of Darunavir plus Low-Dose Ritonavir on the Pharmacokinetics of Sildenafil in Healthy Male Subjects

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. 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. 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 (Cmax) was 38% lower compared with Cmax after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil Cmax and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUClast]) 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. 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.

Sildenafil, a Phosphodiesterase-5 Inhibitor, Enhances the Antinociceptive Effect of Morphine

Various evidence has demonstrated a role of the nitric oxide (NO)/cGMP signaling pathway in the processing of nociception. The exact role of phosphodiesterase-5 (PDE-5) via the NO/cGMP pathway is not fully understood in pain response. The aim of the present study was to investigate the possible peripheral interaction between a PDE-5 inhibitor (sildenafil) and morphine. Carrageenan-induced hyperalgesia in rats and the acetic-acid-induced writhing test in mice were used as animal models. Local administration of sildenafil (50–200 µg/paw, i.pl.) exhibited a dose-dependent antinociceptive effect against the paw pressure test. Sildenafil also demonstrated an antinociceptive effect (1–10 mg/kg, i.p.) against in the writhing test. Co-administration of sildenafil (100 µg/paw, i.pl. and 2 mg/kg, i.p.) significantly enhanced the antinociceptive effect of morphine (2 µg/ paw, i.pl. and 2 mg/kg, i.p respectively). The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paws was ineffective. Pretreatment with N^G-nitro-L-arginine methyl ester (an NO synthesis inhibitor), methylene blue (gunalyl cyclase inhibitor) or naloxone (opioid receptor antagonist) blocked the effect of a sildenafil-morphine combination in both tests. The results suggest that opioid receptor (NO and cGMP) mechanisms are involved in the combined antinociceptive effect. Further, sildenafil produced antinociception per se and increased the response of morphine, probably through the inhibition of cGMP degradation.