This study aimed at comparing the effects of atorvastatin and vitamin E on erectile dysfunction in patients initially irresponsive to sildenafil, with investigation into the underlying possible mechanisms. Sixty patients were randomly divided into three groups: the atorvastatin group received 80 mg daily, the vitamin E group received 400 IU daily and the control group received placebo capsules. Patients were examined both before and after 6 weeks of treatment for biochemical tests; Superoxide dismutase (SOD), glutathione peroxidase (GPO), C-reactive protein (CRP), interleukin-6 (IL-6), nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) and for erectile function tests; International index of erectile function (IIEF-5) scores and Rigiscan. Both atorvastatin and vitamin E showed a statistically significant GPO increase (P<0.05) and a statistically significant IL-6 decrease (P<0.05). Only atorvastatin showed a statistically significant increase in NO (15.19%, P<0.05), eNOS (20.58%, P<0.01), IIEF-5 score (53.1%, P<0.001) and Rigiscan rigidity parameters (P<0.01), in addition to a statistically significant decrease in CRP (57.9%, P<0.01). However, SOD showed a statistically significant increase only after vitamin E intake (23.1%, P<0.05). Both atorvatstain and vitamin E had antioxidant and anti-inflammatory activities. Although activating eNOS by atorvastatin was the real difference, and expected to be the main mechanism for NO increase and for improving erectile dysfunction. Atorvastatin, but not vitamin E, is a promising drug for sildenafil nonresponders.

Hypertension affects almost 50% of the adult American population. Metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the blood pressure-lowering potential of quercetin (QR), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered QR in drinking water at concentrations of 10, 30, and 60 mg/L. Blood pressure was monitored at seven-day intervals. After a total of seven weeks of treatment, rats were killed and kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Medium- and high-dose QR resisted the rise in blood pressure observed in the untreated SHR and significantly inhibited the activity of the CYP4A enzyme in renal cortical microsomes. The activity of the sEH enzyme in renal cortical cytosols was significantly inhibited only by the high QR dose. Our data not only demonstrate the antihypertensive effect of QR, but also provide a novel mechanism for its underlying cardioprotective properties.

Up-regulation of arginase activity in several chronic disease conditions, including cancer and hypertension, may suggest new targets for treatment. Recently, the number of new arginase inhibitors with promising therapeutic effects for asthma, cancer, hypertension, diabetes mellitus, and erectile dysfunction has shown a remarkable increase. Arginase inhibitors may be chemical substances, such as boron-based amino acid derivatives, α-difluoromethylornithine (DMFO), and Nω-hydroxy-nor-L-arginine (nor-NOHA) or, of plant origin such as sauchinone, salvianolic acid B (SAB), piceatannol-3-O-β-D-glucopyranoside (PG) and obacunone. Despite their promising therapeutic potential, little is known about pharmacokinetics and pharmacodynamics of some of these agents. Several studies were conducted in different animal species and in vitro systems and reported significant differences in pharmacokinetics and pharmacodynamics of arginase inhibitors. Therefore, extra caution should be considered before extrapolating these studies to human. Physicochemical and pharmacokinetic profiles of some effective arginase inhibitors make it challenging to formulate stable and effective formulation. In this article, existing literature on the pharmacokinetics and pharmacodynamics of arginase inhibitors were reviewed and compared together with emphasis on possible drug interactions and solutions to overcome pharmacokinetics challenges and shortage of arginase inhibitors in clinical practice.

A simple, accurate, and reproducible high-performance liquid chromatography (HPLC) method has been developed and validated for the quantification of quercetin (QR) in rat plasma. The method involves a simple protein precipitation procedure to extract both QR and thymoquinone (TQ), the internal standard. The chromatographic analysis was achieved on a Shimadzu LC 20 A HPLC system equipped with a Supelcosil LC-18 T C column and an isocratic mobile phase consisting of 0.3% trichloroacetic acid in water and acetonitrile HPLC-grade (50:50, v/v) run at a flow rate of 0.9 mL/min for 13 min. The UV detection wavelength was set at 254 nm. The method exhibited good linearity (R > 0.994) over the assayed concentration range (0.10-25 μg/mL) and demonstrated good intra-day and inter-day precision and accuracy (relative standard deviations and the deviation from predicted values were <20%). This method was also successfully applied for studying the pharmacokinetics of QR in rats following a single oral dose of QR to evaluate its pharmacokinetic parameters in rats.

PurposeSeveral severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose.MethodsWe conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration.ResultsCompared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30–60) and 18 % (90 % CI 108–129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63–75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study.ConclusionsAlthough it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.