Resveratrol reverses diabetes-related decrement in sildenafil-induced relaxation of corpus cavernosum in aged rats.

BACKGROUND: The aim of this study was to investigate the effect of resveratrol (RVT) on sildenafil-induced relaxations of isolated corpus cavernosum in non-diabetic and diabetic aged rats. METHODS: A total of 13 male aged rats (72-80 weeks old) were randomized into two groups including non-diabetic aged rats and diabetic aged rats. Diabetes was induced in aged rats by streptozotocin (single i.p. dose of 45 mg/kg body weight) administration. At the end of the 12th week, corpus cavernosum strips of rats were suspended in an organ bath system. The corpus cavernosum relaxation was evaluated by sildenafil in the presence or absence of RVT (10-4 M) for 45 min. RESULTS: Induction of diabetes resulted in significant inhibition of sildenafil-induced corpus cavernosum relaxation in aged rats. The diminished relaxation in response to sildenafil was significantly improved by acute RVT incubation in both non-diabetic and diabetic aged rats; however, the magnitude of potentiation induced by RVT was more pronounced in diabetic aged rats. The potentiating effect of RVT was significantly inhibited by L-NG-nitroarginine methyl ester (L-NAME, 10-4 M, for 30 min) incubation in both groups. After the L-NAME incubation, the relaxation response of corporal tissues evoked by sildenafil was found to be similar in diabetic and non-diabetic aged rats. CONCLUSIONS: RVT improves sildenafil-induced relaxations of corpus cavernosum in both diabetic and non-diabetic aged rats probably by potentiating the activity of NOS, and this effect seems to be more manifest in diabetic aged group.

Evaluating appropriateness of digoxin, carbamazepine, valproic acid, and phenytoin usage by therapeutic drug monitoring.

BACKGROUND: Therapeutic drug monitoring (TDM) is a useful tool for the optimization of drug therapy. The aim of this retrospective study was to evaluate the appropriateness of carbamazepine, phenytoin, valproic acid, and digoxin therapy by using TDM data. METHODS: We evaluated the appropriateness of drug usage in 325 patients who received carbamazepine, valproic acid, phenytoin, or digoxin in a large teaching hospital during the period from March 2010 to January 2011. The serum drug levels were measured by cloned enzyme donor immunoassay (CEDIA). RESULTS: A total of 325 TDM tests were performed in this period. In our TDM unit, valproic acid was the most evaluated test among the samples obtained. In 100 valproic acid-treated patients, serum levels in 58 patients (58%) were within the therapeutic range. While 11 patients (11%) had serum levels in the above-therapeutic range, 31 patients (31%) had sub-therapeutic levels of valproic acid: The results of TDM were mostly found in the therapeutic range for carbamazepine. A total of 91 request forms were collected. The overall data show that 64 patients (70.3%) had serum carbamazepine levels within the therapeutic range. In the phenytoin assays, the mean plasma concentrations generally did not reach the therapeutic range. Among the total of 49 blood samples, the highest number of sub-therapeutic levels (65.3%) were detected for phenytoin. Similarly, inappropriate levels of digoxin were established in about half of all cases. CONCLUSIONS: This study gives information about the inappropriate usage of digoxin and phenytoin in respect to the results of our TDM practice. Our results suggest that there is a need for interventions to improve the appropriate use of digoxin and phenytoin in patients treated with these drugs.

The potent relaxant effect of resveratrol in rat corpus cavernosum and its underlying mechanisms.

The aim of this study was to evaluate the relaxant effect of resveratrol (RVT), one of the most commonly employed dietary polyphenols, in rat corpus cavernosum, and to further investigate the contribution of possible underlying mechanisms. Strips of corpus cavernosum were used in organ baths for isometric tension studies. RVT (10(-6)-10(-4) M) produced concentration-dependent relaxation responses in rat corpus cavernosum precontracted by phenylephrine. The relaxant responses to RVT partially, but significantly inhibited by removal of endothelium. Nitric oxide (NO) synthase (NOS) blocker N-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10(-5) M) caused a significant inhibition on relaxation response to RVT, whereas cyclooxygenase inhibitor indomethacin (10(-5) M) did not significantly alter relaxant responses of corpus cavernosum strips to RVT. Corpus cavernosum contractions induced by stepwise addition to Ca2+ to high KCl solution with no Ca2+ were significantly inhibited by RVT incubation. The treatment of corpus cavernosum tissues with non-specific potassium channel inhibitor tetraethylammonium (TEA, 10(-2) M) did also significantly affect the relaxant activity of RVT. Otherwise, the relaxation response of corpus cavernosum induced by the phosphodiesterase-5 inhibitor sildenafil increased significantly in the group pretreated with 10(-5) M RVT. These results demonstrated that RVT has a potent relaxant effect on rat corpus cavernosum via endothelium-dependent and -independent mechanisms. Endothelium-dependent relaxation of corpus cavernosum to RVT is thought to be mediated primarily through NO/cGMP signaling pathway, and possibly an additional mechanism, endothelium-dependent hyperpolarization factor (EDHF). The residual endothelium-independent corpus cavernosum relaxation induced by RVT is uncertain but seems to depend on the interactions of RVT with Ca2+ entry mechanism from the extracellular space and also other undefined direct effects in this tissue.

Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation.

Hepatotoxicity is one of the major complications of methotrexate (MTX) therapy. This study was carried out to evaluate the possible protective effect of resveratrol (trans-3,5,4'-trihydroxystilbene, RVT) against MTX-induced hepatotoxicity. Rats were randomly divided into four groups as control, MTX treated (7 mg/kg/day, intraperitoneally (i.p.), once daily for 3 consecutive days), MTX + RVT treated (20 mg/kg/day, i.p.), and RVT treated. First dose of RVT was administrated 3 days before the MTX injection and continued for 3 days. Histopathology of liver was evaluated by light microscopy. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. The levels of thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and activities of hepatic antioxidant enzymes such as catalase (CAT) and glutathione-S-transferase (GST) were used to analyze the oxidative stress-mediated lipid peroxidation in liver sections. Our results showed that MTX administration significantly increased ALT, ASP, and ALP levels. TBARS, CAT, and GST levels were also markedly increased in liver after MTX administration. RVT treatment significantly prevented MTX-induced hepatotoxicity, as indicated by AST, ALT, and ALP levels and liver histopathology. Moreover, administration of RVT significantly decreased the elevated levels of TBARS and activities of CAT and GST in the liver compared to MTX-treated group. These results revealed that RVT may have a protective effect against MTX-induced hepatotoxicity by inhibiting oxidative stress-mediated lipid peroxidation. Consequently, RVT treatment might be a promising strategy against MTX-induced hepatotoxicity.