Shehta A. Said

Role of endogenous endothelin-1 in stress-induced gastric mucosal damage and acid secretion in rats

In rats subjected to 8 h water-immersion stress, gastric and duodenal mucosal hemorrhage and erosions were detected by macroscopic and histopathological examination. Moreover, plasma and gastric mucosal endothelin-1 (ET-1) levels rose appreciably in a time-related manner during water immersion, with a higher concentration detected in gastric mucosa. Thus, the percentage increases in plasma (gastric mucosal) ET-1, relative to basal levels, after 1, 4 and 8 h of water immersion were 86(172), 169(322) and 210(391)%, respectively. Likewise, a marked increase of gastric acid output was demonstrated 30 min after water immersion and lasted for 3 h. Pretreatment with the endothelin ET(A)/ET(B) receptor blocker, bosentan (30 and 100 mg kg(-1)), orally, dose-dependently antagonized gastric and duodenal mucosal damage as indicated by reductions in lesion lengths of 67 and 80%, respectively. Similar protective effects on mucosa were observed when bosentan was given by the intramuscular route. On the other hand, bosentan suppressed the rate of acid output by 30.3+/-2.1% in the stressed rats, but had no such effect in non-stressed animals. Taken together, results from this study implicate the endogenous peptide, ET-1, as a powerful mediator of stress-evoked gastro-duodenal mucosal damage and, moreover, present bosentan as a potential protector against hyperacidity and mucosal erosion that occur as a consequence of stress.

Eicosapentaenoic acid ablates valproate-induced liver oxidative stress and cellular derangement without altering its clearance rate: dynamic synergy and therapeutic utility.

The omega-3 fatty acid eicosapentaenoic acid (EPA) is a superb natures medicine, with still unfolding health benefits. Because hepatotoxicity is a prominent adverse drug reaction, we currently attempted a new approach in which EPA was challenged to both alleviate hepatotoxicity and provide synergy with anticonvulsant effects of valproate (VPA). Besides, we verified whether EPA may kinetically modulate the clearance rate of VPA. VPA (500mg/kg p.o., for 2weeks) caused rat hepatotoxicity that was manifested as notable (2- to 4-fold) rise in serum liver enzymes (GGT, ALT, and ALP), increased hepatic levels of lipid peroxides and TNF-α (3- and 7-fold) and activity of myeloperoxidase (MPO, 4-fold), lowering of serum albumin (42%), and depletion of liver reduced glutathione (GSH, 36%). Furthermore, histopathologic examination revealed hepatocellular degeneration, focal pericentral necrosis, infiltration of inflammatory cells, and steatosis. Joint treatment with EPA (300mg/kg) blunted the oxidative stress, TNF-α levels and MPO activity, while enhanced levels of serum albumin and hepatic GSH. EPA also ameliorated most of the hepatocellular anomalies evoked by VPA. Additionally, in a mouse PTZ convulsion model, EPA markedly augmented the anticonvulsant effects of VPA far beyond their single responses. On the other hand, pharmacokinetic analyses revealed that joint EPA administration had no effect on serum VPA concentrations. Collectively, results demonstrate for the first time that the ω-3 FA (EPA) markedly alleviated VPA-induced hepatotoxicity, oxidative stress, and inflammation, while enhanced its anticonvulsant effects without altering its clearance. Therapeutically, these protective and synergy profiles for EPA foster a more safe and efficacious drug combination regimen than VPA.

Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats.

Context: Doxorubicin (Dox) is an anthracycline antibiotic used as anticancer agent. However, its use is limited due to its cardiotoxicity which is mainly attributed to accumulation of reactive oxygen species. Objective: This study was conducted to assess whether the antioxidant, proanthocyanidins (Pro) can ameliorate Dox-induced cardiotoxicity in rats. Materials and methods: Male Sprague–Dawely rats were divided into four groups. Group I was control. Group II received Pro (70 mg/kg, orally) once daily for 10 days. Group III received doxorubicin 15 mg/kg i.p. as a single dose on the 7th day and Group IV animals were treated with Pro once daily for 10 days and Dox on the 7th day. The parameters of study were serum biomarkers, cardiac tissue antioxidant status, ECG, and effect on aconitine-induced cardiotoxicity. Results: Cardiac toxicity of doxorubicin was manifested as a significant increase in heart rate, elevation of the ST segment, prolongation of the QT interval and an increase in T wave amplitude. In addition, Dox enhanced aconitine-induced cardiotoxicity by a significant decrease in the aconitine dose producing ventricular tachycardia (VT). Administration of Pro significantly suppressed Dox-induced ECG changes and normalized the aconitine dose producing VT. The toxicity of Dox was also confirmed biochemically by significant elevation of serum CK-MB and LDH activities as well as myocardial MDA and GSH contents and decrease in serum catalase and myocardial SOD activities. Administration of Pro significantly suppressed these biochemical changes. Discussion and conclusion: These results suggest that proanthocyanidins might be a potential cardioprotective agent against Dox-induced cardiotoxicity due to its antioxidant properties.

Modulation of thioacetamide-induced liver fibrosis/cirrhosis by sildenafil treatment.

Sildenafil citrate is a phosphodiesterase-5 inhibitor, approved for the treatment of erectile dysfunction. It enhances nitric-oxide-induced vasodilatation and it promotes angiogenesis. A relationship between angiogenesis and hepatic fibrosis has long been speculated, where the 2 are believed to progress together. In this study, the ability of sildenafil (10 mg·(kg body mass)(-1), orally, once daily) to prevent and also reverse liver fibrosis/cirrhosis experimentally induced by thioacetamide injection (200 mg·kg(-1), intraperitoneal (i.p.), 3 times·week(-1)) in male Sprague-Dawley rats has been investigated. Sildenafil administration, either to prevent or to reverse liver fibrosis/cirrhosis significantly improved the estimated hepatic functions, reduced hepatic hydroxyproline and, in turn, hepatic collagen content, as well as reducing serum levels of the pro-fibrogenic mediator transforming growth factor β1. In co-ordination with such improvement, fibrosis grades declined and fibrosis retracted. Herein, the observed results provide evidence for the potential therapeutic efficacy of sildenafil as an antifibrotic agent.

Tranilast ameliorates impaired hepatic functions in Schistosoma mansoni-infected mice

The ability of tranilast, a mast cell stabilizer and anti-transforming growth factorβ (TGFβ) to improve impaired hepatic functions in Schistosoma mansoni (S. mansoni)-infected mice, was investigated, providing the first evidence on the ability of tranilast to improve hepatic impairment due to schistosomal infection. Tranilast had significant beneficial effects against progression of hepatic fibrosis in S. mansoni-infected mice treated with praziquantel and those untreated. Different aspects of drug activity were investigated. Its effect on serum liver functions was evaluated by estimating: alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase and albumin. Its effect on the extent of liver fibrosis, through estimation of hepatic hydroxyproline and hepatic collagen content in liver hydrolysates, was also evaluated. Also, the expression of profibrogenic mediators, such as serum TGFβ1, was estimated. Finally, the effect on S. mansoni infection itself was studied, via histopathological examination of liver specimens stained with both hematoxylin–eosin and Masson’s trichome stains. Tranilast ameliorated the harmful effects of S. mansoni infection on the liver. Such action was manifested in its significant ability to improve impaired hepatic functions, reduce histopathological changes, lower hepatic collagen content and finally reduce serum TGFβ1 levels. The beneficial effect of tranilast may be in part due to its ability to reduce the production of profibrogenic mediators in the infected animals by improving the host immune response or by interfering with critical steps in the fibrogenic cascade.

Prevention of sodium valproate-induced hepatotoxicity by curcumin, rosiglitazone and N-acetylcysteine in rats.

The present study was designed to examine the potential preventive effect of curcumin (CMN; CAS 458-37-7), rosiglitazone (RGN; CAS 155141-29-0), N-acetylcysteine (NAC; CAS 616-91-1), resveratrol (RSV; CAS 501-36-0), and losartan (LOS; CAS 114798-26-4) on sodium valproate-induced hepatotoxicity. Sodium valproate (SVP; CAS 1069-66-5) was given at a dose of 250 mg/kg i. p. 3 times daily for one week. The tested compounds were given simultaneously with SVP for one week. The results demonstrate that CMN, RGN and NAC treatment can confer protection from SVP-induced hepatotoxicity. The second part of the study includes an evaluation of the effect of CMN, RGN and NAC on the anticonvulsant activity of SVP against pentetrazole-induced seizures in mice. The results demonstrate that CMN, RGN and NAC do not affect the anticonvulsant activity of SVP. Combined administration of either of CMN, RGN and NAC with valproate appears to be beneficial in reducing valproate-induced hepatotoxicity.

Myocardial Depression and Inhibition of Positive Inotropic Effect of Digoxin by Rosiglitazone

An UV spectrophotometric area under curve method was developed for the estimation of Levofloxacin Hemihydrate in its mono component tablets. The spectrophotometric method for estimation employed Area under curve method for analysis using 0.1M Sodium Hydroxide as solvent for the drug Levofloxacin Hemihydrate at the wavelength range of 285-295nm. Levofloxacin Hemihydrate obeys Beer’s law in concentration range 10-50µg/ml. The recovery studies ascertained accuracy of the proposed method and the result validated according to ICH guideline. Results of analysis have been valid statistically by recovery studies. The method was successfully for evaluation of Levofloxacin Hemihydrate in tablet dosage form without the interference of common excipients.