Enhancement of amlodipine cardioprotection by quercetin in ischaemia/reperfusion injury in rats

Objectives To investigate the possible modification of the cardioprotective effect of amlodipine when co‐administered with quercetin in myocardial ischaemia/reperfusion‐induced functional, metabolic and cellular alterations in rats. Methods Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 week. Rats were then subjected to myocardial ischaemia/reperfusion (35_min/10_min). Heart rates and ventricular arrhythmias were recorded during ischaemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were determined. In addition, cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NO_x) were estimated. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. Key findings Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiologic functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NO_x contents. Conclusion Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischaemia/reperfusion.     

Recherche des agglutinines irrégulières en milieu obstétrical en Tunisie : étude à propos de 5369 femmes

Purpose of the studyTo evaluate the prevalence of alloimmunization in women followed in an obstetrical environment in Tunisia, to identify the specificities of antibodies found and to determine factors that could influence the appearance of this immunization.MethodsWe proceeded to a retrospective analysis of search for irregular antibodies at women followed up in obstetrical environment over nine consecutive years (2000–2008). The panel was officially defined and produced by the Regional Centre for Blood Transfusion in Sfax (Tunisia).ResultsOverall 5369 women benefited from 6575 antibody testing (average: 1.22; extremes: 1–14). The results were positive for 278 women (5.17 %), allowing to identify 216 antibodies or associations of antibodies. Among identified antibodies, those immune were found in 198 women. The rate of alloimmunization was 3.68 % (198/5369). The majority of the antibodies found was anti-Rh1, isolated or associated with another antibody, in 84.3 % of the total immunized women. The immunization of women according to the number of gestations showed a significant increasing rate ranging from 2.34 % for a first gestation to 5.27 % for four gestations or more. In addition, a significant difference was also noted between the rate of immunization in women who had received anti-Rh1 immunoglobulin and those who had not.ConclusionAnti-Rh1 immunization is the most frequent in the population of studied women. This could denote of an insufficiency in pregnancies follow-up and immunoprophylaxis protocols.     

Familial form of typical childhood absence epilepsy in a consanguineous context

Causative genes for childhood absence epilepsy (CAE) are unknown partly because families are small or phenotypically heterogeneous. In five consanguineous Tunisian families with at least two sibs with CAE, 14 patients fulfilled the diagnostic criteria for CAE (Epilepsia 1989;30:389–399). Linkage analyses or direct sequencing excluded CACNG2, CACNA1A, CACNB4, and CACNA2D2, orthologs of genes responsible for autosomal recessive (AR) absence seizures in mice. These families will help identify (a) gene(s) responsible for CAE.     

Solanum indicum ssp. distichum extract is effective against l‐NAME‐induced hypertension in rats

Solanum indicum ssp. distichum is used as a vegetable in some parts of Africa and claimed in folk medicine to guard against cardiovascular disorders. It was of interest to study the potential blood pressure lowering effects of a standardized extract of the fruit. An ethanolic extract of the fruit, standardized to contain > 0.15% chlorogenic acids, was tested orally in both normotensive rats and in those rendered hypertensive by twice daily intraperitoneal injection of N^W‐nitro‐l ‐arginine methylester (l ‐NAME) for 1 week. The extract was either given at the same time as l ‐NAME or after the establishment of hypertension. The systolic blood pressure (SBP) was measured non‐invasively using a tail cuff computer‐aided monitoring device. Treatment of normotensive rats with the extract (30–300 mg/kg) for 4 weeks showed no hypotensive effect. Giving the extract (100 and 300 mg/kg) orally once daily during the 1 week hypertension induction period with l ‐NAME prevented the development of hypertension. Administration of the extract orally for 1 week after the establishment of hypertension tended to normalize the blood pressure. Pharmacological evidence for the antihypertensive activity of S. distichum is hereby reported for the first time. The extract showed good prophylactic as well as curative effect against l ‐NAME‐induced hypertension, whereby its content of chlorogenic acids may play a minor role. Other constituents may be responsible for the antihypertensive action. The findings support further development of the extract as a potential therapeutically useful antihypertensive agent.     

Additive effects of endogenous cannabinoid anandamide and ethanol on alpha7-nicotinic acetylcholine receptor-mediated responses in Xenopus Oocytes

The interaction between the effects of the endogenous cannabinoid receptor agonist anandamide and ethanol on the function of homomeric alpha(7)-nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes were investigated using the two-electrode voltage-clamp technique. Anandamide and ethanol reversibly inhibited currents evoked with 100 microM acetylcholine in a concentration-dependent manner. Coapplication of anandamide and ethanol caused a significantly greater inhibition of alpha(7)-nACh receptor function than anandamide or ethanol alone. The IC(50) value of 238 +/- 34 nM for anandamide inhibition decreased significantly to 104 +/- 23 nM in the presence of 30 mM ethanol. The inhibition of alpha(7)-mediated currents by coapplication of anandamide and ethanol was not altered by phenylmethylsulfonyl fluoride, an inhibitor of anandamide hydrolyzing enzyme, or N-(4-hydroxyphenyl)-arachidonylamide, an anandamide transport inhibitor. Analysis of oocytes by matrix-assisted laser desorption/ionization technique indicated that ethanol treatment did not alter the lipid profile of oocytes, and there is negligible, if any, anandamide present in these cells. Results of studies with chimeric alpha(7)-nACh-5-HT(3) receptors comprised of the amino-terminal domain of the alpha(7)-nACh receptor and the transmembrane and carboxyl-terminal domains of 5-HT(3) receptors suggest that although ethanol inhibition of the alpha(7)-nACh receptor is likely to involve the N-terminal region of the receptor, the site of action for anandamide is located in the transmembrane and carboxyl-terminal domains of the receptors. These data indicate that endocannabinoids and ethanol potentiate each other's inhibitory effects on alpha(7)-nACh receptor function through distinct regions of the receptor.     

Plasma concentrations of morphine,morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain

Morphine, the recommended drug for the management of moderate to severe cancer pain, is metabolized predominantly to the glucuronides morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). The quantitative clinical importance of these metabolites following the administration of oral morphine is unclear. This study investigates the relationship between plasma concentrations of morphine (M), M6G, M3G and clinical effects in patients receiving sustained release oral morphine for cancer-related pain. Peak and trough plasma concentrations of morphine and its metabolites were determined by high-performance liquid chromatography (HPLC). At corresponding time points, pain [Visual Analogue Scales (VAS), Verbal Rating Scales (VRS), Pain Relief Scores (PRS)] and toxicity (VAS and VRS) were assessed. Renal and liver function tests were performed. Forty-six patients were included in the study. There was a significant correlation between dose and both peak and trough plasma M, M6G and M3G (r > 0.60, P < 0.001 for each). Differences between peak and trough M, M6G, M3G, M+M6G, M6G:M, M3G:M and M3G:M6G were all significant (P < 0.001 for each). Pain was generally well controlled in the group, with a median VAS of 15 mm at the peak blood sampling time point. The differences between peak and trough values for VAS pain, VAS nausea and VAS drowsiness were not statistically significant (P = 0.078, 0.45 and 0.099, respectively). There were no differences in peak or trough morphine and metabolite concentrations or ratios between patients with low (< median) or high pain scores. Similarly, there was no significant relationship between high and low plasma concentrations and clinical effect. This study did not identify a simple relationship between plasma concentrations of morphine, morphine metabolites or metabolite ratios and clinical effects in patients with cancer and pain who were receiving chronic oral morphine therapy. Although overall pain control was good, there was marked interpatient variability in the dose of morphine and the plasma concentrations necessary to achieve this degree of analgesia.