Determinants of day-night difference in blood pressure, a comparison with determinants of daytime and night-time blood pressure.

Blunted day-night difference in blood pressure (BP) is an independent cardiovascular risk factor, although there is limited information on determinants of diurnal variation in BP. We investigated determinants of day-night difference in systolic (SBP) and diastolic (DBP) BP and how these compared with determinants of daytime and night-time SBP and DBP. We analysed the association of mean daytime, mean night-time and mean day-night difference (defined as (mean daytime-mean night-time)/mean daytime) in SBP and DBP with clinical, lifestyle and biochemical parameters from 1562 adult individuals (mean age 38.6) from 509 nuclear families recruited in the GRAPHIC Study. We estimated the heritability of the various BP phenotypes. In multivariate analysis, there were significant associations of age, sex, markers of adiposity (body mass index and waist-hip ratio), plasma lipids (total and low-density lipoprotein cholesterol and triglycerides), serum uric acid, alcohol intake and current smoking status on daytime or night-time SBP and/or DBP. Of these, only age (P=4.7 × 10-5), total cholesterol (P=0.002), plasma triglycerides (P=0.006) and current smoking (P=3.8 × 10-9) associated with day-night difference in SBP, and age (P=0.001), plasma triglyceride (P=2.2 × 10-5) and current smoking (3.8 × 10-4) associated with day-night difference in DBP. 24-h, daytime and night-time SBP and DBP showed substantial heritability (ranging from 18-43%). In contrast day-night difference in SBP showed a lower heritability (13%) while heritability of day-night difference in DBP was not significant. These data suggest that specific clinical, lifestyle and biochemical factors contribute to inter-individual variation in daytime, night-time and day-night differences in SBP and DBP. Variation in day-night differences in BP is largely non-genetic.

Positive inotropic effects of carbon monoxide-releasing molecules (CO-RMs) in the isolated perfused rat heart.

BACKGROUND AND PURPOSE: Carbon monoxide (CO) generated by the enzyme haeme oxygenase-1 (HO-1) during the breakdown of haeme is known to mediate a number of biological effects. Here, we investigated whether CO liberated from two water soluble carbon monoxide-releasing molecules (CO-RMs) exerts inotropic effects on the myocardium. EXPERIMENTAL APPROACH: Rat isolated hearts perfused either at constant flow or constant pressure were used to test the effect of CO-RMs. KEY RESULTS: CORM-3, a fast CO releaser, produced a direct positive inotropic effect when cumulative doses (3, 10 and 30 microg min(-1)) or a single dose (5 microM) were infused at either constant coronary pressure (CCP) or constant coronary flow (CCF). The inotropic effect mediated by CORM-3 was abolished by blockade of soluble guanylate cyclase or Na(+)/H(+) exchanger, but not by inhibitors of L-type Ca(2+) channels and protein kinase C. CORM-3 also caused a slight reduction in heart rate but did not alter coronary flow. In contrast, the slow CO releaser CORM-A1 produced significant coronary vasodilatation when given at the highest concentration (30 mug min(-1)) but exerted no effect on myocardial contractility or heart rate. CONCLUSION AND IMPLICATIONS: A rapid CO release from CORM-3 exerts a direct positive inotropic effect on rat isolated perfused hearts, whereas CO slowly released by CORM-A1 had no effect on myocardial contractility but caused significant coronary vasodilatation. Both cGMP and Na(+)/H(+) exchange appear to be involved in this effect but further work is needed to determine the relative contribution of each pathway in CO-mediated inotropic effect.

Bioequivalence evaluation of two brands of cefaclor 500 mg capsules: quantification of cefaclor using solid phase extraction technique.

OBJECTIVE: To assess the bioequivalence of two cefaclor 500 mg capsule formulations, and to develop a new high performance liquid chromatographic (HPLC) method using solid phase extraction technique for the quantification of cefaclor in human plasma. METHOD: An open, randomized, two-way, crossover trial with a one-week washout period in 25 healthy volunteers. The two commercial brands used were Recocef(Julphar, United Arab Emirates) as test and Ceclor(Eli Lilly, UK) as reference product. The drug was administered with 240 mL of water after a 10-h overnight fast. After dosing, serial blood samples were collected for a period of 8 h. Plasma harvested from blood was analysed for cefaclor by a new HPLC method using a solid phase extraction technique. The limit of detection of cefaclor was 17.6 ng/mL; average recovery was 96.5%; the intraday CV was less than 8% and interday CV was less than 13%. Various pharmacokinetic parameters, including AUC0-t, AUC0-infinity, Cmax, Tmax, T1/2, and Kel, were determined from plasma concentrations for both formulations. Statistical analysis (ANOVA and 90% confidence intervals) were applied to AUC0-t, AUC0-infinity and Cmax for bioequivalence evaluation of two brands. The new HPLC method with solid phase extraction circumvented the problem of mixed polarity of cefaclor and facilitated its extraction from the complex plasma matrix while keeping the background free from interference due to endogenous plasma compounds. RESULTS: No significant difference was observed between the two brands of cefaclor capsules. CONCLUSION: Recocef was judged bioequivalent to Ceclor and the two products can therefore be considered to be interchangeable in medical practice.