Antihypertensive efficacy of metoprolol XL/Low dose chlorthalidone (6.25 mg) combination: a randomized,comparative study in Indian patients with mild-to-moderate essential hypertension

Objective

High blood pressure is one of the most important risk factors, directly responsible for increasing the cardiovascular morbidity and mortality. The primary objective was to evaluate the efficacy of metoprolol XL/chlorthalidone against metoprolol XL/hydrochlorothiazide with respect to mean fall in systolic and diastolic blood pressure. The secondary objective was to compare the response rates and to evaluate the tolerability of study medications in patients with mild-tomoderate essential hypertension.

Methods

Total 130 eligible patients (65: metoprolol XL 25 mg/chlorthalidone 6.25 mg; 65: metoprolol XL 25 mg/HCTZ 12.5 mg) were enrolled in this randomized, comparative, multicentric, 12-weeks study. Sixty-two patients from each group completed the study. After 4-weeks of treatment, non-responders from chlorthalidone 6.25 mg combination group were shifted to metoprolol XL 50 mg/chlorthalidone 12.5 mg and non-responders from HCTZ 12.5 mg combination group were escalated to metoprolol XL 50 mg/HCTZ 12.5 mg.

Results

The study treatment groups were comparable with respect to demography and baseline disease characteristics. Both the starting therapies were comparable with respect to mean fall in SBP (p = 0.788) and DBP (p = 0.939), and response rates (p = 1.0) after 4-weeks of therapy. Also both the step-up therapies showed similar mean fall in SBP (p = 0.277) and DBP (p = 0.507) at the end of 12-weeks. However, significantly more number of patients from chlorthalidone 12.5 mg/metoprolol XL 50 mg group responded to therapy as compared to that from HCTZ 12.5 mg/metoprolol XL 50 mg group (p = 0.045). All the reported adverse events were of mild-to-moderate intensity. There were no clinically significant trends in electrolytes (Na⁺, K⁺, Cl^-)and fasting blood sugar, evident across the treatment groups.

Conclusion

Chlorthalidone in combination with metoprolol XL is as effective and well tolerated as widely used combination of metoprolol XL/HCTZ, thus providing an alternative therapeutic option.     

Glycosylation improves the central effects of DAMGO

A series of mu-agonist DAMGO analogs were synthesized and pharmacologically characterized to test the 'biousian' hypothesis of membrane hopping. DAMGO was altered by incorporating moieties of increasing water solubility into the C-terminus via carboxamide and simple glycoside additions. The hydrophilic C-terminal moieties were varied from glycinol in DAMGO (1) to l-serine amide (2), l-serine amide beta-d-xyloside (3), l-serine amide beta-d-glucoside (4), and finally to l-serine amide beta-lactoside (5). Opioid binding and mouse tail-flick studies were performed. Antinociceptive potency (intravenous) increased, passing through a maximum (A(50) approximately 0.2 micromol/kg) for 2 and 3 as membrane affinity versus water solubility became optimal, and dropped off (A(50) approximately 1.0 micromol/kg) for 4 and 5 as water solubility dominated molecular behavior. Intravenous A(50) values were plotted versus hydrodynamic values (glucose units, g.u.) for the glycoside moieties, or the hydrophilic/hydrophobic Connolly surface areas (A(50) versus e(-Awater/Alipid)), and provided either a V-shaped or a U-shaped curve, as predicted by the 'biousian' hypothesis. The mu-selective receptor profile was maintained (K(i)'s = 0.66-1.3 nm) upon modifications at the C-terminus. The optimal 'degree of glycosylation' for the DAMGO peptide message appears to be between 1.25 and 1.75 g.u. (hydrodynamic g.u.), or 0.75 and 0.90 in terms of the surface-derived amphipathicity values.     

Increasing Preload Volume with Water Reduces Rated Appetite But Not Food Intake in Healthy Men Even with Minimum Delay Between Preload and Test Meal

Abstract

The role of gastric volume in the short-term control of eating in humans remains unclear, with some studies reporting that food volume alone can reduce appetite but others finding no such effect. A recent study in our laboratory, found effects of preload volume on subjective appetite (hunger, fullness) but not intake, and found effects of preload energy on intake but not appetite. That study used an interval of 30 min between serving preloads and the test meal, and the present study attempted to maximise the effects of the volume manipulation by removing the delay between the preload and test meal. We administered four soup-based preloads varying in volume (150 and 450 ml) using water, and energy density (1.4 and 4.2 kJ/ml) using maltodextrin, producing three energy levels (209, 629, 629 and 1886 kJ; repeated measures). These were followed immediately by an unlimited hot pasta lunch, during which food weight was monitored continuously by computer. Increasing soup volume at constant energy (629 kJ) reduced appetite ratings, but not intake. In contrast, increasing soup energy at constant volume (450 ml) reduced intake, without affecting appetite. The discrepancies between our results and other reported studies suggest that volume is more influential when intakes are large, or that there may be a threshold concentration for nutrients in the GI tract before volume alone is tangibly expressed in subsequent eating.     

Pericanalicular location of hepatocyte lysosomes and effects of fasting: a morphometric analysis

Lysosomes constitute a small proportion of hepatocyte volume, but they play a key degradative role, particularly during catabolic states such as nutritional deprivation. Our preliminary observations in hepatocytes suggested that fasting may alter the distribution of lysosomes, which are thought to congregate about the biliary canaliculus. The current study aimed to provide, in both fed and fasted rats, a quantitative morphometric analysis of lysosomes in the immediate pericanalicular and successively more distant regions. We selected three regions of radius 0 to 2 (region 1), 2 to 4 (region 2) and 4 to 6 micron (region 3) about the bile canaliculus and compared lysosomal numerical and volume densities. In fed rats, numerical and volume densities of both primary and secondary lysosomes were 5 to 10 times greater in region 1 than in region 3. After a 72-hr fast, this gradient was lost due largely to a reduced number of primary and secondary lysosomes in region 1. Our calculations suggest that during fasting, lysosomes are redistributed away from the bile canaliculus towards the more distant cytoplasm rather than being lost from the cell, for example, into bile. The number of overt macroautophagic vacuoles was not altered by fasting. We estimate that, in fed rats, there are approximately 270 lysosomes per hepatocyte, and that 43% of lysosomes are contained in the immediate pericanalicular region 1, which comprises only 7 to 8% of the cytoplasmic volume. The reason for this pericanalicular concentration of lysosomes and the mechanism of the redistribution with fasting remain to be determined.     

Characterization of the p67phox gene: genomic organization and restriction fragment length polymorphism analysis for prenatal diagnosis in chronic granulomatous disease

The genetic defect in the p67phox-deficient form of chronic granulomatous disease (CGD) follows an autosomal recessive pattern of inheritance. When genomic DNA from normal individuals is digested with HindIII and probed with p67phox cDNA an allelic restriction fragment length polymorphism (RFLP) of 4.0 kb or 2.3 kb is detected. We cloned and characterized the p67phox gene using the cDNA and sequenced the exon/intron boundaries, mapping 16 exons on the 40-kb gene. The polymorphic region was then sequenced to identify the inheritance pattern of amniocentesis-derived fetal cells by genomic amplification. The proband, a 9-year-old female patient with p67phox-deficient CGD, and her phenotypically normal mother are homozygous for the RFLP marker, whereas the father and two brothers are heterozygous. The fetus was shown to be heterozygous as well, showing it had inherited at least one normal p67phox gene from the father and that it was predicted to have a normal phenotype. Cord blood samples at birth showed normal oxidative function. Amplification allows rapid detection of the inheritance pattern for fetal diagnosis in informative families. We report the genomic structure of p67phox and an amplification-based method for detection of the marker on chromosome 1q25, used here for prenatal diagnosis of CGD.     

Human hedonic responses to sweetness: role of taste genetics and anatomy

While past research has suggested an association between the ability to taste PROP and liking for the taste of sucrose, many aspects of this relationship remain ambiguous. To clarify this further, 60 volunteers (40 women and 20 men) were classified as PROP super-medium or non-tasters and as sweet likers or dislikers depending on hedonic and intensity ratings for PROP and sucrose. 67% of PROP super-tasters were sweet dislikers, compared to 12% of PROP non-tasters. PROP super-tasters also rated the intensity of salty and sweet tastes as greater than did non- or medium PROP tasters, but these differences in sweet intensity could not explain the group differences in sweet liking. The groups did not differ in restraint or BMI. Taste bud density was higher in PROP super-tasters and sweet dislikers than in PROP medium or non-tasters or sweet likers. Overall these data confirm that PROP super-tasters are more likely to be sweet dislikers, and that this cannot be explained as secondary to cognitive attitudes to sweetness (restraint) or enhanced sweet intensity.