Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population.

AIMS/HYPOTHESIS: Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance. METHODS: A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women). RESULTS: A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: -43% to -30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: -20% to -10%; p<0.0001) and NEFA by 40% (95% CI: -51% to -27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to -24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (-35%; p<0.0001) and plasma glucose concentration (-0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups. CONCLUSIONS/INTERPRETATION: Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.

Environmental temperature during gestation and body mass index in adolescence: new etiologic clues?

OBJECTIVE: Being born during certain parts of the year is linked to the presence of obesity in later years. Animal studies suggest that environmental temperature during fetal development may be one aspect of the link to later weight status, but this relationship has not been extensively studied in humans. The present study investigates whether environmental temperature during different stages of human gestation is associated with body mass index (BMI) during late adolescence. METHODS: Questionnaire data were collected from adolescents (n=578; ages 15-19 y) attending public schools in a mid-Atlantic US city. Pearson correlations were used to assess association of BMI with mean environmental temperature (from meteorological records) during trimesters of intrauterine development and at birth. RESULTS: BMI was significantly correlated with environmental temperatures in the second and third trimester, but only among female African Americans. Among females, those 'at risk for overweight' or overweight (BMI >85th percentile) tended to be born during periods of warmer average environmental temperatures (>13.2 degrees C). However, this effect was reliable only among African American females (relative risk=2.51, CI 1.07-5.91). A similar, non-significant tendency emerged among Caucasian females, but there was no such effect in males. CONCLUSIONS: Environmental temperatures during pregnancy and at birth are associated with the likelihood that African American females become overweight as adolescents. Possible biological and dietary mechanisms for this finding are discussed.

Prophylactic iron supplementation in pregnant women in Norway.

In the present study 67 non-anaemic women were randomly allocated to either 100 mg or 15 mg iron daily at about the 10. week of pregnancy. At about week 18, 30 and 36 of pregnancy, as well as 6 weeks after delivery, hemoglobin and the serum concentrations of ferritin, vitamin B12, folates, Zn, Cu and Se were monitored. Dietary allowances of other minerals and vitamins are also increased in pregnancy, and the 15 mg iron tablet was enriched with Zn (10 mg), Cu (2 mg), Se (50 microg), vitamin B12 (3 microg), and folate (0.1 mg). Neither ferritin, nor Cu, Zn or Se concentrations differed statistically significantly between the treatment groups during pregnancy. Ferritin and Zn appeared to decrease approximately parallel to the hemodilution, whereas Cu concentrations increased from a non-pregnant reference mean of 18 micromol Cu/L to a maximum mean of nearly 33 micromol Cu/L during pregnancy. Se decreased concomitantly to about 1.0 micromol Se/L. Serum folate (around 15 micromol/L) was essentially unaffected by pregnancy in the group given multivitamin/mineral supplementation, whereas the mean concentration fell below 10 micromol/L in the group supplemented with 100 mg iron daily. Our results indicate that supplementation of 15 mg Fe daily during pregnancy results in a small reduction of hemoglobin. It is suggested that additional supplementation with folate might be of importance to maintain the serum folate concentration during pregnancy.

The systemic load and efficient delivery of active 5-aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine.

BACKGROUND: There have been reports of nephrotoxic reactions in patients with ulcerative colitis treated with 5-aminosalicylic acid (5-ASA) preparations. AIM: To compare the efficacy in delivery of active 5-ASA to the colon and the systemic load as the basis for potential long-term toxicity during treatment with olsalazine or mesalazine in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Fifteen patients with ulcerative colitis were treated with olsalazine or mesalazine, each for 7 days in an open, randomized, crossover design study. 5-ASA and acetyl-5-ASA (Ac-5-ASA) in plasma and urine were measured by high performance liquid chromatography. RESULTS: The plasma concentration of 5-ASA was 1.2 +/- 0.1 micromol/L (mean +/- S.E.M.) for olsalazine and 8.0 +/- 1.9 micromol/L for mesalazine, while the plasma concentration of Ac-5-ASA was 2.8 +/- 0.2 micromol/L for olsalazine and 10.8 +/- 1.6 micromol/L for mesalazine. The amount of 5-ASA excreted in the urine was 68 +/- 30 micromol/24 h for olsalazine and 593 +/- 164 micromol/24 h for mesalazine. The amount of Ac-5-ASA in the urine was 1260 +/- 102 micromol/24 h for olsalazine and 3223 +/- 229 micromol/24 h for mesalazine. The urinary recovery of total 5-ASA plus Ac-5-ASA (as a percentage of the given dose) was 23 +/- 2.1% for olsalazine and 39 +/- 3.6% for mesalazine. The ratio between the plasma concentrations of mesalazine and olsalazine differed significantly both for 5-ASA (5.1) and Ac-5-ASA (3.6); for 5-ASA (9. 9) and Ac-5-ASA (2.6) in urine, and for the urinary recovery of total 5-ASA plus Ac-5-ASA (1.7). Moreover, in the mesalazine group there was a large variation in the individual plasma concentrations of 5-ASA and Ac-5-ASA, with maximal values 5-6-fold higher than that in the olsalazine group. CONCLUSION: The systemic load of active 5-ASA is significantly higher for mesalazine than for olsalazine, when based on the dosages given and when calculated on an equimolar basis. Some of the patients in the mesalazine group showed unexpected high levels of plasma and urinary 5-ASA concentrations, a finding which may have long-term safety implications.

Cimetidine reduces weight and improves metabolic control in overweight patients with type 2 diabetes.

OBJECTIVE: To investigate the weight-reducing effect of cimetidine in overweight patients with Type 2 diabetes. DESIGN: A 12-week clinical intervention study of 400 mg cimetidine prescribed three times daily in a randomised, double-blind, placebo-controlled design. SUBJECTS: Forty-three overweight patients with Type 2 diabetes (age 18-65 y, body mass index (BMI) 27.2-48.2 kg/m2). MEASUREMENTS: Body weight, BMI, body fat, waist and hip circumference, waist/hip ratio, blood pressure, fasting blood glucose, HbA1c, plasma concentrations of insulin, insulin/glucose ratio and lipids at the start and after 12 weeks, and daily recordings of appetite. RESULTS: Subjects given cimetidine (n = 19) and placebo (n = 24) lost 5.0 +/- 2.2 kg (mean +/- s.d.) and 1.3 +/- 1.1 kg, respectively. Significant reductions were observed in appetite, body fat (29.9 +/- 6.6% to 25.3 +/- 7.4%), waist circumference (111.5 +/- 10.3 cm to 107.4 +/- 10.6 cm), waist/hip ratio (0.96 +/- 0.08 to 0.94 +/- 0.08), and systolic and diastolic blood pressure (reductions of 6.9 +/- 11.4 mm Hg and 6.0 +/- 6.6 mm Hg, respectively) in cimetidine group only. Significant decreases in fasting concentrations of blood glucose, HbA1c, plasma insulin, insulin/glucose ratio, plasma triglycerides and a significant increase in plasma high-density lipoprotein cholesterol were observed in the cimetidine group only. CONCLUSIONS: Cimetidine reduces appetite and body weight, and improves metabolic control in overweight subjects with Type 2 diabetes.

Effect of cimetidine on basal and postprandial plasma concentrations of cholecystokinin and gastrin in humans.

Cimetidine reduces the appetite and weight in healthy overweight subjects. Gastrointestinal regulatory peptides such as cholecystokinin (CCK) have been proposed to mediate the satiety signal from gut to brain. Therefore, the effect of cimetidine on basal and postprandial plasma concentrations of cholecystokinin and gastrin was studied. After an overnight fast, 12 healthy volunteers were given cimetidine (400 mg) on day 1, breakfast on day 2, and cimetidine 20 min before breakfast on day 3. Plasma concentrations of cholecystokinin and gastrin were measured by radioimmunoassay. Plasma cholecystokinin concentration increased with one major peak observed 30 min and one smaller peak observed 120 min after intake of cimetidine. The meal induced an increase in the plasma concentration of cholecystokinin, while cimetidine prior to the meal elicited a sustained postprandial cholecystokinin response. Cimetidine had no effect on the basal plasma concentration of gastrin. The meal induced an increase in the plasma concentration of gastrin, while cimetidine prior to the meal elicited a sustained postprandial gastrin response. In conclusion, cimetidine increases the basal concentration of plasma cholecystokinin and elicits a sustained postprandial response of both cholecystokinin and gastrin. At least the cholecystokinin response may be one mechanism by which cimetidine reduces the appetite.

H2-receptor antagonist reduces food intake and weight gain in rats by non-gastric acid secretory mechanisms.

The H2-receptor antagonist cimetidine reduces appetite and weight in overweight healthy subjects and in overweight subjects with type II diabetes mellitus. The aim of this study was to characterize the mechanisms of this effect in rodents. Drugs were administered three times a day, 30 min before 1 h periods of free access to food. In one group of rats (n = 9), cimetidine (8 mg) treatment resulted in significantly lower cumulative food intake than in a control group (n = 9). The total intakes of food during the observation period of 22 days were 325.3 +/- 29.1 g and 346.3 +/- 16.7 g in the cimetidine and control groups, respectively. During the observation period, the weight gain in the cimetidine group was 63.3 +/- 15.8 g, which was significantly lower than the weight gain of 74.8 +/- 14.2 g in the control group, i.e. the cimetidine induced a 15.4% reduction in the weight gain during the observation period of 22 days. The weight gained per weight of food ingested was 0.20 +/- 0.04 (g/g) and 0.22 +/- 0.04 (g/g) in the cimetidine and control groups, respectively (NS). In other experiments, ranitidine (3 mg) and famotidine (0.4 mg), but not omeprazole (0.4 mg), taken three times a day for 8 days reduced the weight gain when compared with a control group (n = 7 in each group). We therefore conclude that the effects of the H2-receptor antagonists are not mediated by inhibitory mechanisms on the gastric acid secretion.

Body fat as a predictor of the antihypertensive effect of nifedipine.

OBJECTIVE: The aim of this study was to investigate the relationship between the blood pressure response and body fat in patients treated with the calcium entry blocker nifedipine. SUBJECTS: Forty untreated subjects with moderate hypertension completed the study. INTERVENTIONS: Height, weight, body mass index (BMI) and body fat (measured by near infrared spectrophotometry using Futrex 5000) were measured before the start of the study. Based on blood pressure measurements before and 30 min after one capsule of 10 mg nifedipine, the patients were allocated to treatment with 10 mg nifedipine daily in the responder group (reduction in diastolic blood pressure > or = 10 mmHg) and with 20 mg nifedipine daily in the non-responder group. Finally, the blood pressure was measured after 1 week. RESULTS: Twelve patients were classified as responders and 28 patients as non-responders. The responder/non-responder groups were comparable with respect to the blood pressure readings initially and to age, whereas the non-responders had higher weight (P < 0.01) and BMI (P < 0.01), more body fat (P < 0.01) and were smaller in height (P < 0.01). After 1 week no additional antihypertensive effect was observed in either group. The blood pressure reduction was negatively correlated to the body fat mass in kilogrammes (P < 0.05 for systolic and P < 0.01 for diastolic blood pressure) in the responder group but not in the non-responder group, whereas no significant correlations were found to BMI in either group. CONCLUSION: Our data indicate that the body fat can be used to predict the antihypertensive effect of nifedipine.

Effect of cimetidine suspension on appetite and weight in overweight subjects.

OBJECTIVE: To investigate the weight reducing effect of cimetidine, comparing it with placebo. DESIGN: Block randomised parallel group double blind study using suspensions with identical appearance and taste. SETTING: Primary care practice. SUBJECTS: 55 women and 5 men aged 18-59, body mass index 25-37 kg/m2, completed the study according to the protocol. INTERVENTIONS: Cimetidine suspension 200 mg or placebo 30 minutes was given before the three main meals for eight weeks. Subjects followed a diet restricted to 5 MJ/day supplemented with 9 g fibre per day. MAIN OUTCOME MEASURES: Weight reduction; abdominal and hip circumferences and systolic and diastolic blood pressures were also recorded. RESULTS: Subjects given cimetidine lost a mean of 7.3 (95% confidence interval 6.5 to 8.3) kg more than subjects given placebo (p < 0.001); body mass index decreased 3.33 (SD 0.76) and 0.77 (0.43), respectively (p < 0.001). Abdominal and hip circumference was decreased more in the cimetidine group (8.6 (3.9) cm and 7.8 (3.1) cm) than in the placebo group (2.2 (1.5) cm and 2.1 (1.5) cm). Mean reductions in systolic and diastolic blood pressure were greater in the cimetidine group than the placebo group (mean 5.8 v 0.4 and 6.5 v 0.4, p < 0.001). CONCLUSION: Intake of cimetidine suspension 30 minutes before meals in overweight subjects may lead to reduced hunger, less food intake, and subsequent weight loss. This effect may be due to the suppression of gastric acid secretion. Cimetidine suspension may be a valuable adjunct in treating obesity.