ContextThe protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss.ObjectiveTo determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults.DesignA randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998.SettingFour university nutrition and obesity clinics and 2 contract clinical research clinics.ParticipantsFifty-four lean (body mass index, 20.0-27.5 kg/m2; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m2; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years.InterventionsRecombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight.Main Outcome MeasuresBody weight, body fat, and incidence of adverse events.ResultsWeight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from −0.4 (2.0) kg for placebo (n = 36) to −1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from −0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to –7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects.ConclusionsA dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.
A prospective, randomized study was conducted to determine the effect of biofeedback-assisted relaxation training on foot ulcer healing. For patients with chronic nonhealing foot ulcers, medical care was combined with a standardized biofeedback-assisted relaxation training program in the experimental group. The intervention was designed to increase peripheral perfusion, thereby promoting healing. A total of 32 patients with chronic nonhealing ulcers participated in the study. In the experimental group, 14 out of 16 ulcers (87.5%) healed, as compared with 7 out of 16 ulcers (43.8%) in the control group.
OBJECTIVE: To investigate the metabolic effects and frequency of adverse events with 6 mg of glimepiride, a new oral sulfonylurea, given both in once- and twice-daily dosages to patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: This 15-week study involved 161 subjects with NIDDM. Subjects were randomized into two groups. For 4 weeks, group 1 received glimepiride 3 mg twice daily, and group 2 received glimepiride 6 mg once daily. After a 3-week placebo-washout period, twice- and once-daily regimens were crossed over for a second 4-week treatment period. Subjects were hospitalized at the end of each placebo or active-treatment phase. Their glucose concentrations were recorded at 20 time points over a 24-hour period, and their insulin and C-peptide concentrations were recorded at 16 time points over the same period. Parameters that were calculated included fasting, 24-hour, and postprandial concentrations of glucose, insulin, and C-peptide. RESULTS: One hundred six patients were randomized to receive treatment; 94 completed the entire study. Existing physiologic mechanisms of glucose control were apparently unimpaired by glimepiride treatment. Insulin concentrations increased more during the postprandial glucose peaks than when subjects were fasting. Both twice- and once-daily regimens proved equally effective in reducing concentrations of fasting, postbreakfast, postlunch, and postdinner plasma glucose. Twenty-four-hour mean glucose concentrations showed a slightly greater decrease from baseline for the twice-daily regimen; the difference between the regimens was statistically significant but not clinically meaningful. The incidence of adverse events with glimepiride approximated that obtained with placebo, with both groups reporting only one adverse event, headache, in more than 5% of the subjects. CONCLUSIONS: Glimepiride is equally effective whether administered once or twice daily. Glimepiride seems to stimulate insulin production primarily after meals, when plasma glucose concentrations are highest, but controls blood glucose throughout the day.
We are developing a DNA vaccine toward hepatitis-B virus (HBV) using PowderJect's proprietary needle-free technology to deliver DNA-coated gold particles directly into cells of the skin. Preclinical studies in animals showed that (i) microgram doses of the DNA vaccine were sufficient to immunize pigs and non-human primates to antibody levels comparable to those obtained with a commercial recombinant subunit vaccine; (ii) the DNA vaccine was effective in mouse strains that respond poorly to protein subunit vaccines; (iii) the vaccine induces robust cytotoxic T-cell responses, and (iv) the vaccine is non-toxic and well tolerated. Based on these findings, this DNA vaccine was evaluated for safety, tolerability, and the induction of immune responses in phase 1 clinical studies in healthy, hepatitis-naïve human volunteers. Preliminary results indicate that the vaccine is safe and well tolerated, and elicits both humoral and cellular immune responses in man.
Study Objectives . To evaluate the safety, tolerability, and pharmacokinetics of single, escalating doses of oral dolasetron mesylate, a new 5‐HT 3 receptor antagonist. Design . Double‐blind, placebo‐controlled, dose‐escalating phase I study. Setting . A clinical research center. Patients . One hundred twenty healthy male volunteers. Interventions . Subjects received either placebo or oral dolasetron mesylate 50, 100, 150, 200, 250, 300, or 400 mg. Measurements and Main Results . Compared with placebo, subjects receiving dolasetron mesylate reported a greater frequency of headache, lightheadedness, dizziness, increased appetite, and nausea. There were no clinically significant changes in mean laboratory values from before to after treatment. Adverse events were transient, mild or moderate, and similar to those after single intravenous doses of the drug. No clinically significant electrocardiographic changes occurred, but lengthening of the QRS complex duration and dose‐dependent lengthening of PR and QT c intervals were observed 1–2 hours after dosing. These effects were asymptomatic and were mainly associated with higher doses (≥ 300 mg). Conclusion . Dolasetron mesylate is well tolerated when administered in single oral doses up to 400 mg to healthy volunteers. Clinical trials are under way to evaluate the agent's efficacy in preventing chemotherapy‐induced and postoperative nausea and vomiting with doses up to 200 mg.
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