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We tested the safety and efficacy of sibutramine, 5 and 20 mg, and placebo on weight loss. Medication was added to caloric restriction, behavior modification, and exercise in a parallel-group, double-blind clinical trial. Participants were 130% to 180% of ideal body weight and in good health. The study lasted 12 weeks over Thanksgiving, Christmas, and New Year's Day. Weight loss during 8 weeks of study medication was: placebo, 1.4 ± 2.1 kg (n = 19); 5 mg sibutramine, 2.9 ± 2.3 kg (n = 18); and 20 mg sibutramine, 5.0 ± 2.7 kg (n = 18) (p < 0.05 sibutramine, 5 and 20 mg, versus placebo; p < 0.05 sibutramine, 20 mg versus 5 mg). There is a significant dose-effect relationship. Five participants left the study before completion, all because of adverse events: placebo (one patient), 5 mg sibutramine (one patient), and 20 mg sibutramine (three patients). Sleep difficulties were noted by eight participants (20 mg sibutramine, seven patients; 5 mg, one patient; and placebo, no patients). Six of 21 participants receiving 20 mg complained of irritability, unusual impatience, or “excitation.” Sibutramine, 5 and 20 mg, added to a multimodal program assisted participants in losing weight. Clinical Pharmacology and Therapeutics (1991) 50, 330–337; doi:10.1038/clpt.1991.144

Ninety-two children with juvenile rheumatoid arthritis were randomly assigned to treatment in a multicenter, double-blind, 12-week trial designed to compare the efficacy and safety of a liquid formulation of ibuprofen at a dosage of 30 to 40 mg/kg/day versus those of aspirin at a dosage of 60 to 80 mg/kg/day. No significant intergroup differences in response rates or in the amount of improvement in articular indexes of disease activity were observed. More children treated with aspirin discontinued treatment early because of adverse reactions. After this trial, 84 additional patients with juvenile rheumatoid arthritis entered a 24-week, multidose (30, 40, and 50 mg/kg/day), open trial of ibuprofen suspension. Favorable response rates for the three groups were similar, and continued improvement was observed throughout the 24-week period. A dose-response relationship was observed with respect to adverse reactions of the upper gastrointestinal tract. We conclude that ibuprofen suspension is an effective nonsteroidal antlinflammatory drug and that its tolerability in children is acceptable.

Sibutramine HCl, a monoamine reuptake inhibitor type of antidepressant, was administered to healthy male volunteers as either a single dose (12.5 or 50 mg) or repeated treatment (5-20 mg once daily or 15 mg twice daily). Plasma, obtained at regular intervals during and after sibutramine HCl or placebo treatment, was assayed in vitro for its ability to inhibit the uptake of [3H]-noradrenaline (NA) by rat cortical synaptosomes, [3H]-5-hydroxytryptamine (5HT) by human platelets and [14C]-dopamine (DA) by rat striatal synaptosomes. After both single and repeated sibutramine HCl administration, the rank order of uptake inhibition was [3H]-NA greater than [3H]-5HT greater than [14C]-DA. The level of monoamine uptake inhibition increased on daily administration to a plateau 4-6 days after initiation of treatment, for example, approximately 60% and 40% inhibition of [3H]-NA and [3H]-5HT, respectively, following 15 mg sibutramine HCl twice daily. The pattern of monoamine uptake inhibition following sibutramine HCl administration to man is similar to that observed in sibutramine HCl-treated rats, and probably at least partly reflects inhibition of uptake by drug metabolites in both species. The inhibition of monoamine uptake following sibutramine HCl administration to man is consistent with an antidepressant effect.

BRAY, GEORGE A., GEORGE L. BLACKBURN, JAMES M. FERGUSON, FRANK L. GREENWAY, ADESH K. JAIN, CARL M. MENDEL, JOSEPH MEN-DELS, DONNA H. RYAN, SHERWYN L. SCHWARTZ, MONTE L. SCHEINBAUM, AND TIMOTHY B. SEATON. Sibutramine produces dose-related weight loss. Obes Res. Objective Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. Research Methods and Procedures Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. Results Weight loss was dose-related and statistically significant vs. placebo (p

Sibutramine is a serotonin and norepinephrine reuptake inhibitor that has shown efficacy as a weight loss and weight maintenance agent. Because of the abuse liability and physical dependence potential of amphetamines and related antiobesity agents, this study evaluated the abuse potential of sibutramine and compared it with that of dextroamphetamine and placebo in recreational stimulant users. Thirty-one male recreational stimulant users participated in this single-site, Latin square crossover study that compared the effects of two doses of sibutramine (20 mg and 30 mg) to dextroamphetamine (20 mg and 30 mg) and placebo, using a series of validated subjective scales or questionnaires. For scales measuring stimulation and euphoria, there was a greater mean response for dextroamphetamine 30 mg versus 20 mg, with both doses having a significantly greater stimulant and euphoric effect than placebo at the majority of time points (p < 0.05); responses for both doses of sibutramine were statistically indistinguishable from placebo at all time points. Responses to "street value" and "most enjoyed study session" questions confirmed that sibutramine lacks abuse potential; mean cash value estimates of street value were significantly greater for both dextroamphetamine doses than for placebo or either sibutramine doses (p < 0.05), and the rank order of session enjoyment placed both doses of sibutramine last. Together with the relatively late Tmax of the active metabolites (3-4 hours), this short-term, single-dose study provides strong evidence that sibutramine does not have the potential for abuse that is characteristic of amphetamines and that it is indistinguishable from placebo in abuse potential.

• Objective. —To determine whether febrile children receiving 2.5-, 5-, or 10-mg/kg ibuprofen therapy via a liquid or 15-mg/kg acetaminophen therapy via an elixir every 6 hours for 24 to 48 hours show equivalent fever reduction or suffer adverse effects of the drug administered. Design. —Randomized, double-blind, multidose, parallel-group, variable-duration (24 to 48 hours) clinical trial. Setting. —The academically affiliated Children's Hospital in Columbus, Ohio. Participants. —64 febrile (defined as oral or rectal temperature of 39°C to 40.5°C) but otherwise healthy children aged 6 months to 11 years 7 months randomly assigned to one of the four drug regimens. Interventions. —Treatment with either ibuprofen or acetaminophen as described above. Administration of antibiotics or intravenous fluids was allowed only after at least 24 hours of treatment with the assigned drug. Measurements/Main Results. —In 61 of the 64 evaluable patients, treatments were effective and well tolerated during the entire study. While the rates of temperature reduction and maximal reduction of fever after administration of the initial dose were equal for patients receiving 10-mg/kg ibuprofen therapy and 15-mg/kg acetaminophen therapy, and both regimens were more effective than smaller doses of ibuprofen in reducing fever, after the second dose (and continuing to the end of the study) there were no statistically significant differences in temperature response among the treatment groups. Six children were withdrawn from the study, two because of dosing errors, three because of hypothermia (temperature of less than 35.6°C; all three patients were in the acetaminophen group), and one because of gastrointestinal distress (this child was in the group receiving 2.5-mg/kg ibuprofen therapy). No other significant symptoms or adverse laboratory or physical findings were noted. While further confirmatory studies are needed, ibuprofen liquid (10 mg/kg) and acetaminophen elixir (15 mg/kg) administered every 6 hours for 24 to 48 hours appeared to be most effective in reducing fever. These two regimens were equally effective and equally tolerated in febrile children. Lower ibuprofen doses (2.5 and 5 mg/kg) were less effective than acetaminophen and 10-mg/kg ibuprofen therapy after the initial dose but were at least equally effective as these two higher-dose regimens thereafter. (AJDC. 1992;146:626-632)

• Objective. —To compare the antipyretic efficacy of ibuprofen, placebo, and acetaminophen. Design. —Double-dummy, double-blind, randomized, placebo-controlled trial. Setting. —Emergency department and inpatient units of a large, metropolitan, university-based, children's hospital in Michigan. Participants. —37 otherwise healthy children aged 2 to 12 years with acute, intercurrent, febrile illness. Interventions. —Each child was randomly assigned to receive a single dose of acetaminophen (10 mg/kg), ibuprofen (7.5 or 10 mg/kg), or placebo. Measurements/Main Results. —Oral temperature was measured before dosing, 30 minutes after dosing, and hourly thereafter for 8 hours after the dose. Patients were monitored for adverse effects during the study and 24 hours after administration of the assigned drug. All three active treatments produced significant antipyresis compared with placebo. Ibuprofen provided greater temperature decrement and longer duration of antipyresis than acetaminophen when the two drugs were administered in approximately equal doses. No adverse effects were observed in any treatment group. Conclusions. —Ibuprofen is a potent antipyretic agent and is a safe alternative for the selected febrile child who may benefit from antipyretic medication but who either cannot take or does not achieve satisfactory antipyresis with acetaminophen. (AJDC. 1992;146:622-625)

The effect of single 0.25 mg, 0.75 mg, 1.5 mg, and 3.0-mg oral doses of trimoprostil and placebo on the inhibition of meal-stimulated gastric acid secretion was investigated in duodenal ulcer patients. Drug and placebo were administered in a double-blind, randomized, crossover study under fasting conditions. A bactopeptone meal was administered 30 minutes after dosing. Gastric acid output was measured by intragastric titation (pH 5.5) and trimoprostil plasma concentrations were measured by a specific gas chromatography-negative chemical ionization-mass spectrometric method. Meal-stimulated gastric acid secretion was significantly reduced when compared to placebo for one hour after 0.25 mg, 1.5 hours after 0.75 mg, and for 2.5-3.0 hours after both 1.5 mg and 3.0 mg doses. The maximal inhibition of gastric acid ranged from 65% reduction after 0.75 mg to 74% after 1.5 mg to 82% after 3.0-mg doses. Trimoprostil was rapidly absorbed and eliminated; terminal elimination half-life ranged from 21 to 45 minutes. Both maximum concentration and area under the plasma concentration-time curve increased proportionately with an increase in the dose. The concentration-effect data at a given dose were simultaneously fit to a pharmacokinetic/pharmacologic effect model. An IC50 (plasma concentration needed to elicit a 50% inhibition effect) value of 0.2 ng/mL was observed at doses of 0.75 mg to 3.0 mg. Overall, trimoprostil was effective in inhibiting acid output in a dose-related manner in duodenal ulcer patients.

A single, oral, 1.5-mg dose of trimoprostil was taken before a standard meal and a matching placebo was taken after a standard meal by 10 subjects (group A). A second group of 10 subjects took placebo before a meal and trimoprostil after the meal (group B), while a third group took placebo both before and after the standard meal (group C). Food-stimulated gastric acid production was measured by intragastric titration for 6.5 hr after dosing. Trimoprostil taken after the meal had a greater effect on gastric acid secretion than when taken before the meal: Duration of effect was 5 to 5.5 hr in group B and 2 to 2.5 hr in group A. Blood samples were drawn and assayed for trimoprostil by gas chromatography–mass spectrometry. Mean trimoprostil plasma concentration and mean inhibition of gastric acid secretion data were fit to two models by the Hill equation. The mean plasma concentration associated with 50% inhibition of gastric acid secretion was 1.25 ng/ml. Trimoprostil plasma concentrations between 3 and 4 ng/ml were associated with 70% to 80% gastric acid inhibition. Overall, there appears to be a pharmacokinetic-pharmacologic correlation between trimoprostil plasma concentrations and inhibition of gastric acid secretion. Trimoprostil (1.5 mg) in the presence of food appears to have a therapeutic advantage, in that it decreases acid secretion longer than when taken without food and suffers no loss of bioavailability. Clinical Pharmacology and Therapeutics (1985) 37, 113–117; doi:10.1038/clpt.1985.21

Excerpt To the editor: Dr. Leo Hollister ("Treatment of Depression with Drugs," Ann Intern Med 89:78-84, 1978) states in his discussion of secondary amine versus tertiary amine tricyclic antidepres...