Anabolic action of parathyroid hormone on cortical and cancellous bone differs between axial and appendicular skeletal sites in mice.

The mouse is being increasingly used to study the anabolic action of parathyroid hormone (PTH) on the skeleton. The efficacy of intermittent PTH treatment on bone varies widely among tested strains of mice with differences in peak bone mass and structure. We have therefore examined the responses of skeletal sites with high or low cancellous bone mass to PTH treatment in a single strain with genetically low bone mass. Mature C57BL/6 mice were ovariectomized (ovx) or sham operated and, after 4 weeks, treated with PTH(1-34) (40 microg/kg/day, 5 days/week sc) or vehicle for 3 or 7 weeks. Two doses of fluorescent labels were given to the animals 9 and 3 days before euthanasia. Histomorphometry was performed on sections of the proximal tibia, tibial diaphysis, and vertebral body. The results indicate that 4 to 11 weeks of ovx induced a approximately 44% loss of cancellous bone in the proximal tibia and a approximately 25% loss of cancellous bone in the vertebra with impaired trabecular architecture and high bone turnover. In the intact animals, PTH increased cancellous bone volume to a greater extent in the vertebral body than in the proximal tibia, a site with lower cancellous bone volume at the outset. In the ovx mice, PTH increased cancellous bone volume to a greater extent in the vertebral body, a site displaying moderate cancellous bone loss, than in the proximal tibia, a site with severe cancellous bone loss. Conversely, the treatment added a little cortical bone to the tibia, a highly loaded site, but did not significantly increase cortical width of the vertebral body, a less loaded site. We conclude that, for intermittent PTH treatment to be maximally effective, there must be an adequate number of trabeculae present at the beginning of treatment, regardless of estrogen status. Our results also support an interaction between PTH anabolic action and mechanical loading.

Fluoxetine: a randomized clinical trial in the treatment of obesity.

Fluoxetine hydrochloride (Lovan, Eli Lilly and Company, Indianapolis, Indiana, USA), a specific serotonin uptake inhibitor, was compared with placebo in 458 obese outpatients in a 52-week double-blind randomized ten-site trial to study its effect on weight reduction. Patients in the fluoxetine and placebo groups were predominantly Caucasian (81% and 85%, respectively) and female (81% and 79%, respectively), with a mean body mass index (BMI) of 36.2 and 35.8 kg/m2, respectively, and a mean age of 43 years (both groups). Fluoxetine therapy (60 mg/day) resulted in statistically significantly (P < or = 0.05) greater mean weight loss than placebo to week 28. Although some patients continued to lose weight throughout the 52-week therapy period, maximum mean weight loss occurred at week 20. There was no treatment difference at 52 weeks. The change in visit frequency (biweekly to week 8, monthly to week 20, then bimonthly to week 52) may have affected results. Patients with higher baseline BMIs (> 40 kg/m2) attained and maintained a greater weight loss than patients with lower baseline BMIs (< 40 kg/m2). Two sites demonstrated greater efficacy than the study as a whole. The use of nutrition counselling at one site and behaviour modification at the other, or other site-to-site differences, may account for the improved efficacy. Fluoxetine was well tolerated and appeared to be safe therapy for the treatment of obesity with efficacy demonstrated for 28 weeks.

Nizatidine prevents peptic ulceration in high-risk patients taking nonsteroidal anti-inflammatory drugs.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use is increasingly recognized as a major factor associated with peptic ulcer disease and complications. We undertook a multicenter, double-blind, placebo-controlled trial to evaluate efficacy and safety of nizatidine in preventing ulcer formation in patients with osteoarthritis who were taking NSAIDs. METHODS: After endoscopy to rule out the presence of an acute ulcer, 496 patients were randomized to receive nizatidine, 150 mg twice daily (248 patients) or placebo (248 patients) for 3 months. Repeated endoscopies were performed monthly. We defined failure as development of a peptic ulcer (> or = 0.3 cm in diameter). RESULTS: Baseline characteristics tested were comparable for the two groups with regard to age, sex, ulcer history, and Helicobacter pylori status. Overall ulcer occurrence in the nizatidine group (9.7%) was not significantly different from that in the placebo group (13.7%; P = .163). High-risk subgroups (patients with ulcer history and patients > or = 65 years of age), however, revealed statistically fewer ulcers for patients receiving nizatidine (P = .035 and P = .042, respectively). Analysis of antacid use showed significantly less use in nizatidine recipients, although there were similar percentages of patients showing improvement in dyspeptic symptoms in each treatment group. We failed to observe a conclusive correlation between H pylori status at baseline, as measured by serum immunoglobulin antibody, and development of an ulcer. CONCLUSIONS: This study showed that nizatidine, 150 mg, twice daily, significantly reduces the incidence of ulcer formation in high-risk patients taking long-term NSAID therapy. It also relieves NSAID-associated dyspeptic symptoms in some patients.

Fluoxetine: a randomized clinical trial in the maintenance of weight loss.

Because current weight-reduction treatments have considerable recidivism, a therapy that could help patients maintain weight loss would be of benefit. A six-center, randomized, double-blind trial compared the effects of the specific serotonin uptake inhibitor, fluoxetine hydrochloride, and placebo on maintenance of weight loss. Obese outpatients who had lost > or = 3.6 kg after 8 weeks of single-blind fluoxetine 60 mg/day in the qualification phase (N=317 [70.4% of patients entered]; mean +/- standard deviation [SD] weight loss, 6.8 +/- 2.8 kg) were randomly assigned to fluoxetine 20 mg/day (N=104), fluoxetine 60 mg/day (N=106), or placebo (N=107) for 40 weeks (maintenance phase). Patients received minimal nutrition/dietary counseling. Qualification phase clinic visits were biweekly; maintenance phase visits were monthly for 4 months, then bimonthly for 6 months. Patients treated with fluoxetine 60 mg/day continued to lose weight for 8 additional weeks (16 weeks total; maximum mean +/- SD weight loss, 7.2 +/- 4.6 kg); those treated with fluoxetine 20 mg/day or placebo began to regain weight. Mean weights remained below baseline values at week 48 (all groups); treatment differences were not statistically significant. Study completion rates were comparable (fluoxetine 20 mg/day, 67.3%; fluoxetine 60 mg/day, 56.6%; placebo, 67.3%; p = 0.175). Among commonly reported adverse events (> 10% incidence), only asthenia was reported statistically significantly (p < 0.050) more frequently with fluoxetine than with placebo. Few patients discontinued for any single adverse event. Fluoxetine 60 mg/day was effective for a longer period than fluoxetine 20 mg/day or placebo in maintaining weight loss. Overall, fluoxetine was safe and well tolerated.

Use of fluoxetine, a selective serotonin-uptake inhibitor, in the treatment of obesity: a dose-response study (with a commentary by Michael Weintraub).

Pharmacologic measures which increase serotonergic activity in the brain decrease food consumption and lead to decreased weight in animals. Fluoxetine, an inhibitor of serotonin reuptake, decreases food intake in animals and is associated with weight loss in depressed and otherwise healthy obese patients. To determine the most effective daily fixed dose which causes weight loss in nondepressed obese patients, fluoxetine (10, 20, 40 or 60 mg) or placebo was administered once daily for 8 weeks to 655 patients consisting primarily of women (mean age 40 years, mean weight 95 kg). Diet and activity were not controlled. The placebo-treated patients lost 0.6 +/- 2.3 kg. With the 60-mg fluoxetine dose, patients lost an average of 4.0 +/- 3.9 kg (P less than 0.001), with intermediate responses at the lower doses. Weight loss was proportional to the initial body mass index (weight/height squared). There were no statistically significant differences between any fluoxetine treatment group and placebo for discontinuations from the study. There were statistically significant dose-dependent increases in reports of asthenia, somnolence and sweating. Thus, fluoxetine 60 mg daily appears to be potentially effective for use in weight reduction.

Use of a serotonin re-uptake inhibitor, fluoxetine, in the treatment of obesity.

Health risks associated with obesity are well known and compliance with standard regimens for weight reduction is frequently unsatisfactory. Fluoxetine is a specific inhibitor of serotonin re-uptake with very minimal affinity for serotonergic or other receptors. It causes a decrement in food intake in animals. Placebo or fluoxetine was given for up to 8 weeks to non-depressed, otherwise healthy, obese patients given minimal dietary advice. Patients given fluoxetine lost 4.5 +/- 4.0 kg, significantly more than those receiving placebo, 1.4 +/- 0.1 kg. The weight loss was correlated with the degree of obesity in the fluoxetine-treated patients. Asthenia was the only event reported significantly more frequently by fluoxetine-treated patients (23 percent) than by those treated with placebo (3 percent) (P less than 0.01). Fluoxetine appears to be safe and effective in inducing weight loss over periods of up to 8 weeks.

Quantitative comparison of adverse reactions to cefaclor vs. amoxicillin in a surveillance study.

During an 18-month adverse events surveillance period, children with a history of recurrent suspected or proved bacterial infections were treated with either cefaclor (1017 patients, 2513 courses) or amoxicillin (1009 patients, 2358 courses) and followed prospectively to determine the relative incidence and character of adverse events. Patients were from 1 month to 16 years old. Otitis media, the principal diagnosis, occurred in 883 patients (2014 episodes) receiving cefaclor and in 856 (1888 episodes) receiving amoxicillin. Others were diagnosed as having pharyngitis (482 episodes), bronchitis (267 episodes), sinusitis (130 episodes), pneumonia (63 episodes) and urinary tract infection (27 episodes). Adverse events were elicited by telephone during therapy and by follow-up for 2 weeks after therapy and were reported in 5.7% of the cefaclor courses and 5.2% of courses of amoxicillin. Serum sickness-like reactions and erythema multiforme occurred in 5 and 6 children, respectively, given cefaclor (1.1%) and in no children given amoxicillin. Children in the cefaclor group had a greater incidence of urticaria. Other adverse experiences, including gastrointestinal events, were approximately equally distributed for the two groups.

Cefamandole in the treatment of serious bone and joint diseases.

The safety and efficacy of treatment with cefamandole were evaluated in 77 patients (from 33 institutions) with serious bone and joint infections. The antibiotic was given intramuscularly or intravenously in doses ranging from 1.5 to 12 g/day for 6 to 58 days. Seventy-three of the 77 patients responded satisfactorily, and 63 (of 70 from whom material for culture was obtainable) patients had a bacteriologic cure. Forty-one of 81 isolates were identified as Staphylococcus aureus. Other pathogens included Streptococcus epidermidis, Haemophilus influenzae, Enterobacter sp., Escherichia coli, aerobic and anaerobic cocci, as well as Bacteroides fragilis. The drug was well tolerated. Pharmacological studies indicated that cefamandole penetrated the bones and joints. Cefamandole would seem to be a safe and efficacious drug, for the treatment of serious bone and joint infections due to a wide variety of gram-positive and gram-negative microorganisms.

Hypersecretion of mucus glycoproteins in rat airways induced by tobacco smoke.

An animal model of chronic bronchitis has been produced in vivo by exposing rats for 6 weeks to tobacco smoke: the laryngeal and tracheal glands have been studied in vitro by organ culture to analyze glycoprotein precursor incorporation and glycoprotein secretion by individual cells, a feature not previously studied. In the hypertrophied glands produced by tobacco smoke exposure, the cellular rate of glycoprotein secretion was increased. The in vivo administration of phenylmethyloxadiazole (PMO) to rats exposed to tobacco smoke blocked this effect. In vitro analysis of glands from unexposed rats that received PMO showed that it modified cell function directly by reducing the rates both of glycoprotein discharge and or precursor incorporation into intracellular glycoproteins.

Clinical experience with cefamandole for treatment of serious bone and joint infections.

The safety and efficacy of treatment with cefamandole were evaluated in 30 patients (from 18 institutions) with serious bone and joint infections. Five of the subjects were children. The antibiotic was given intramuscularly or intravenously in doses ranging from 2 to 12 g daily for five to 44 days. Twenty-six of the 30 patients responded satisfactorily. Fourteen of the fifteen infections due to Staphylococcus aureus were among the successful cases. Other pathogens were streptococci, Escherichia coli, Proteus mirabilis, and Bacteroides fragilis. The drug was well tolerated in patients in this series. Studies indicated that cefamandole penetrated the bones and joints. Further investigation of cefmandole in the treatment of bone and joint infections is warranted.

Cefamandole in the treatment of infections due to Enterobacter and indole-positive Proteus.

Clinical and bacteriologic results are reported for 80 patients treated with 1.5--12 g of cefamandole daily for a variety of infections caused by Enterobacter and indole-positive Proteus, organisms that have been resistant to most available cephalosporins. Of 45 patients with infections due to Enterobacter, 41 (91%) had satisfactory clinical responses; 36 were bacteriologic successes, and six cases of complicated urinary tract infections relapsed. Of 37 patients with infections due to indole-positive Proteus, 28 (88%) were clinical successes and 30 (81%) were bacteriologic successes. Fourteen cases of complicated urinary tract infection relapsed. Of 104 patients in whom the drug was evaluated for safety, use of cefamandole was discontinued in five; nine adverse reactions were considered drug-related. A summary of published in vitro data shows that the majority of strains of these organisms were susceptible to cefamandole at concentrations achievable in the serum. Minimal inhibitory concentrations are variable, and there is a significant inoculum effect, the clinical significance of which has not been determined.