Misoprostol: a prostaglandin E1 analogue.

The pharmacology, pharmacokinetics, clinical efficacy, contraindications and precautions, adverse effects, dosage, and cost of misoprostol are reviewed. Misoprostol is a synthetic analogue of natural prostaglandin E1. It produces a dose-related inhibition of gastric acid and pepsin secretion and enhances mucosal resistance to injury. Misoprostol is extensively absorbed from the stomach and undergoes rapid de-esterification to its biologically active metabolite, misoprostol acid. The average absorption after an oral dose is 88%; peak plasma concentrations of misoprostol acid are achieved in less than 30 minutes. Clinical trials have demonstrated ulcer healing rates of approximately 60-80% in patients with duodenal ulcers who received misoprostol 800 micrograms daily for four weeks. Misoprostol was generally no more efficacious than conventional therapy with the H2-receptor antagonists cimetidine and ranitidine. The healing rate observed for gastric ulcers was less than that observed for duodenal ulcers. In trials involving healthy volunteers and patients with arthritis receiving aspirin, naproxen, tolmetin, ibuprofen, or piroxicam, misoprostol was consistently superior to placebo, cimetidine, and sucralfate in the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. The majority of these studies have been of short duration; however, long-term studies (up to three months) have corroborated superiority over placebo. Misoprostol is an abortifacient and is contraindicated in pregnant women and women of childbearing potential not using effective contraception. The most common adverse effect of misoprostol therapy is diarrhea, which is often mild and self-limiting and can be minimized by administration of misoprostol after meals and at bedtime. The cost (based on retail price) of four weeks of therapy with misoprostol is comparable to that of other antiulcer agents. Misoprostol has been shown to be an effective agent for the prevention of NSAID-induced gastric ulcers. However, there is no evidence that it offers any clinical advantage over H2-receptor antagonists for the treatment of gastric or duodenal ulcer disease.

Neutropenia associated with mezlocillin and piperacillin.

Neutropenia associated with beta-lactam antibiotics has been widely reported since the first case was described in 1946. Cross-reactivity between beta-lactam antibiotics for this phenomenon rarely has been reported. This case describes the development of neutropenia after a course of mezlocillin, resolution upon discontinuation, and recurrence promptly after initiation of piperacillin, with resolution subsequent to discontinuation. Clinical practitioners should be aware that this adverse drug reaction has been associated with the newer beta-lactam antibiotics and that cross-reactivity may occur between these antibiotics.

Influence of a decision analysis model on selection of drug therapy.

The impact of a decision analysis model on pharmacists' preferences for a drug therapy was studied. Three hundred forty members of the American College of Clinical Pharmacy were randomly assigned to receive either a copy of a drug therapy review alone (control group) or the review plus a decision analysis of the same clinical problem (experimental group). The disease selected was pseudomembranous colitis, and the drugs to be considered were vancomycin, metronidazole, and bacitracin. The review and the decision analysis recommended metronidazole as the best agent. Each subject completed a short questionnaire, read the review or the review plus the analysis, and completed a follow-up questionnaire. Both questionnaires asked the subjects to rank the agents in order of preference. There were 164 usable responses, 86 from the control group and 78 from the experimental group; the total response rate was 48.2%. The difference in the proportion of respondents in each group who chose metronidazole as the most preferred agent, both before and after the intervention, was not significant. Of the 40 experimental-group subjects who ranked metronidazole as their second or third choice in the pretest, 16 (40%) ranked it as the most preferred agent in the posttest. Ten of these 16 stated that the model influenced their decision. Decision analysis plus a drug therapy review had no greater impact on pharmacists' opinions on the selection of drug therapy for pseudomembranous colitis than did the review alone. The model did influence some of those who changed their opinion.

Therapeutic evaluation of omeprazole.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of omeprazole are reviewed. Omeprazole, a substituted benzimidazole, has a unique site and mechanism of action because it inhibits the proton pump--i.e., hydrogen, potassium adenosine triphosphatase (H+,K+-ATPase)--and consequently blocks the final common step in the gastric acid secretory pathway. Omeprazole inhibits basal and histamine-, gastrin- and pentagastrin-stimulated gastric hydrochloric acid secretion. It produces a dose-dependent reduction in gastric acidity, gastric acid output, and gastric juice volume and has variable effects on pepsin secretion. Omeprazole has no documented effect on esophageal motility or lower esophageal sphincter pressure. Omeprazole is variably absorbed from the gastrointestinal tract, and food appears to decrease the rate, but not the extent, of drug absorption. The drug is approximately 95% bound to plasma proteins and is metabolized to inactive components that are enterohepatically or renally eliminated. Omeprazole is more effective (in most studies) than H2-receptor antagonists in treating duodenal ulcer, at least as effective in treating benign gastric ulcer, and more effective in treating reflux esophagitis. Omeprazole has been used successfully in patients with Zollinger-Ellison syndrome refractory to treatment with H2-receptor antagonists. Gastrointestinal complaints (nausea and diarrhea) are the most commonly reported adverse effects associated with omeprazole therapy. The most frequently reported laboratory abnormality occurring with omeprazole use is elevation of serum aspartate aminotransferase and alanine aminotransferase concentrations. Omeprazole will serve a valuable role in the management of gastrointestinal tract ulcers and hypersecretory conditions.

Neutropenia associated with beta-lactam antibiotics.

Two patients who developed neutropenia while receiving beta-lactam antibiotics are presented, and the literature on beta-lactam-induced neutropenia is reviewed. A 55-year-old white woman was admitted to the hospital with a white blood cell (WBC) count of 8700/cu mm (68% neutrophils, 12% neutrophil bands, 0% eosinophils, 14% lymphocytes, 5% monocytes). Moxalactam 2 g i.v. (as the disodium salt) every eight hours was started on hospital day 15 after a postoperative fever failed to respond to a regimen of intravenous tobramycin and clindamycin. The patient again had surgery on hospital day 27, and the moxalactam regimen was continued postoperatively. Approximately one week later the patient's WBC count had dropped to 1900/cu mm (8% neutrophils, 14% neutrophil bands, 6% eosinophils, 54% lymphocytes, 16% monocytes); moxalactam was discontinued, and the WBC count gradually increased after substitution of tobramycin and clindamycin for moxalactam. The second patient was a 75-year-old white man who was being treated with intravenous tobramycin and cefoxitin for a hospital-acquired pneumonia. Ticarcillin 3 g i.v. (as the disodium salt) every four hours was added to this regimen on hospital day 23 after sputum cultures revealed Pseudomonas aeruginosa; four days previously, the WBC count had been 25,100/cu mm (64% neutrophils, 31% neutrophil bands, 1% eosinophils, 3% lymphocytes, 0% monocytes). The WBC count on hospital day 36 was 11,900/cu mm (39% neutrophils, 33% neutrophil bands, 11% eosinophils, 10% lymphocytes, 6% monocytes). Two days later it had dropped to 3700/cu mm (2% neutrophils, 0% neutrophil bands, 53% eosinophils, 24% lymphocytes, 16% monocytes), and ticarcillin was discontinued. The WBC count gradually increased and returned to normal within three days after discontinuing ticarcillin. Neutropenia associated with the administration of beta-lactam antibiotics appears to result from an immunologic reaction characterized by rapid destruction of peripheral neutrophils. Among penicillin analogs, penicillinase-resistant penicillins are involved most frequently, especially in pediatric patients receiving dosages of 150 mg/kg/day or greater. Two case reports have implicated ticarcillin as a cause of neutropenia; moxalactam has not been associated with this adverse effect in previous literature reports. Discontinuation of the suspected agent and initiation of an alternative antibiotic regimen is recommended as initial treatment of this condition since recovery usually occurs within days after discontinuing the offending drug.

The pharmacokinetics of meperidine in acute trauma patients.

Traumatic injury has the potential to alter the hepatic clearance and hence the efficacy and toxicity of drugs by a variety of mechanisms. These include changes in hepatic microsomal enzyme activity, hepatic blood flow rate, and plasma protein binding. Unfortunately, there have been few pharmacokinetic studies in trauma patients. Thus, few data are available to provide guidance in drug regimen design for these individuals. Meperidine clearance was therefore evaluated in patients with traumatic injury and an effort was made to identify physiologic and/or clinical predictors of clearance which could facilitate initial dosage selection. Meperidine total body clearance (TBC) was determined on 12 occasions at steady state following IM administration of meperidine to nine severely injured nonseptic trauma patients with normal renal and hepatic function. TBC of this drug averaged 684 +/- 206 ml/min (mean +/- SD) and was highly correlated with ideal body weight (IBW) (r2 = 0.735; F = 27.75; n = 12; p less than 0.01). The serum concentration of the acute phase reactant protein, alpha 1 acid glycoprotein (AGP), which binds meperidine and many other basic drugs increased strikingly in an apparent linear manner at a rate of 27 mg/dl/day up to 9 days after the traumatic event (r2 = 0.828; F = 42.30; n = 12; p less than 0.01). However, this increase in binding protein concentration was not associated with an alteration in meperidine TBC as has been reported for other drugs. It is concluded that IBW may be a useful guide initial dosage selection of meperidine in acute trauma patients.(ABSTRACT TRUNCATED AT 250 WORDS)