Unanticipated plasma concentrations in two clozapine-treated patients.

OBJECTIVE: To report two cases of lower than anticipated clozapine plasma concentrations despite near maximum recommended doses of clozapine 800-900 mg/d in two medication-compliant schizophrenic inpatients. CASE SUMMARIES: Clozapine therapy was initiated in two male schizophrenic inpatients for treatment of psychotic symptoms refractory to other typical and atypical antipsychotics. Despite receiving adequate doses of clozapine for at least two months, these patients remained symptomatic. Therapeutic drug monitoring was used to target a clozapine plasma concentration of > or =250 ng/mL, the minimum value reported in the literature to be associated with increased clinical response. Clozapine plasma concentrations remained at 200 ng/mL in one patient despite dosage increases from 600 to 800 mg/d. In the second patient, administration of the maximum recommended dose resulted in concentrations between 200 and 250 ng/mL. Increasing the clozapine dosage to 1000 mg/d did not increase the clozapine plasma concentration. Evaluation of the ratio of clozapine plasma concentration clozapine to dose yielded lower than expected values compared with those reported in the literature. DISCUSSION: These two patients exhibited lower than anticipated clozapine plasma concentrations despite receiving high doses of clozapine. Several studies evaluating clozapine serum concentrations and clinical response have suggested threshold concentrations of > or =350 ng/mL, > or =370 ng/mL, or > or =420 ng/mL. The only study that randomized patients to three concentration ranges found that patients who achieved a clozapine serum concentration in a medium range (mean 251 ng/mL) responded better than patients in a low range (mean 91 ng/mL) and similar to patients in a high range (mean 396 ng/mL). However, attaining plasma concentrations in this range for these patients proved difficult. Reasons for the low concentrations are unclear and may be related to increased metabolic activity at several cytochrome P450 isoenzymes involved in the metabolism of clozapine. CONCLUSIONS: These cases illustrate lower than anticipated clozapine plasma concentrations despite high-dose clozapine therapy. Strategies to increase clozapine plasma concentrations in such patients might include adding a drug to partially inhibit the metabolism of clozapine. If those strategies are unacceptable based on risk assessment, patient compliance, or other reasons, clinicians may consider addition of a low-dose typical or other atypical antipsychotic drug to augment clozapine response.

Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials.

OBJECTIVE: To reconcile conflicting published reports concerning the absolute and comparative clinical efficacy of antimicrobial drugs for acute otitis media in children. STUDY SELECTION: Articles were identified by MEDLINE search, Current Contents, and references from review articles, textbook chapters, and retrieved reports. Randomized, controlled trials of therapeutic antimicrobial drugs used in the initial empiric therapy for simple acute otitis media were selected by independent, blinded observers, and scored on 11 measures of study validity. Thirty English and three foreign-language articles met all inclusion criteria. DATA EXTRACTION: Data were abstracted for an end point of complete clinical resolution (primary control), exclusive of middle ear effusion, within 7 to 14 days after therapy started. DATA SYNTHESIS: The spontaneous rate of primary control--without antibiotics or tympanocentesis--was 81% (95% confidence interval, 69% to 94%). Compared with placebo or no drug, antimicrobial therapy increased primary control by 13.7% (95% confidence interval, 8.2% to 19.2%). No significant differences were found in the comparative efficacy of various antimicrobial agents. Extending antimicrobial coverage to include beta-lactamase-producing organisms did not significantly increase the rates of primary control or resolution of middle ear effusion. Pretreatment tympanocentesis was positively associated with individual group primary control rates, negatively associated with the ability to detect differences in clinical efficacy and unassociated with resolution of MEE. CONCLUSIONS: Antimicrobial drugs have a modest but significant impact on the primary control of acute otitis media. Treatment with beta-lactamase-stable agents does not increase resolution of acute symptoms or middle ear effusion; initial therapy should be guided by considerations of safety, tolerability, and affordability, and not by the theoretical advantage of an extended antibacterial spectrum.

Repeated oral administration of activated charcoal for treating aspirin overdose in young children.

The data from our two patients indicates that gastrointestinal dialysis with repeated oral doses of activated charcoal may significantly enhance the elimination of overdoses of salicylate in young children. Limited experience precludes precise recommendations, but current evidence suggests that gastrointestinal dialysis should be evaluated further for treating pediatric salicylate intoxication.

Rapid death resulting from mesoridazine overdose.

A 23-year-old mentally retarded woman was brought to the emergency department 2-2.5 hr after ingesting an unknown quantity of mesoridazine. She was lethargic and somewhat uncooperative, but did answer questions. Her ECG was normal. She was treated with gastric lavage, 50 g activated charcoal, and 10 oz magnesium citrate solution. Her condition continued to decline until, at 2 hr after arrival, she was comatose and becoming increasingly hypotensive. Her ECG showed long runs of markedly widened QRS complexes. The patient was given an iv infusion of dobutamine to maintain blood pressure. She suffered a convulsion, loss of blood pressure, and developed ventricular tachycardia which progressed to ventricular fibrillation unresponsive to electrical cardioversion, pacing, and vigorous prolonged CPR. She was pronounced dead 6-6.5 hr after the ingestion. Antemortem blood level of mesoridazine was 16 micrograms/ml and no other drugs were detected. While sudden deaths have been reported with therapeutic doses of mesoridazine and its parent thioridazine, deaths are uncommon in overdose. Rapid death seen in this case emphasizes the importance of close monitoring and aggressive treatment of phenothiazine overdoses.