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A woman was found unresponsive with an empty bottle of Cogentin(®) prescribed to another. Admitted to an area hospital, her condition steadily declined until death 29 h after admission. Following toxicological screening on hospital (admission) whole blood, the only significant compound detected was benztropine. Benztropine was confirmed at 0.28 mg/L - the highest antemortem blood concentration recorded in a case of toxicity or fatality uniquely associated with benztropine. A second serum antemortem specimen showed a benztropine concentration of 0.19 mg/L. Despite over 24 h in the hospital, benztropine was also found in the postmortem specimens collected at autopsy. Peripheral blood, central blood, liver, and gastric concentrations were 0.47 mg/L, 0.36 mg/L, 9.6 mg/kg, and 44 mg, respectively. These results indicate that benztropine exhibited a potential difference between whole-blood and serum (plasma) concentrations. Additionally, in consideration of literature data, benztropine was found indicative of a compound prone to at least some postmortem redistribution.

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Benztropine is an anticholinergic agent used in the treatment of Parkinson's disease and drug induced extrapyramidal disorders. We report a case of fatal benztropine toxicity. This drug is regarded as relatively safe and reports of isolated toxicity are scarce. In ascribing a particular death to fatal drug toxicity the forensic pathologist must take into account the circumstances surrounding the death, the presence and significance of any co-existent natural disease and the potential contribution of any other detected therapeutic or illicit agents. This interpretation will occur in the knowledge that certain drugs will not be detected and that with respect to quantification of postmortem drug levels, the notion of postmortem redistribution should always be considered.

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Today, anticholinergic antiparkinsonian drugs are primarily used to ameliorate extrapyramidal side-effects induced by neuroleptic agents. Orphenadrine dominates quantitatively among these drugs in Norway, presumably because it is assumed to carry a lower risk of abuse. There are numerous reports of deaths following orphenadrine overdoses. Orphenadrine has complex pharmacokinetic properties and a narrow therapeutic index. After an overdose, it confers toxic effects of rapid onset to several organ systems. No specific and effective therapy for orphenadrine intoxication has been established. For the two other drugs in this class which are marketed in Norway, biperiden and benztropine, toxicity is mainly connected to their anticholinergic properties. Notably, no reports of lethalities after overdoses of biperiden seem to be available. A small number of accounts of deaths following benztropine intoxication have been published. Neither of these two agents, and benztropine in particular, has been subjected to comprehensive pharmacokinetic evaluations. The relatively extensive use of orphenadrine should be discouraged.

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For a human fatality involving suspected overdose with the anticholinergic agent benztropine, GC-MS analysis was utilized for identification, quantitation, and investigation of metabolism. Organic extracts of blood and urine were analyzed by a capillary-column gas chromatograph interfaced with an ion-trap mass spectrometer, which was programmed for wide-spectrum data acquisition. Electron impact and chemical ionization were used for benztropine detection. The chemical structures of the ion fragments are proposed. Benztropine-d3 was synthesized and used as an internal standard. Quantitative determinations of benztropine revealed 0.183 mg/L in blood and 7.12 mg/L in urine from the decedent. Drug concentrations were interpreted relative to the case findings, published data, and a limited evaluation of the therapeutic concentrations in psychiatric patients. In addition, the possible metabolic conversion to norbenztropine was investigated by the synthesis of the norbenztropine derivative. Chromatographic evaluation of samples from the case study did not reveal significant bioconversion via the N-desmethylation pathway.

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A 38-year-old man overdosed on benztropine mesylate (Cogentin; Merck Sharpe & Dohme, West Point, PA) and developed anticholinergic poisoning syndrome, which lasted nine days. Serial serum benztropine concentrations were obtained during his hospitalization. Fluctuating benztropine levels suggested that his lengthy intoxication may have been secondary to prolonged, intermittent absorption rather than from slow plasma clearance. This is believed to be the first report of serial serum benztropine concentrations after overdose.

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We report an unusual case of benztropine-induced acute dystonia and dyskinesia without findings of acute anticholinergic toxicity in a 20-month-old child. Laboratory analysis of blood, urine, and gastric contents demonstrated the presence of an atropinic compound and diphenhydramine only, suggesting the association of benztropine and acute dystonia. Effects of benztropine on neuronal uptake of dopamine may represent a possible mechanism for this unusual adverse effect.

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A case of acute methylmercury ingestion was treated sequentially with oral D-penicillamine, hemodialysis during N-acetylcysteine (NAC) infusion, and 2,3-dimercaptopropane sulfonate (DMPS) an experimental oral agent. Urinary organic mercury elimination rate increased almost 40-fold during and 84-fold after hemodialysis with NAC infusion, compared with elimination during initial D-penicillamine therapy. Mean clearance during hemodialysis was only 13 ml/min with an extraction rate of 3.7 mcg/min. Although whole blood mercury concentrations decreased from 568 to 265 ng/ml during dialysis, a rebound to 525 ng/ml occurred. A total of 1.6 mg mercury was renally eliminated during hemodialysis and in the following 24 hours. A total of 3.3 mg of predominantly organic mercury was renally eliminated during 18 days of combined therapies. Since renal elimination of inorganic mercury is seen with chronic methylmercury poisoning, the high ratio of organic to inorganic mercury in urine supports the acute nature of this exposure. DMPS was begun on day 4 and during the two weeks of administration whole blood concentrations fell by 15% to 355 ng/ml. An expected decrease in elimination half-life to 10 days was not observed during DMPS therapy, possibly due to concurrent administration of vitamins containing zinc and copper. The amount of methylmercury ingested was estimated as 45 mg, based on a post-distribution blood concentration of approximately 450 ng/ml. The patient developed no symptoms of methylmercury poisoning during the one year after the episode. We conclude that NAC may be useful to enhance renal elimination of methylmercury and merits further investigation as a potential binding agent to reduce the body burden of methylmercury.

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A continuous intravenous infusion of physostigmine was successfully used in the management of a case of anticholinergic poisoning. In selected patients, intravenous physostigmine can be a safe and specific means of reversing the signs and symptoms of anticholinergic toxicity.

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