Albert D. Fraser

Early Adequate Mycophenolic Acid Exposure is Associated with Less Rejection in Kidney Transplantation

This study examines the importance of early mycophenolic acid (MPA) exposure in the cyclosporine‐ and mycophenolate mofetil (MMF)‐treated kidney transplant population.

Massive carbamazepine overdose Clinical and pharmacologic observations in five episodes

We report five episodes of carbamazepine (CBZ) intoxication in four patients. Clinically, there were four distinct stages: I—coma, seizures (CBZ levels more than 25 μg/ml [105 μmol/1]); II—combativeness, hallucinations, choreiform movements (15 to 25 μg/ml [65 to 105 μmol/1]); III—drowsiness, ataxia (11 to 15 μg/ml [45 to 65 μmol/1]); and IV—potentially catastrophic relapse (less than 11 μg/ml [45 μmol/1]). Pharmacokinetic studies revealed a prolongation of the CBZ half-life, elevation of the CBZ-epoxide/CBZ ratio, and emergence of CBZ-epoxide as a significant toxic metabolite. A treatment approach is proposed including repeated gastric lavage, detection of an insoluble tablet coagulum, electrolyte monitoring, avoidance of cathartics, and treatment of seizures with diazepam and phenytoin.

NEW DRUGS FOR THE TREATMENT OF EPILEPSY

OBJECTIVES This article will review current data on the metabolism, interactions, methods of analysis, and adverse effects observed with the use of new anticonvulsant drugs. The role of the laboratory in the provision of therapeutic drug monitoring for these drugs is discussed. CONCLUSION Certain of the newer anticonvulsant drugs require therapeutic drug monitoring for their optimal use in the treatment of epileptic seizures. The requirement for therapeutic drug monitoring has not been established for some of these drugs. Many of the newer anticonvulsant drugs, including lamotrigine, felbamate, vigabatrin, and zonisamide, interact clinically with established drugs, such as phenytoin, phenobarbital, carbamazepine, and valproic acid. Introduction of these new drugs will result in the need for more frequent monitoring of the established drugs during polytherapy. The need for a drug-monitoring service for anticonvulsant drugs overall will continue, due to the frequency of drug interactions, the incidence of adverse effects, and concerns about compliance with the dosing regimen in these patients.

Clinical valproate toxicity induced by acetylsalicylic acid

We report three patients with serious clinical valproate (VPA) toxicity induced by interaction with acetylsalicylic acid (ASA). Two patients had a documented rise in VPA free level, and the third showed only clinical signs of toxicity. Symptoms resolved in all three when the ASA was stopped. This interaction has been previously documented under experimental conditions, and is due to displacement of VPA from plasma protein binding sites and a probable interference in metabolism. This is the first report of the clinical significance of this interaction.

Colorimetric and Gas Chromatographic Procedures for Glycolic Acid in Serum: The Major Toxic Metabolite of Ethylene Glycol

Monitoring of individuals poisoned with ethylene glycol involves analysis of ethylene glycol in serum. The objective of this procedure was to validate a colorimetric and gas chromatographic procedure for glycolic acid in serum. The colorimetric procedure requires no sophisticated instrumentation and has been shown to be specific for glycolic acid. A gas chromatographic procedure has also been developed involving methyl derivatization of glycolic acid and the internal standard (propionic acid). These methods have been used for the analysis of serum specimens from ethylene glycol poisoned patients. Glycolic acid has been recognized as the major toxic agent in ethylene glycol poisoning but current methods available do not allow analysis in a clinically relevant turnaround time. These two procedures allow glycolic acid quantitation by procedures readily set up in most clinical toxicology laboratories.

Toxicological Analysis of a Fatal Baclofen (Lioresal) Ingestion

A fatality following ingestion of the drug baclofen (Lioresal) is described. Baclofen was identified in urine by gas chromatography/mass spectrometry. After derivatization with trinitrobenzene sulfonic acid, baclofen was quantitated in serum and urine by high-performance liquid chromatography. The concentration of baclofen was 17 mg/L in serum and 760 mg/L in urine collected approximately 12 h after the overdose. To our knowledge, this is only the second reported fatality involving a baclofen overdose. The previous case did not include quantitation of baclofen in any biological fluid.

Drug and chemical metabolites in clinical toxicology investigations: The importance of ethylene glycol, methanol and cannabinoid metabolite analyses

Metabolic pathways in humans have been elucidated for most therapeutic drugs, drugs of abuse, and various chemical/solvents. In most drug overdose cases and chemical exposures, laboratory analysis is directed toward identification and quantitation of the unchanged drug or chemical in a biologic fluid such as serum or whole blood. Specifically, most clinical laboratories routinely screen and quantitate unchanged methanol and/or ethylene glycol in suspected poisonings without toxic metabolite analysis. Martin-Amat established in 1978 that methanol associated toxicity to the optic nerve in human poisonings was due to the toxic metabolite formic acid found in methanol poisonings and not due to the direct action by unchanged methanol. Jacobsen reported in 1981 that ethylene glycol central nervous system and renal toxicity were primarily due to one acidic metabolite (glycolic acid) and not due to unchanged ethylene glycol. The first objective of this review is to describe clinical experience with formic acid and glycolic acid analysis in methanol and ethylene glycol human poisonings. Drug metabolite analysis also provides useful information in the assessment and monitoring of drug use in psychiatry and substance abusing populations. Drug analysis in substance abuse monitoring is focused on urine analysis of one or more major metabolites, and less frequently on the unchanged drug(s). Serial monitoring of the major urinary cannabinoid metabolite (delta(9)-THC-COOH) to creatinine ratios in paired urine specimens (collected at least 24 h apart) could differentiate new marijuana or hashish use from residual cannabinoid metabolite excretion in urine after drug use according to Huestis. The second objective is to demonstrate that creatinine corrected urine specimens positive for cannabinoids may help differentiate new marijuana use from the excretion of residual delta(9) -THC-COOH in chronic users of marijuana or hashish. Analysis of toxic chemical metabolites are helpful in the assessment and treatment of chemical poisoning whereas serial monitoring of urinary cannabinoid metabolites are predictive of illicit drug use in the substance abusing population.

Urinary excretion profiles of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol: a Δ9-THC-COOH to creatinine ratio study #2

Huestis and Cone reported in [J. Anal. Toxicol. 22 (1998) 445] that serial monitoring of Delta9-THC-COOH/creatinine ratios in paired urine specimens collected at least 24h apart could differentiate new drug use from residual Delta(9)-THC-COOH excretion following acute marijuana use in a controlled setting. The best accuracy (85.4%) for predicting new marijuana use was for a Delta(9)-THC-COOH/creatinine ratio > or = 0.5 (dividing the Delta9-THC-COOH/creatinine ratio of specimen no. 2 by the specimen no. 1 ratio). In previous studies in this laboratory [J. Anal. Toxicol. 23 (1999) 531 and Forensic Sci. Int. 133 (2003) 26], urine specimens were collected from chronic marijuana users > or = 24 h or > = 48 h apart in an uncontrolled setting. Subjects with a history of chronic marijuana use were screened for cannabinoids with the EMIT II Plus cannabinoids assay (cut-off 50 ng/ml) followed by confirmation for Delta9-THC-COOH by GC-MS (cut-off 15 ng/ml). Creatinine was analyzed as an index of dilution. The objective of the present study was to evaluate whether creatinine corrected specimens could differentiate new marijuana or hashish use from the excretion of residual Delta(9)-THC-COOH in chronic marijuana users based on the Huestis 0.5 ratio. Urine specimens (N=376) were collected from 29 individuals > or = 96 h between urine collections. The mean urinary Delta9-THC-COOH concentration was 464.4 ng/ml, mean Delta9-THC-COOH/creatinine ratio (ng/(ml Delta9-THC-COOH mmoll creatinine)) was 36.8 and the overall mean Delta9-THC-COOH/creatinine ratio of specimen 2/mean Delta9-THC-COOH/creatinine ratio of specimen 1 was 1.37. The Huestis ratio calculation indicated new drug use in 83% of all sequentially paired urine specimens. The data were sub-divided into three groups (Groups A-C) based on mean Delta9-THC-COOH/creatinine values. Interindividual mean Delta9-THC-COOH/creatinine values ranged from 4.7 to 13.4 in Group A where 80% of paired specimens indicated new drug use (N=10) and 20.4-39.6 in Group B where 83.6% of paired specimens indicated new drug use (N=7). Individual mean Delta9-THC-COOH/creatinine values ranged from 44.2 to 120.2 in Group C where 84.5% of paired urine specimens indicated new marijuana use (N=12). Correcting Delta9-THC-COOH excretion for urinary dilution and comparing Delta9-THC-COOH/creatinine concentration ratios of sequentially paired specimens (collected > or = 96 h apart) may provide an objective indicator of ongoing marijuana or hashish use in this population.

Toxicologic studies in a fatal overdose of 2,4-D, mecoprop, and dicamba.

A suicidal poisoning committed by a 61-year-old woman, who ingested an unknown quantity of Killex, containing in aqueous solution 100 g/L of (2,4-dichlorophenox)acetic acid (2,4-D), 50 g/L of mecoprop, and 9 g/L of dicamba as amine salts is described. Quantitation of chlorophenoxy acids was performed by extraction from an acidified mixture and concentration before high performance liquid chromatography analysis. All three herbicides were separated in a phosphate buffer/acetonitrile mixture at 280 nm on a RP-8 column. Concentrations of herbicides found were: in blood--520-mg/L 2,4-D, 530-mg/L mecoprop, and 170-mg/L dicamba; in urine--670-mg/L 2,4-D and 520-mg/L mecoprop; in bile--340-mg/L 2,4-D, 530-mg/L mecoprop, and 140-mg/L dicamba; and in liver--540-mg/Kg 2,4-D, 500-mg/Kg mecoprop, and less than 100-mg/Kg dicamba. Liquid chromatography was found to be a reliable method for herbicide quantitation in biological tissues and fluids. The technique offered definite advantages over ultraviolet spectrophotometry and avoids the derivatization requirement for gas chromatography.

A Fatality Involving Clomipramine

A fatality following ingestion of the tricyclic antidepressant clomipramine (Anafranil), alprazolam (Xanax), and ethyl alcohol is described. Clomipramine and N-desmethylclomipramine were quantitated by high performance liquid chromatography and alprazolam by gas liquid chromatography. Concentrations of clomipramine and N-desmethylclomipramine were: in blood--0.84 and 1.4 mg/L; in urine--0.56 and 0.62 mg/L. Alprazolam concentration in blood was 0.069 mg/L. Ethyl alcohol was measured by headspace gas chromatography and found to be 375, 385, and 435 mg/dL in blood, urine, and vitreous humor, respectively. These findings are compared to previous reports of clomipramine related fatalities and alprazolam toxicity combined with ethyl alcohol.