Stephen W. Borron

Chemical Submission: GHB, Benzodiazepines, and Other Knock Out Drops

AbstractWe leave to Sartre this sweeping generalization but the infliction of involuntary intoxication or chemical submission is clearly an attempt at annihilation or, at least, domination of the conscience of others. Chemical aggression is increasingly frequent and the popularization of gamma-hydroxybutyrate (GHB) as an uncontrolled intoxicant is expected to increase the diagnostic dilemmas of contemporary “knock out drops”1,2

Pharmacokinetics of Hydroxocobalamin in Smoke Inhalation Victims

OBJECTIVE Hydroxocobalamin has been proposed as a cyanide antidote. Little is known, however, about its pharmacokinetics in human cyanide poisoning. METHODS We prospectively studied the pharmacokinetics of hydroxocobalamin in 11 smoke inhalation victims of whom all but one had objective evidence of cyanide exposure. Serum hydroxocobalamin levels were followed from just before drug administration to six days after a single 5 g dose of hydroxocobalamin. RESULTS The results (mean +/- standard error) suggest a two compartment model. Distribution half-life is on the order of 1.86 +/- 0.34 h and the elimination half-life 26.2 +/- 2.7 h. The apparent volume of distribution is 0.45 +/- 0.03 L/kg. Renal and total body clearance are 0.31 +/- 0.06 and 0.83 +/- 0.07 L/h, respectively. CONCLUSION The apparent volume of distribution suggests a predominantly extracellular partitioning of the antidote, even in the presence of cyanide, an important factor in terms of its antidotal effect. Hydroxocobalamins elimination half-life in these cyanide-exposed patients far exceeds those found in previous studies of dogs and minimally-exposed humans. If confirmed, this half-life suggests that a single dose of hydroxocobalamin, sufficiently large enough to bind the cyanide present, should be adequate.

Markedly altered colchicine kinetics in a fatal intoxication: Examination of contributing factors

1 Colchicine poisoning, which is relatively rare, is associated with significant morbidity and mortality. Whilst a new treatment modality, in the form of colchicine-specific Fab fragments is on the horizon, currently available therapy is largely supportive. 2 The elimination of colchicine occurs primarily by hepatic metabolism, following a first-order process, with significant enterohepatic circulation. Renal extraction is responsible for approximately 20% of colchicine elimination. 3 We report a case of colchicine intoxication, compli cated by the presence of co-ingestants, in which serum colchicine concentrations remained quasi-constant over the 3 days of the patients survival, consistent with marked alterations both in metabolism and excretion. The initial presentation was relatively benign but the subsequent course was one of severe colchicine poisoning, resulting in death. 4 Severe colchicine toxicity appears to have resulted in a vicious cycle of progressive organ dysfunction and impaired elimination. 5 Josamycin, one of the co-ingestants and an inhibitor of P-glycoprotein, the membrane pump responsible for multidrug resistance, may have played a significant role in impeding the cellular and biliary elimination of colchicine. Co-ingested opioid and anticholinergic compounds may have altered colchicine absorption and gastrointestinal transit. 6 This case serves as a reminder of the need for attention to co-ingested drugs, to early aggressive therapy, and if available, to consideration of immunotherapy.

Modifying toxicokinetics with antidotes

Five approaches may be described through which antidotes can modify toxicokinetics: (1) Decreased bioavailability of the toxins; (2) Cellular redistribution of the toxin in the organism; (3) Promotion of elimination in an unchanged form; (4) Slowing of metabolic activation pathways; (5) Acceleration of metabolic deactivation pathways. However, the ability to modify toxicokinetics with a new treatment, while demonstrating an understanding of the mechanism of action, must never be construed to be, in and of itself, the goal of therapy. The ultimate evaluation of an antidote modifying toxicokinetics is strictly clinical.

Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity.

ObjectiveAcute chloroquine intoxication is responsible for a membrane-stabilising effect which results in electrocardiographic (ECG) and hemodynamic disturbances. Diazepam is used in acute chloroquine intoxication on the basis of clinical and experimental observations, but its utility alone, in man, remains unproven. The goal of this study was to verify whether diazepam alone has an effect on the membrane-stabilising effect observed in moderately severe chloroquine intoxications.DesignProspective, multi-center, double-blind, placebo-controlled study.SettingPrehospital mobile intensive care units (Paris) and hospital intensive care units (Paris and Dakar).Patients and participantsAdults with moderately severe intoxication defined as: a suspected ingested dose of 2 or more but less than 4 g, systolic blood pressure (SBP) higher than 80 mmHg, QRS duration less than 0.12 s and the absence of dysrhythmia at inclusion.InterventionsPatients received either a loading dose of 0.5 mg/kg diazepam followed by an infusion of 1 mg/kg over 24 h or an equivalent volume of placebo.Measurements and resultsOutcome was measured by serial assessments of SBP, ECG (QRS and QT segments) and clinical deterioration. There were no significant differences observed in the initial or serial ECG or SBP measurements. There were no deaths and no patient had to be removed from the study due to clinical deterioration.ConclusionsDiazepam, at the dose studied, does not appear to reverse the chloroquine-induced membrane-stabilising effect in acute moderately severe chloroquine intoxication. Supportive intensive care of these intoxications appears to be all that is necessary.

Isofenphos poisoning: prolonged intoxication after intramuscular injection

We report a unique case of attempted suicide by intramuscular injection of the organophosphate isofenphos which resulted in a muscarinic and nicotinic syndrome lasting 15 days and requiring prolonged mechanical ventilation and hospitalization. The patient, who demonstrated no signs of delayed polyneuropathy on hospital day 25, subsequently died of pneumonia. Toxicological investigations showed isofenphos plasma decay and confirmed the intramuscular route of poisoning. We believe continuous isofenphos absorption resulted in the prolonged intoxication observed in this patient.

Immunotoxicotherapy : Successes, disappointments and hopes

was quite limited until the late 1960’s, when another breakthrough was to occur, in the form of development of toxin-specific antibody fragments. This exemplary story unfolded in two steps: (1) active immunization and (2) passive immunization with whole antibody, and subsequently with antibody fragments. In 1967, Butler and Chen reported that coupling of the digoxin hapten to serum albumin resulted in

An early study of pulmonary asbestosis among manufacturing workers : Original data and reconstruction of the 1932 cohort

A cross-sectional prevalence survey of asbestosis, including all 1,140 employees of a diversified asbestos products manufacturer, was conducted in 1932 by Drs. Anthony J. Lanza and Frank V. Meriwether. Occupational histories were obtained from workers in order to identify job tasks with exposure to asbestos and other fibrogenic dusts. Abbreviated medical histories, physical examinations, fluoroscopy, and chest radiographs were performed. Radiographs were interpreted according to applicable criteria for pneumoconiosis, the presence of which was confirmed in 327 subjects (29%). Among those, 64% had previous exposure to dusts in addition to asbestos, coal being the leading non-asbestos exposure. Thirty-six percent of cases had prior exposure only to asbestos dust. The original conclusions do not survive. Contemporaneous related documents suggest that the original authors believed asbestosis to be a milder form of lung disease than silicosis. It was subsequently recommended that the company institute pre-employment physicals, including chest radiographs; not hire people with prior coal-dust exposure; warn workers against excessive exposure to asbestos dust; remove those with disease to less dusty areas; and begin periodic medical surveillance for pneumoconiosis. The study, which has never appeared in the medical or scientific literature, holds important lessons for those concerned with occupational health today and in the future.

A Critical Review of Antidotal Immunotherapy for low Molecular Weight Toxins. Current Antidotes and Perspectives

Immunotoxicotherapy (ITT) has been defined by Scherrmann et al. (Scherrmann et al. 1989) as a procedure able to simultaneously sequester, extract or redistribute, and eliminate the toxin by using specific active binding sites derived from different antibody molecular entities. Since the initial report in 1976 by Smith et al. of the reversal of a digoxin intoxication by an equimolar dose of digoxin-specific Fab fragments, immunotoxicotherapy (ITT) has become first-line treatment of all life-threatening intoxications by cardiac glycosides. The efficacy of ITT is such that one might pose the question as to whether all other approaches (anti-arrhythmics, hemoperfusion, etc.) are obsolete. While it appears evident that ITT rapidly reverses digitalis-induced cardiac toxicity, improved outcome, in terms of decrease in mortality rate, has not been proven. This may be in part due to the underlying health of the patients treated or to delays in treatment with Fab. However, this points to the importance of refining the place of ITT in the treatment of digitalis poisoning.

Assessment of erythrocyte cholinesterase activity in victims of smoke inhalation

BACKGROUND The nature of the toxic gases that cause death from smoke inhalation is incompletely understood, and the mechanisms leading to incapacitation remain to be determined. Thermal degradation products of various compounds, including phosphorous-based fire retardants, are suspected capable of impairing human cholinesterase activity. The aim of this study was to measure the erythrocyte cholinesterase activity in victims of smoke inhalation. METHODS We prospectively measured the erythrocyte cholinesterase activity in blood samples obtained at the scene of residential fires from 49 fire victims. We compared the results with those in an unmatched group of 45 persons with acute drug poisoning. RESULTS The median (25th-75th percentiles) erythrocyte cholinesterase activity in the 49 fire victims, 1968 IU/L (1660-2276), was significantly lower than in the 45 control subjects 2460 IU/mL (1968-2890), (p = 0.0004). There was no significant difference of the red blood cell counts or plasma protein levels between the 2 groups, while the hematocrit was significantly greater in the fire victims than in the drug-poisoned patients. There was a significant correlation between blood cyanide and carbon monoxide concentrations in the fire victims (r = 0.494, p = 0.002). There was no correlation between erythrocyte cholinesterase activity and either blood cyanide (r = 0.11, p = 0.44) or blood carbon monoxide concentrations (r = 0.04, p = 0.78). CONCLUSIONS We found a significantly lower level of erythrocyte cholinesterase activity in victims of residential fires, when compared with a convenience sample of hospitalized poisoned patients. Despite the limitations of the study, investigations of the toxic gases potentially responsible for impairment of cholinesterase activity and the clinical significance of this lower enzymatic activity merit further investigation.