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K McMartin

Publications and source records attributed to K McMartin.

11 recordsLinked to original sources
PubMed2001

Fomepizole for the treatment of methanol poisoning.

BACKGROUND: Methanol poisoning may result in metabolic acidosis, blindness, and death. The inhibition of alcohol dehydrogenase is fundamental to the treatment of methanol poisoning. We performed a multicenter study to evaluate fomepizole, an inhibitor of alcohol dehydrogenase, in the treatment of patients with methanol poisoning. METHODS: We administered intravenous fomepizole to 11 consecutive patients who presented with methanol poisoning at a participating center. Serial clinical and laboratory studies, including measurements of plasma formic acid and fomepizole, were performed. The outcomes measured were the preservation of visual acuity, the resolution of metabolic acidosis, the inhibition of formic acid production, the achievment of therapeutic plasma concentrations of fomepizole with the dosing regimen, residual illness or disability, and death. RESULTS: Plasma formic acid concentrations were detectable in eight patients, and these concentrations were closely correlated with the initial arterial pH values (r=0.92, P<0.001). In response to fomepizole, plasma formic acid concentrations fell and metabolic abnormalities resolved in all patients. Nine patients survived. Seven patients initially had visual abnormalities, but at the end of the trial no surviving patient had any detectable visual deficits related to methanol poisoning. Fomepizole had few adverse effects. The two patients who died had anoxic brain injury that was present at the time of enrollment. During treatment, methanol had an elimination half-life of 54 hours. CONCLUSIONS: Fomepizole appears to be safe and effective in the treatment of methanol poisoning.

Acidosis↗
PubMed1999

Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group.

BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis and renal failure and may cause death. The standard treatment is inhibition of alcohol dehydrogenase with ethanol, given in intoxicating doses, and adjunctive hemodialysis. We studied the efficacy of fomepizole, a new inhibitor of alcohol dehydrogenase, in the treatment of ethylene glycol poisoning. METHODS: We administered intravenous fomepizole to 19 patients with ethylene glycol poisoning (plasma ethylene glycol concentration, > or =20 mg per deciliter [3.2 mmol per liter]). Patients who met specific criteria also underwent hemodialysis. Treatment was continued until plasma ethylene glycol concentrations were less than 20 mg per deciliter. Acid-base status, renal function, the kinetics of fomepizole, and ethylene glycol metabolism were assessed at predetermined intervals. RESULTS: Fifteen of the patients initially had acidosis (mean serum bicarbonate concentration, 12.9 mmol per liter). Acid-base status tended to normalize within hours after the initiation of treatment with fomepizole. One patient with extreme acidosis died. In nine patients, renal function decreased during therapy; at enrollment, all nine had high serum creatinine concentrations and markedly elevated plasma glycolate concentrations (> or =97.7 mg per deciliter [12.9 mmol per liter]). None of the 10 patients with normal serum creatinine concentrations at enrollment had renal injury during treatment; all 10 had plasma glycolate concentrations at or below 76.8 mg per deciliter (10.1 mmol per liter). Renal injury was independent of the initial plasma ethylene glycol concentration. The plasma concentration of glycolate and the urinary excretion of oxalate, the major metabolites of ethylene glycol, uniformly fell after the initiation of fomepizole therapy. Few adverse effects were attributable to fomepizole. CONCLUSIONS: In patients with ethylene glycol poisoning, fomepizole administered early in the course of intoxication prevents renal injury by inhibiting the formation of toxic metabolites.

Adult↗
PubMed1998

Diagnosing intrauterine exposure to cocaine by hair testing: six years of clinical use.

Intrauterine exposure to cocaine results in a variety of perinatal and long-term neurobehavioral sequlae. Maternal history and neonatal urinalysis miss most instances of exposure. After establishing the high sensitivity, specificity, and predictive value of neonatal hair testing for cocaine, the authors embarked on a study to evaluate the clinical use of the test. Between October 1991 and September 1997, they assessed the presence of cocaine in 509 hair samples; 422 were from neonates and were based on clinical suspicion of intrauterine exposure, although history and urine test results were negative. Thirty-two percent were positive, a rate fivefold higher than the incidence found by the authors in population-based studies. Neonates referred by children's aid workers had significantly higher percentages of positivity (60%). Because neonatal hair grows only during the last 4 months of pregnancy, positive neonatal hair test results reflect maternal addiction, and this warrants close follow-up of the baby after release because of the high rate of postnatal risks secondary to suboptimal parental care and because of the proven perinatal risks inflicted by the drug itself.

Cocaine-Related Disorders↗
PubMed1997

Treatment of methanol poisoning with intravenous 4-methylpyrazole.

Treatment of human methanol poisoning with the alcohol dehydrogenase inhibitor, 4-methylpyrazole (fomepizole), has not been previously described. We report the clinical and toxicokinetic data of a patient with methanol poisoning who was treated with fomepizole. Formic acid levels remained undetectable during fomepizole treatment, the toxic effects of methanol were prevented, and the patient made a full recovery.

Adult↗
PubMed1996

4-Methylpyrazole (4-MP) is effectively removed by haemodialysis in the pig model.

The safety and pharmacokinetics of the alcohol dehydrogenase inhibitor 4-MP have recently been evaluated and its clinical use in ethylene glycol poisoning in France is promising. The dialysability of 4-MP is not known. This is important as hemodialysis is one of the cornerstones in the treatment of (late) ethylene glycol and methanol poisonings. We therefore studied the dialysability of 4-MP in the pig model. Anesthesized pigs (maintained on respirator) given 4-MP, 10 mg/kg, served as controls (n = 3) to the pigs (n = 3) given 15 mg/kg and hemodialyzed for 4 h. 4-MP plasma elimination curves for both groups were compared for 12 h and dialysance data calculated. 4-MP (MW 82) was removed by the same rate as urea (MW 60) by the 0.3 m2 dialysator, thus indicating no significant protein binding of 4-MP. The mean dialysance of 4-MP (and urea) in the three pigs were 61 (63), 51 (53) and 56 (48) ml/min, at a blood flow of 75 ml/min. The amount of 4-MP removed by hemodialysis in 4 h was 57-76 mg compared to a urinary excretion of 1-3 mg over 12 h. We conclude that the dialysability of 4-MP is significant and this must be taken into account when these two treatment procedures are combined.

Animals↗
PubMed1981

Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame.

Blood methanol concentrations were measured in 30 normal adult subjects administered aspartame, a dipeptide methyl ester. The doses studied included the 99th percentile of projected daily ingestion (34 mg/kg body weight) and three doses considered to be in the abuse range (100, 150, and 200 mg/kg body weight). Methanol concentrations were below the level of detection (0.4 mg/dl) in the blood of the 12 normal subjects who ingested aspartame at 34 mg/kg. They were significantly elevated (p less than or equal to 0 .001) after ingestion of each abuse dose, with the mean peak blood methanol concentrations and the areas under the blood methanol concentration-time curve increasing in proportion to dose. Mean (+/- SD) peak blood methanol concentrations were 1.27 +/- 0.48 mg/dl at the 100 mg/kg dose, 2.14 +/- 0.35 mg/dl at the 150 mg/kg dose, and 2.58 +/- 0.78 mg/dl at the 200 mg/kg dose. Blood methanol concentrations returned to predosing levels by 8 h after administration of the 100 mg/kg dose. Methanol was still detected in the blood 8 h after the subjects had ingested aspartame at 150 or 200 mg/kg. Blood formate analyses were carried out in the 6 subjects who ingested aspartame at 200 mg/kg, since recent studies indicate that the toxic effects of methanol are due to formate accumulation. No significant increase in blood formate concentrations over predosing concentrations was noted. No changes were noted in any of the blood chemistry profile parameters measured 24 h after aspartame ingestion, compared to values noted before administration. Similarly, no differences were noted in ophthalmologic examinations carried out before and after aspartame loading.

Adult↗
PubMed1979

Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: an approach to therapy against methanol poisoning.

4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD(+) oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 weeks. Their weight curves remained normal. Electron microscopy of liver, kidney, and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical chemical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the two compounds or the metabolites, leading to increased concentration in the blood of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys, elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of at most 10% of that of 4-methylpyrazole. Concurrent administration of methanol inhibited the elimination of 4-methylpyrazole about 25%, and 4-methylpyrazole produced a profound inhibition of the oxidation of methanol. 4-Methylpyrazole, at a level in the plasma of more than 10 muM, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. The present investigation indicates that 4-methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.

Alcoholism↗
PubMedDate not supplied

Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study.

CONTEXT: Numerous women of childbearing age are exposed occupationally to organic solvents. Previous retrospective studies have reported conflicting results regarding teratogenic risk. OBJECTIVE: To evaluate pregnancy and fetal outcome following maternal occupational exposure to organic solvents. DESIGN: A prospective, observational, controlled study. SETTING: An antenatal counseling service in Toronto, Ontario. PATIENTS: One hundred twenty-five pregnant-women who were exposed occupationally to organic solvents and seen during the first trimester between 1987 and 1996. Each pregnant woman who was exposed to organic solvents was matched to a pregnant woman who was exposed to a nonteratogenic agent on age (+/-4 years), gravidity (+/-1), and smoking and drinking status. MAIN OUTCOME MEASURE: Occurrence of major congenital malformations. RESULTS: Significantly more major malformations occurred among fetuses of women exposed to organic solvents than controls (13 vs 1; relative risk, 13.0; 95% confidence interval, 1.8-99.5). Twelve malformations occurred among the 75 women who had symptoms temporally associated with their exposure, while none occurred among 43 asymptomatic exposed women (P<.001). (One malformation occurred in a woman for whom such information was missing.) More of these exposed women had previous miscarriage while working with organic solvents than controls (54/117 [46.2%] vs 24/125 [19.2%]; P<.001). However, exposed women who had a previous miscarriage had rates of major malformation that were similar to exposed women who had no previous miscarriage. CONCLUSIONS: Occupational exposure to organic solvents during pregnancy is associated with an increased risk of major fetal malformations. This risk appears to be increased among women who report symptoms associated with organic solvent exposure. Women's exposure to organic solvents should be minimized during pregnancy. Symptomatic exposure appears to predict higher fetal risk for malformations.

Abortion, Spontaneous↗
PubMedDate not supplied

The effect of chronic cocaine exposure throughout pregnancy on maternal and infant outcomes in the rhesus monkey.

To explore the effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were either treated (N = 10) with escalating doses of cocaine up to 7.5 mg/kg (IM), three times per day, 5 consecutive days per week, prior to conception and throughout gestation, or were not treated (N = 10) with cocaine at all. Substantial levels of both cocaine and its major metabolite, benzoylecgonine, were observed in samples of hair taken at birth from mothers and infants of the cocaine-treated group. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to maternal outcome, as measured by body weight again during pregnancy and length of pregnancy. On the other hand, the experimental groups did differ significantly with respect to infant outcome, as measured at birth by body weight, overall length, and crown circumference, all of which were decreased in the cocaine-treated group. A variety of reflexes tested at birth were normal in the cocaine-treated group. It was concluded that, in a rhesus monkey model, chronic cocaine exposure throughout pregnancy had no significant effect on maternal outcome, but did significantly affect infant outcome as assessed in this investigation.

Animals↗