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Biomedical subjects

L F Prescott

Publications and source records attributed to L F Prescott.

At least 73 records · Page 4Linked to original sources
PubMed1985

Death and blindness due to overdose of quinine.

During 1953-83 there were 48 admissions to the regional poisoning treatment centre, Edinburgh, for overdose of quinine including 19 since 1978. Six patients were blind and one had ventricular tachycardia. Stellate ganglion block was performed without benefit in seven patients. No patient died, but three deaths from cardiotoxicity occurred in a further 71 patients reported to the Scottish Poisons Information Bureau. Plasma quinine concentration related to time from ingestion was found to be a useful predictor of visual toxicity.

Adolescent↗
PubMed1985

Drugs prescribed for self poisoners.

Of 230 adults admitted for self poisoning over two months, 153 (67%) had previously been taking a total of 309 prescribed drugs. Of these patients, 119 (78%) had been given psychotropic drugs (usually benzodiazepines), 81 (53%) obtained them on repeat prescription, and 47 (31%) had been prescribed multiple psychotropic drugs, often in seemingly illogical combinations. The use of these drugs increased progressively with age and most patients took the same drugs in overdosage as they had been prescribed. Psychotropic drugs were prescribed for more than a third of patients with no psychiatric illness and a normal personality, nearly half of those with existing alcohol or drug abuse problems, and for most of the unemployed. Fewer than a third of the patients suffering from depression were prescribed antidepressants but half had been given benzodiazepines and other potentially depressing drugs. Psychotropic drug use, psychotropic polypharmacy, and the repeat prescribing of these drugs were strongly associated with repeated overdosage and, under certain circumstances, with personality disorder, alcohol or drug abuse, unemployment, and conflict with the law. In the long term psychotropic drugs are unlikely to benefit most self poisoners, and they may do positive harm by inducing apathy and depression and predisposing to self poisoning. The incidence of self poisoning (and repeat overdosage in particular) might be reduced by more care and restraint in the prescribing of these drugs.

Adolescent↗
PubMed1985

Pharmacokinetics and clinical toxicity of quinine overdosage: lack of efficacy of techniques intended to enhance elimination.

We report clinical details in 16 cases of quinine poisoning. Plasma quinine concentrations above 15 mg/l were associated with increased risks of permanent visual damage and of cardiac arrhythmias from which one of our patients died. The rate of quinine elimination was not significantly altered by forced acid diuresis in five patients (t 1/2 25.1 +/- SEM 4.6 h) as compared to eight patients treated conservatively (t 1/2 26.5 +/- SEM 5.78 h). Neither urinary pH or flow rate correlated consistently with urinary quinine clearance. In three other patients charcoal column haemoperfusion, haemodialysis and exchange transfusion were performed. These were also ineffective in increasing quinine elimination. It is concluded that techniques advocated to increase quinine elimination are ineffective in the management of quinine poisoning.

Adolescent↗
PubMed1984

Drug conjugation in clinical toxicology.

Conjugation is an important mechanism for the rapid inactivation and extensive removal of drugs and poisons from the body, and as such it is of major significance in clinical toxicology. The capacity for conjugation of some drugs is large, but with others, saturation may occur with overdosage or even high therapeutic doses. Glutathione conjugation is an important mechanism of protection against toxicity produced by heavy metals, alkylating agents and some compounds which undergo metabolic activation.

Adult↗
PubMed1984

Paracetamol metabolites in the neonate following maternal overdose.

A case of paracetamol overdose in a 36 week pregnant woman is described. The baby was delivered by Caesarian section 6 h after the overdose. The mother but not the baby was treated with N-acetylcysteine and neither suffered liver damage. The plasma paracetamol half-life was prolonged to 10 h in the neonate compared to 2.5 h in the mother and was unaffected by a two volume exchange transfusion. The pattern of urinary metabolites in the neonate was similar to that observed in the mother, but there was a marked delay in the time taken to reach peak plasma concentrations of metabolites. This is consistent with a very slow biotransformation of the drug and may explain the relative resistance of very young children to the hepatotoxicity of paracetamol. There was no evidence of limited or decreasing capacity in sulphate conjugation nor was sulphation the major metabolic pathway. In retrospect both the obstetrical intervention and the exchange transfusion were unnecessary.

Acetaminophen↗
PubMed1984

The role of sulphate conjugation in the metabolism and disposition of oral and intravenous paracetamol in man.

The effects of paracetamol dose (5 and 20 mg/kg) and route of administration (intravenous and oral) on the urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were studied in five healthy subjects. The fractional urinary excretion of unchanged paracetamol and its conjugates was independent of the route of administration at both dose levels, suggesting that the gastrointestinal tract is not an important site for paracetamol metabolism. The percentage of the dose excreted as the sulphate conjugate was significantly higher after 5 than after 20 mg/kg (37.7% and 33.3% respectively) and this is consistent with saturation of sulphate conjugation. No significant effect of paracetamol dose upon the area under the plasma concentration-time curve (AUC), corrected for dose, was found for the sulphate or glucuronide conjugates. The total plasma clearance of paracetamol and the renal clearance of the sulphate conjugate were significantly higher after the 5 than the 20 mg/kg dose (331 +/- 42 ml/min and 295 +/- 48 ml/min; 273 +/- 74 ml/min and 205 +/- 46 ml/min respectively). The oral systemic availability of paracetamol was 80% and independent of dose.

Acetaminophen↗
PubMed1984

Clinical features and management of analgesic poisoning.

Analgesic poisoning is a common medical emergency, and these drugs account for about 30% of self-poisoning in adults. Aspirin and paracetamol are taken most often, and can cause significant morbidity and mortality. However, problems with the hepatotoxicity of paracetamol have been greatly reduced by the introduction of effective treatment with agents such as N-acetylcysteine. The non-steroidal anti-inflammatory analgesics are not commonly taken in overdosage but the incidence of self-poisoning with mefenamic acid is increasing at an alarming rate. With the exception of phenylbutazone and mefenamic acid these drugs rarely seem to cause serious toxicity. The narcotic analgesics can cause profound respiratory depression and are the most dangerous drugs in overdosage.

Acetaminophen↗
PubMed1983

Drug interactions affecting analgesic toxicity.

Most reports of interactions involving analgesics deal with their effects on the actions of other drugs rather than vice versa. Aspirin and ethanol have synergistic effects on the development of gastritis, gastrointestinal bleeding, and chronic gastric ulcer. This must be the most common and most important interaction affecting analgesic toxicity. Combined overdosage of aspirin with central nervous system depressants may be particularly hazardous because suppression of the salicylate-induced respiratory stimulation further shifts the disordered acid-base balance towards acidosis. The toxicity of acetaminophen (paracetamol) depends primarily on the balance between the rate of formation of the hepatotoxic metabolite and the rate of glutathione synthesis in the liver. In animals, prolonged pretreatment with ethanol increases the metabolic activation and acute toxicity of acetaminophen, and there is some evidence that chronic alcoholics are more susceptible to hepatotoxicity following acute overdosage. It has been assumed that this sensitivity in chronic alcoholics is due to microsomal enzyme induction with enhanced metabolic activation of acetaminophen. However, the metabolic activation of acetaminophen, as judged by the urinary excretion of its cysteine and mercapturic acid conjugates, is not increased in heavy drinkers or in patients induced by long-term treatment with anticonvulsants or rifampicin. Microsomal enzyme induction is complex. There are important species differences and different agents may selectively induce different variants of the multiple forms of cytochrome P-450. The acute administration of ethanol greatly reduces the metabolic activation of acetaminophen in heavy drinkers with more than a 50 percent decrease in cysteine and mercapturic acid conjugate production. Thus ingestion of ethanol should reduce the risk of liver damage following acetaminophen overdosage. Cimetidine, which inhibits the oxidative metabolism of some drugs, reduces the hepatotoxicity and increases the dose of acetaminophen in mice required to kill 50 percent of the animals. However, contrary to expectations, cimetidine does not inhibit the oxidative metabolism of acetaminophen in man. Salicylamide competes with acetaminophen for sulphate conjugation but is unlikely to potentiate toxicity following overdosage since sulphate conjugation is rapidly saturated anyway. Animal studies suggest that the hepatotoxicity of acetaminophen after overdosage may be increased by other agents which deplete glutathione, but there is no information on this point in man.

Acetaminophen↗
PubMed1983

The ventilatory effects of doxapram in normal man.

1. To determine the mode of action of doxapram in man we have measured ventilation, oxygen uptake, CO2 production, hypoxic and hypercapnic ventilatory responses in six healthy men before and during intravenous infusion to maintain a constant plasma level. 2. Doxapram changed neither resting oxygen uptake nor CO2 production but produced a substantial increase in resting ventilation at both levels of end-tidal CO2 studied. 3. Doxapram increased the ventilatory response to isocapnic hypoxia from -0.8 +/- 0.4 litre min-1 (%SaO2)-1 to -1.63 +/- 0.9 litres min-1 (%SaO2)-1. This was similar to the increase in hypoxic sensitivity which resulted from raising the end-tidal CO2 by 0.5 kPa without adding doxapram. 4. The slope of the ventilatory response to rebreathing CO2 rose from 11.6 +/- 5.3 litres min-1 kPa-1 to 20.4 +/- 9.8 litres min-1 kPa-1 during doxapram infusion. 5. The marked increase in the ventilatory response to CO2 implies that doxapram has a central action, but the potentiation of the hypoxic drive also suggests that the drug acts on peripheral chemoreceptors, or upon their central connections, at therapeutic concentrations in normal unanaesthetized subjects.

Adult↗
PubMed1983

Mexiletine disposition: individual variation in response to urine acidification and alkalinisation.

The disposition of mexiletine has been studied in five subjects on two occasions with urine pH controlled at 5.0 and at 8.0. With acid urine total plasma clearance was similar in all subjects (462 to 497 ml min-1) and the plasma half-life ranged from 3.8 to 9.2 h (mean 6.7 h). With alkaline urine the total plasma clearance varied considerably (239 to 441 ml min-1); the mean half-life, 9.7 h, (range 7.6 to 12.7 h) was not significantly different from that in the acid urine study. Renal clearance fell greatly in every subject on alkalinisation of the urine. The total plasma clearance fell by a similar amount in two. In the remaining three the fall in total clearance was much smaller because of an increase in non-renal clearance. The reduction in total plasma clearance only just achieved statistical significance. The increase in predicted steady-state plasma mexiletine concentrations during infusion with change in urine pH from 5 to 8 varied between +5% and +95% (mean +39%). Changes in urine pH have a predictable effect upon renal clearance of mexiletine. However, disposition is changed in an unpredictable manner and inter-subject variation in distribution volume and non-renal clearance are important factors.

Adult↗
PubMed1983

The treatment of acetaminophen poisoning.

Acetaminophen has become a very popular over-the-counter analgesic in some countries and as a result it is used increasingly as an agent for self-poisoning. Without treatment only a minority of patients develop severe liver damage and 1 to 2% die in hepatic failure. Until Mitchell and his colleagues discovered the biochemical mechanisms of toxicity in 1973 there was no effective treatment. They showed that the metabolic activation of acetaminophen resulted in the formation of a reactive arylating intermediate, and that hepatic reduced glutathione played an essential protective role by preferential conjugation and inactivation of the metabolite. Early treatment with sulphydryl compounds and glutathione precursors has been dramatically effective in preventing liver damage, renal failure, and death following acetaminophen overdosage. It seems likely that these agents act primarily by stimulating glutathione synthesis. Inhibition of the metabolic activation of acetaminophen is another potential therapeutic approach that has not yet been put to the test clinically. The clinical management of acetaminophen poisoning has been transformed and it is particularly gratifying to have effective treatment based on a well established biochemical mechanism of toxicity. It is likely that effective treatment will be developed for toxicity caused through similar mechanisms by other agents.

Acetaminophen↗