Long term treatment of ventricular arrhythmias with oral mexiletine.
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Biomedical subjects
Publications and source records attributed to L F Prescott.
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60 patients with paracetamol poisoning have been treated with intravenous cysteamine, L-methionine, or D-penicillamine and the incidence and severity of hepatic necrosis compared with those observed in 70 patients receiving supportive therapy only. Of 31 patients with 4-hour plasma-paracetamol concentrations greater than 250 mug/ml given supportive therapy 22 sustained severe liver damage, 3 died in hepatic failure, and 4 developed acute renal failure. None of 23 similarly poisoned patients given cysteamine within 10 hours of ingestion suffered severe liver damage or renal failure and none died. Cysteamine was partially effective at 10-12 hours, but ineffective 12 hours or more after ingestion. Liver damage was absent or mild in 17 patients given L-methionine within 10-12 hours of ingestion but severe in 3 treated within 10 hours. Of 5 patients treated with D-penicillamine, 1 developed severe liver damage with acute renal failure. It is concluded that cysteamine prevents severe liver damage after paracetamol poisoning if given within 10 hours in adequate dosage.
Plasma concentrations of lignocaine were measured during and after infusion of lignocaine at 1.4 mg/min for 36-46 hours in 12 patients with myocardial infarction and one patient with cardiac failure due to uncontrolled ventricular tachycardia. In six patients without cardiac failure the plasma concentrations of lignocaine rose progressively during the infusion and the mean lignocaine half life was 4.3 hours compared with 1.4 hours in healthy subjects. Mean plasma lignocaine concentrations were significantly higher in seven patients with cardiac failure, and concentrations also rose during the infusion and the half life was considerably prolonged to 10.2 hours. Lignocaine concentrations rose rapidly to toxic levels when cardiogenic shock developed in one patient and did not fall when the infusion was stopped. The mean plasma antipyrine half life was moderately prolonged (19.4 hours) in a larger group of patients with myocardial infarction and cardiac failure but returned to normal during convalescence (13.2 hours). The metabolism of lignocaine is grossly abnormal in patients with cardiac failure and cardiogenic shock after myocardial infarction.
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Twenty-four patients with ventricular arrhythmias were treated with oral mexiletine for periods of from one to 16 months (total 10.4 patient-years). In 19 patients arrhythmias were satisfactorily controlled and plasma levels previously shown to be within the therapeutic range were maintained on an 8 hourly regimen. The drug was well tolerated in most patients and regular hematological and biochemical screening revealed no problems of toxicity.
Compartmental analysis of plasma paracetamol concentrations following intravenous injection of 12 mg kg-1 in aqueous solution to normal subjects was performed using analogue and digital computer methods. Using a "simplex" non-linear optimization procedure, the pharmacokinetic parameters were found to be influenced considerably by the choice of the weighting factors (W1) attributed to individual data points. The plasma half-life of paracetamol varied by up to a seven-fold with the weighting factors selected. However, the predicted mean steady-state plasma concentrations were shown to be relatively little affected by the different weighting factors.
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The incidence of ventricular arrhythmias after myocardial infarction has been compared in a controlled study of procainamide, mexiletine, and placebo. Sixty male patients who has sustained a myocardial infarction and had received lignocaine for ventricular tachycardia or ventricular ectopic beats which were R-on-T, multiform, or close-coupled took part. The efficacy of the drugs was evaluated by continuous 24-hour recordings of the electrocardiogram on the 4th and 10th days after admission to the study. Procainamide was given as 500 mg. 4-hourly and mexiletine as 250 mg. 8-hourly with corresponding placebo regimens for 12 days. 77% of patients receiving placebo showed serious ventricular rhythm disorders compared with 33% receiving antiarrhythmic therapy (p smaller than 0.05). Although only 35% of patients receiving procainamide achieved accepted therapeutic plasma concentrations compared with 95% of those receiving mexiletine, both drugs were equally effective antiarrhythmically. The only major adverse effect of therapy noted was development of a positive antinuclear factor in a procainamide-treated patient. These results demonstrate the efficacy of oral antiarrhythmic agents in the management of ventricular arrhythmias after acute myocardial infarction. Mexiletine has the advantage of less frequent administration and lower toxicity.
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The rate of gastric emptying in women during labour was estimated indirectly from the kinetics of absorption of orally administered paracetamol (acetaminophen). Gastric emptying was normal in patients who had not received a narcotic analgesic but was markedly delayed in women given pethidine, diamorphine, or pentazocine. The inhibitory effect of diamorphine and pethidine on gastric emptying was not reversed by metoclopramide.
The effect of intramuscular pethidine or diamorphine on gastric emptying and the absorption of orally administered paracetamol was assessed in eight normal subjects. 2 Both drugs produced a significant and striking delay in gastric emptying and absorption of paracetamol. 3 It seems inevitable that pethidine and diamorphine will retard the absorption of other orally administered drugs.
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Drug-metabolizing capacity has been assessed by serial measurements of the plasma antipyrine half life in 11 patients with severe barbiturate intoxication and in 17 patients with acute hepatic necrosis due to paracetamol overdosage. Drug metabolism was strikingly enhanced after barbiturate over-dosage, and this effect was still present six weeks later. In contrast the antipyrine half life was greatly prolonged in patients with paracetamol-induced acute hepatic necrosis but returned to normal or near-normal values within seven to 21 days.