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Plasma levels of lidocaine were measured in 5 normal male volunteers following both intravenous and oral administration of the drug. Each subject received a constant-rate intravenous infusion lasting for 60 minutes and an exponential intravenous infusion which allowed administration of the drug at an ever-decreasing rate having a half-life of 50 minutes.In each case the total dose of lidocaine was 250 mg. The subjects also received a 250 mg. and a 500 mg. oral dose administered in tablet form. The plasma level data were subjected to pharmacokinetic analysis with the use of a two-compartment open model to describe the lidocaine disposition. These calculations suggest that approximately 5 to 7 hours of constant intravenous infusion would be required to approach steady-state plasma levels in human subfects. The plasma level data after oral administration indicate that approximately 35 per cent of the 250 and 500 mg. oral doses reached the systemic circulation. Subfective symptoms typical of lidocaine were noted in some cases after the 500 mg. oral doses. Since these symptoms were noted when the blood levels of lidocaine were lower than those following intravenous administration, it is suggested that they may, in part, be due to a metabolite formed during the first passage of the drug through the liver.

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The cytochrome P450 superfamily of enzymes is of enormous interest in the biological sciences due to the wide range of endogenous and xenobiotic compounds which it metabolises, including many drugs. We describe the use of first principles quantum mechanical modeling techniques, based on density functional theory, to determine the outcome of interactions between an enzyme and a number of compounds. Specifically, we calculate the spin state of an Fe 3ϩ ion present in a haem moiety at the active site of these enzymes. The spin state of this ion indicates if the catalytic reaction will proceed. The computational results obtained compare favorably with experimental data. Only the principle components of the active site of the enzyme are included in the computational models, demonstrating that only a small fragment of the protein needs to be included in the models in order to accurately reproduce this aspect of the enzymes' function. These results open the way for further investigation of this superfamily of enzymes using the methods detailed in this paper.

The haemodynamic effects of prenalterol, a new selective beta-1 adrenoreceptor agonist, have been studied in patients with coronary heart disease. The drug was administered intravenously in a dosage of 0.5 to 2.5 micrograms/kg body weight to 20 patients undergoing coronary angiography and to 10 patients with a recent myocardial infarction, who had clinical evidence of left ventricular dysfunction. Left ventricular performance was enhanced in both groups of patients--left ventricular dP/dt (max) increased by 33 per cent and the systolic time intervals, pre-ejection period, and the ratio of pre-ejection period and left ventricular ejection shortened by 28 and 21 per cent, respectively. Cardiac output and stroke volume increased with no change in heart rate nor in left ventricular filling pressure. These results indicate that prenalterol enhances the contractile state of the myocardium without altering heart rate, and suggest that prenalterol could be of value in the management of patients with coronary heart disease, who have impaired left ventricular function.