Several (+)- and (-)-α-pinene derivatives were synthesized and evaluated for their antimicrobial activity toward Gram-positive bacteria Micrococcus luteus and Staphylococcus aureus, Gram-negative bacterium Escherichia coli, and the unicellular fungus Candida albicans using bioautographic assays. (+)-α-Pinene 1a showed modest activity against the test organisms, whereas (-)-α-pinene 1b showed no activity at the tested concentration. Of all the α-pinene derivatives evaluated, the β-lactam derivatives (10a and 10b) were the most antimicrobial. The increase in the antimicrobial activity of 10a compared to 1a ranged from nearly 3.5-fold (C. albicans) to 43-fold (S. aureus). The mean ± standard deviation for the zone of inhibition (mm) for 10a (C. albicans) was 31.9 ± 4.3 and that for S. aureus was 51.1 ± 2.9. Although (-)-α-pinene 1b was not active toward the test microorganisms, the corresponding β-lactam 10b, amino ester 13b, and amino alcohol 14b showed antimicrobial activity toward the test microorganisms. The increase in the antimicrobial activity of 10b compared to 1b ranged from 32-fold (S. aureus) to 73-fold (M. luteus). The mean ± standard deviation for the zone of inhibition (mm) for 10b (S. aureus) was 32.0 ± 0.60 and that for M. luteus was 73.2 ± 0.30.
Efavirenz induces the metabolism of co-administered drugs through the induction of CYP A4. It is often necessary to switch fron efavirenz to nevirapine because of intolerance or toxicity. In a pharmacokinetic study we determined whether to dose-escalate nevirapine or start the full dose when switching from efavirenz. It was found that when changing from efavirenz to nevirapine individuals should commence on 200 mg twice a day, as this dose is associated with therapeutic plasma drug levels.
Enoximone and enoximone sulphoxide concentrations were measured in plasma of 20 infants, median age 6.0 (range 0.6-49.7) weeks, during and after prolonged continuous infusions. Patients were given enoximone 1 mg kg-1 and an infusion at 10 micrograms kg-1 min-1 just before being weaned from cardiopulmonary bypass (CPB). The infusion was stopped when clinically indicated, after a median 97 (range 24-572) h. Arterial blood samples were taken 30 min and 12 h after CPB, every 24 h during the infusion, and then 2, 4, 8, 12 and 24 h after the infusion was stopped. Pharmacokinetic non-compartmental analysis was performed using TOPFIT software. Fourteen patients who retained normal hepatic function had a median (95% confidence intervals) clearance of 9.7 (6.3-14.1) ml min-1 kg-1, elimination half-life of 5.2 (2.4-6.8) h and a volume of distribution of 3.6 (2.0-5.7) litre kg-1. The six patients with significant hepatic dysfunction had a lower clearance, 5.7 (2.4-14.5) ml min-1 kg-1, and significantly longer elimination half-life, 7.6 (6.5-10.9) h (P = 0.02). Enoximone sulphoxide elimination half-life was significantly prolonged in three patients with renal dysfunction, 16.2 (10.5-17.7) h versus 6.9 (6.1-9.4) h (P = 0.03). These results confirm that enoximone pharmacokinetics in infants is similar to that found in adults. The infusion rate of enoximone should be reduced if hepatic or renal dysfunction supervenes.
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