The general pharmacology of buprenorphine, a potent analgesic agent derived from oripavine, is described. 2 After acute administration of buprenorphine, the spontaneous locomotor activity of mice was increased; rats displayed stereotyped licking and biting movements; behavioural depresssion was marked in guinea-pigs but mild in rhesus monkeys. The behaviour of cats was unchanged. 3 In general, buprenorphine reduced heart rate but had no significant effect on arterial blood pressure in conscious rats and dogs. 4In anaesthetized, open-chest cats buprenorphine (0.10 and 1.0 mg/kg, i.v.) caused no major haemodynamic changes. 5 Buprenorphine (0.01-10 mg/kg, i.a.) and morphine (0.30-30 mg/kg, i.a.) increased arterial Pco2 values and reduced P02 values in conscious rats. With doses of buprenorphine greater than 0.10 mg/kg (a) the duration of respiratory depression became less, (b) ceiling effects occurred such that the maximum effects produced were less than those obtained with morphine. 6 Buprenorphine was a potent and long-lasting antagonist of citric acid-induced coughing in guineapigs.7 At a dose level 20 times greater than the ED50 for antinociception (tail pressure), morphine suppressed urine output to a greater extent than the corresponding dose of buprenorphine in rats. 8 Over the range 0.01-1.0 mg/kg (s.c.), buprenorphine slowed the passage of a charcoal meal along the gastrointestinal tract in rats. After doses in excess of I mg/kg, the meal travelled increasingly further such that the distances measured after 10 and 30 mg/kg did not differ significantly from control values. In contrast, the morphine dose-response relationship was linear.

β-Lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) contribute significantly to the longevity of the β-lactam antibiotics used to treat serious infections. In the quest to design more potent compounds and to understand the mechanism of action of known inhibitors, 6β-(hydroxymethyl)penicillanic acid sulfone (6β-HM-sulfone) was tested against isolates expressing the class A TEM-1 β-lactamase and a clinically important variant of the AmpC cephalosporinase of Pseudomonas aeruginosa, PDC-3. The addition of the 6β-HM-sulfone inhibitor to ampicillin was highly effective. 6β-HM-sulfone inhibited TEM-1 with an IC50 of 12 ± 2 nM and PDC-3 with an IC50 of 180 ± 36 nM, and displayed lower partition ratios than commercial inhibitors, with partition ratios (kcat/kinact) equal to 174 for TEM-1 and 4 for PDC-3. Measured for 20 h, 6β-HM-sulfone demonstrated rapid, first-order inactivation kinetics with the extent of inactivation being related to the concentration of inhibitor for both TEM-1 and PDC-3. Using mass spectrometry to gain insight into the intermediates of inactivation of this inhibitor, 6β-HM-sulfone was found to form a major adduct of +247 ± 5 Da with TEM-1 and +245 ± 5 Da with PDC-3, suggesting that the covalently bound, hydrolytically stabilized acyl-enzyme has lost a molecule of water (H–O–H). Minor adducts of +88 ± 5 Da with TEM-1 and +85 ± 5 Da with PDC-3 revealed that fragmentation of the covalent adduct can result but appeared to occur slowly with both enzymes. 6β-HM-sulfone is an effective and versatile β-lactamase inhibitor of representative class A and C enzymes.

No abstract

No abstract

No abstract