Interaction of aminoglycoside antibiotics and calcium channel blockers at the neuromuscular junctions.

Aminoglycoside antibiotics (mmol.l-1) gentamicin (0.74), streptomycin (1.02), netilmicin (1.24), amikacin (2.23), sisomicin (2.74), dactimicin (2.75), kanamycin (3.43), kanendomycin (3.45), tobramycin (3.53) and dibekacin (4.35) produce a complete neuromuscular blockade at the isolated phrenic nerve-hemidiaphragm preparation of the rat, which is only reversed by calcium chloride. On the other hand, verapamil (2.04 mmol.l-1), a calcium channel blocker, also produces a complete neuromuscular blockade at the above preparation which is reversed by calcium chloride. Aminoglycoside antibiotics are potentially capable of interacting with verapamil and produce a complete neuromuscular blockade at concentrations significantly reduced. The neuromuscular blockade which is produced by the concurrent administration of the aminoglycoside antibiotics and verapamil is obtained with the usual therapeutic blood concentrations of the individual agents. Furthermore, the neuromuscular blockade which is produced during verapamil-aminoglycoside antibiotics interactions is completely reversed after calcium chloride administration. The mechanism by which aminoglycoside antibiotics and verapamil produce neuromuscular blockade must be the same. Both classes of drugs interfere with calcium ions movements through the calcium channels of the membrane of the motor nerve-endings inhibiting acetylcholine release at the synaptic cleft. The interaction of aminoglycoside antibiotics and calcium channel blockers is of clinical significance because when these agents are given concurrently during the perioperative period they may lead to respiratory depression or prolonged apnoea. These respiratory disturbances can be managed by slow intravenous infusion of 50 to 200 mg of calcium gluconate.

Aminoglycoside antibiotics: interaction with trimethaphan at the neuromuscular junctions.

Trimethaphan, a ganglionic blocking agent which is administered by intravenous drip to produce controlled hypotension during surgery, produces a complete neuromuscular blockade at the isolated phrenic nerve-hemidiaphragm preparation of the rat at a concentration of 0.3 mmol X l-1. This blockade is not reversed by neostigmine, a cholinesterase inhibitor, nor by calcium chloride, and this action is attributed to the local anaesthetic activity of the drug. Trimethaphan (1.5 X 10(-2) mmol X l-1) interacts with the following aminoglycoside antibiotics: gentamicin (0.04), streptomycin (0.05), netilmicin (0.06), amikacin (0.11), sisomicin (0.14), kanamycin (0.17), tobramycin (0.18) and dibekacin (0.21 mmol X l-1) to produce a complete neuromuscular blockade. These pharmacodynamic interactions of trimethaphan and aminoglycoside antibiotics occur at significantly reduced concentrations of the interacting drugs which are very close to the ones obtained after administration of therapeutic doses. When trimethaphan or aminoglycoside antibiotics are used alone at the above reduced concentrations they do not exert any neuromuscular blocking activity. The neuromuscular blockade which is obtained after the interaction of trimethaphan with aminoglycoside antibiotics is not reversed by either neostigmine or calcium chloride, although the neuromuscular blockade which is produced by aminoglycoside antibiotics alone is reversed by calcium chloride. It is concluded that the local anaesthetic effect of trimethaphan is the predominant factor of the mechanism of the above interactions. These interactions may produce severe respiratory disturbances (respiratory depression or apnoea) to the patients, during the perioperative period, which can be reversed only with artificial ventilation.

Comparative in vitro activity of aztreonam and other antimicrobial agents against Salmonella species.

The in vitro activity of aztreonam, the first monobactam antibiotic, was compared with that of 17 other antimicrobial agents against 79 strains of Salmonella species. The microorganisms were isolated from hospitalized patients, surface waters and seafoods during the decade 1975-1984. They included the following species: Salmonella typhi 63, Salmonella typhimurium 5, Salmonella wien 5, Salmonella heidelberg 2, Salmonella arizonae 2, Salmonella paratyphi B 1 and Salmonella enteritidis 1. The minimum inhibitory concentration (MIC) values of the antibiotics were determined using a serial dilution method in agar. A final inoculum size of 10(5) colony-forming units (CFU) X ml-1 of the tested microorganisms was used. Aztreonam exhibited a superior antimicrobial activity to that of the other antibiotics tested. Aztreonam inhibited 90% of the strains by 0.8 micrograms X ml-1 (MIC range was 0.05 to 1.56 micrograms X ml-1). There was no major difference between minimum bactericidal concentration and MIC values of aztreonam and the effect of inoculum size upon MIC values was observed at 10(7) CFU X ml-1.

The influence of age on the distribution and activity of histamine receptors in the rat uterus.

In immature rat uterus histamine (10(-6) mol.l-1) potentiates by 25%, the carbachol (2 x 10(-6) mol.l-1) induced uterine contractions. This potentiation is abolished by mepyramine (6 x 10(-9) mol.l-1), an H1-receptor antagonist. Higher concentrations of histamine, up to 10(-4) mol.l-1, did not exert any inhibitory effect on carbachol-induced uterine contractions. In mature rat uterus carbachol-induced contractions are inhibited by histamine by about 25%. This inhibitory effect of histamine is significantly enhanced by mepyramine by about 50%. Inhibitory effects of higher concentrations of histamine, up to 10(-4) mol.l-1, are not enhanced by mepyramine. Cimetidine (4 x 10(-4) mol.l-1), an H2-receptor antagonist, abolished the inhibitory effects of histamine on carbachol-induced uterine contractions. In conclusion, in immature rat uterus there exists only H1 histamine receptors, activation of which exert an excitatory effect. In mature rat uterus there exists both H1 and H2 histamine receptors. The relaxant effect of histamine on mature rat uterus is exerted by activation of H2-receptors which predominate.

Antibacterial activity of aztreonam: a synthetic monobactam. A comparative study with thirteen other antibiotics.

The in vitro activity of aztreoman (SQ 26, 776), a new monocyclic beta-lactam antimicrobial agent, was determined against 1720 bacteria, all clinical isolates, and compared with that of thirteen beta-lactam and aminoglycoside antibiotics. Aztreonam inhibited 90% of Citrobacter diversus, Citrobacter freundii, Enterobacter agglomerans, E. coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, Proteus rettgeri, Proteus vulgaris and Salmonella sp. by less than or equal to 0.4 micrograms ml-1. This activity was superior to moxalactam, piperacillin, cefamandole, cefoperazone, cefoxitin, cefsulodin, ceftazidime and aminoglycoside antibiotics. Aztreonam was as active as moxalactam against Enterobacter aerogenes, Enterobacter cloacae and Shigella species. Pseudomonas aeruginosa strains resistant to moxalactam, piperacillin, cefamandole, cefoperazone, cefotaxime, cefoxitin, cefsulodin and ceftazidime were inhibited by aztreonam 50% by 6.3 micrograms ml-1 and 90% by 16 micrograms ml-1. Aztreonam was as active as ceftazidime against Serratia marcescens, all strains were inhibited by 3.1 micrograms ml-1 and 90% by 1.6 micrograms ml-1. There was no major difference between MBC and MIC values of aztreonam and the effect of inoculum size upon MIC values was observed at 10(7) CFU.