Neuromuscular blocking actions of the aminoglycoside antibiotics sisomicin and micronomicin in the rabbit.

The neuromuscular blocking actions of sisomicin sulfate (SISO), micronomicin sulfate (MCR) and d-tubocurarine (dTc) were studied in 20 rabbits anesthetized with halothane. The i.v. administration of SISO 20-40 mg/kg, MCR 40-80 mg/kg or dTc 0.1-0.3 mg/kg resulted in dose-dependent decreases in twitch tension. The ED50s for SISO, MCR and dTc were 23.5, 58.2 and 0.2 mg/kg, respectively. SISO- and MCR-induced neuromuscular blockade was partially antagonized by neostigmine or by calcium.

[Effect of ethyl ether of apovincaminic acid (Cavinton) on the ototoxic action of sisomicin in guinea pigs]. / Wplyw estru etylowego kwasu apowinkaminowego (cavintonu) na efekt ototoksyczny sisomycyny u swinek morskich.

The aim of this work was to evaluate the protective effect of etyl ether of apovincaminic acid (Cavinton) against the ototoxic effect of sisomycin in the experimental condition. The first group of guinea pigs were given 14 days sisomycin. The second sisomycin and cavinton. The third was the control group. Hearing acuity was tested by the shivering audiometry. The spiral ganglion function was tested by the microphonic potentials and the integrity of cochlea was diagnosed by scanning microscopy. The results pointed out the ototoxicity of sisomycin. There were the deterioration of hearing acuity, lowering of microphonic potentials and degenerative changes in spiral ganglion. The damages were lowered by use of cavinton before the administration of sisomycin.

[Biochemical characteristics of the determinants of drug resistance to gentamycin from clinical strains of gram-negative microorganisms]. / Biokhimicheskaia kharakteristika determinantov lekarstvennoi ustoichivosti k gentamitsinu iz klinichekikh shtammov gramotritsatel'nykh mikroorganizmov.

Three to four aminoglycoside inactivating enzymes were detected in cell-free extracts of clinical strains of gram-negative bacteria including Pseudomonas, Escherichia, Serratia, Enterobacter and Klebsiella and in cell-free extracts of their transconjugants. The clinical strains were selected by the feature of gentamicin resistance. All the strains contained AAC(3), APH(3') and APH(3"). In addition to these enzymes 12 out of 25 investigated strains contained AAD(2"). The biochemical characteristics of the gentamicin resistance determinant cloned from the clinical strains on the plasmid vector pUC 19 were studied. By the size of the insertion element pAA4 was the smallest among the constructed hybrid plasmids determining gentamicin resistance. It was shown that just this plasmid determined formation of the two gentamicin inactivating enzymes: AAC(3) and AAD(2") in the transformants carrying it.

[Decrease of sisomicin nephrotoxicity as affected by cephalothin: pharmacokinetic evaluation]. / Oslablenie nefrotoksichnosti sizomitsina pod vliianiem tsefalotina: popytka farmakokineticheskogo ob'iasneniia.

The effect of cephalothin on the nephrotoxicity and pharmacokinetics of sisomicin was studied on Wistar rats. Sisomicin was injected intramuscularly in doses of 12.5 and 25 mg/kg alone or in combination with cephalothin in a dose of 360 mg/kg once a day for 16 days. It was shown that the combined use of sisomicin and cephalothin resulted in less pronounced functional and morphological changes in the kidneys as compared to the use of sisomicin alone. The decrease in the nephrotoxic effect was accompanied by a decrease in the sisomicin concentration in the blood serum and the site of the nephrotoxic effect (the kidney cortical layer) and the period of the aminoglycoside half-life in the kidney cortical layer under the action of cephalothin. The analysis of the relation between the nephrotoxic effect and the concentration of sisomicin in the kidney cortical layer and blood serum demonstrates that the nephrotoxicity of the sisomicin combination with cephalothin is mainly due to a decrease in the aminoglycoside concentration in the zone of the nephrotoxic effect.

Interactions between mezlocillin and sisomicin in vitro and in patients with normal and various degrees of impaired renal function.

During in vitro experiments using pooled human plasma at 37 degrees C, sisomicin alone showed only a small loss of activity of 12% in 24 hr. Incubation with 80 micrograms/ml mezlocillin did not alter the rate of inactivation. But, after the addition of 300 micrograms/ml mezlocillin to either 5.0 or 2.5 micrograms/ml sisomicin, the sisomicin half-life was reduced by 50% and 100% respectively. When the mean drug concentration ratios are compared, inactivation of sisomicin by mezlocillin was significantly less than that reported for carbenicillin or ticarcillin. Sisomicin pharmacokinetics were studied in 27 patients with normal and various degrees of impaired renal function (Part A) and were not changed by the simultaneous administration of mezlocillin 60 mg/kg (Part B). Furthermore, even in far advanced renal insufficiency, sisomicin inactivation by mezlocillin could not be demonstrated. The differing results obtained with mezlocillin compared to carbenicillin or ticarcillin might be explained by differences in the physico-chemical properties of the drugs in addition to the different kinetic behavior of mezlocillin in patients with impaired renal function.

Effects of two new aminoglycoside antibiotics on the rat sciatic nerve-gastrocnemius muscle preparation.

2'-Amino-2'-deoxy-kanamycin (bekanamycin, Kanendomycin) and pentisomicin displayed a neuromuscular blocking activity on the rat sciatic nerve-gastrocnemius muscle preparation. Pentisomicin showed the highest neuromuscular blocking effect; the neuromuscular blocking potency of bekanamycin was similar to that of tobramycin, another new aminoglycoside. The neuromuscular block produced by these antibiotics was reversed by calcium chloride whereas it was not influenced by neostigmine methylsulfate.

[Sisomicin. The mechanism of admixture inactivation and formation]. / Sizmotisin. K. voprosu o mekhanizme inaktivatsii i obrazovaniia primesei.

Inactivation of sisomicin in aqueous solutions was studied under various conditions. At pH 4-10 and a temperature of 60 degrees C the inactivation rate constant was equal to (5-10) X 10(-5) hour-1 and remained stable. At lower pH values the inactivation rate constant increased: 5.5 10(-3) (60 degrees C) at pH 0.5. The activation energy of the inactivation reaction was 27 (pH 0.5) and 32 (pH 4.0) kcal/mol. The study on the behaviour of sisomicin in solutions with different pH values under the environmental conditions and in the atmosphere of nitrogen showed that at low pH values the inactivation was mainly determined by hydrolysis of the glycoside bond. Formation of coloured compounds did not include the oxidation reaction. At pH about 7.0 oxidation of the antibiotic or of the products of its degradation with respect to the double bond played a significant role in the inactivation and formation of the coloured substances.