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V Nigrovic

Publications and source records attributed to V Nigrovic.

At least 37 records · Page 2Linked to original sources
PubMed1989

Generation of reactive metabolites during spontaneous degradation of atracurium in vitro.

The hypothesis was tested in vitro that the spontaneous degradation of atracurium leads to formation of electrophilic metabolites. Variable amounts of atracurium were incubated in saline (0.9% NaCl) for 120 minutes at pH 8.0 and 37 degrees C. Subsequently, cysteine was added to the incubation solutions and the incubation was continued at pH 7.4 and 37 degrees C. Frequent determination of the mercapto groups of cysteine revealed a progressive diminution of the mercapto groups remaining in the incubation solutions. The consumption of sulfhydryl groups was maximal at 20 minutes after the addition of cysteine and amounted to approximately twice the molar amount of atracurium. Kinetic analysis indicated that one mercapto group was consumed almost instantly, whereas the consumption of the other proceeded with a half-life of 4 minutes. No consumption of mercapto groups was observed when laudanosine was incubated with cysteine. Incubation of atracurium or of its degradation products with carboxylesterase markedly reduced the amount of reactive metabolites present in the incubation solutions. The results are compatible with the working hypothesis that spontaneous degradation of atracurium via Hofmann elimination results in generation of two equivalents of reactive electrophilic esters, probably acrylates. We propose that in vivo the portion of the aliphatic chain in the atracurium molecule that is converted to acrylates by Hofmann elimination may be eliminated in part in urine as a conjugate of mercapturic acid.

Atracurium↗
PubMed1987

Involvement of nucleophiles in the inactivation of atracurium.

Atracurium was incubated in 0.9% sodium chloride solution at pH 7.4 and 37 degrees C. The following compounds were added to the incubation solution: propionic acid, alanine and cysteine (0.1 mol litre-1 final concentration). Metocurine was also incubated with cysteine under identical conditions. Aliquots of the incubation solutions were injected i.v. to anaesthetized rats at the start (0 min) and at the end of incubation (45 min), and the indirectly elicited, single twitches of the gastrocnemius muscle were observed. Whereas inactivation of atracurium proceeded slowly in the control solution and in the presence of sodium propionate, the presence of alanine and, especially, of cysteine markedly enhanced the inactivation. Incubation of metocurine with cysteine did not alter the pharmacological responses. The concentration of cysteine decreased progressively during its incubation with atracurium (37 degrees C, pH 7.4). We conclude that the data are compatible with the postulate that a nucleophile may enhance the degradation of atracurium by a reaction with the parent compound (nucleophilic substitution reaction), by reaction with acrylates (Michael addition) or both.

Alanine↗
PubMed1987

Potentiation of atracurium toxicity in isolated rat hepatocytes by inhibition of its hydrolytic degradation pathway.

This study tested the hypothesis that the esters of acrylic acid might be responsible for the previously observed cytotoxic effect of atracurium. Rats were pretreated with triorthotolyl phosphate (TOTP), an inhibitor of the hydrolytic degradation of atracurium. Because hydrolysis of acrylates is also inhibited by TOTP and because the hydrolysis represents a detoxification pathway for these esters, we postulated that the leak of lactic dehydrogenase (LDH) induced by atracurium would be enhanced in hepatocytes harvested from rats pretreated with TOTP. Hepatocytes isolated from rats previously treated with TOTP (25 or 50 mg/kg intraperitoneally, 20 hr before induced death) were incubated for 4 hr in the absence of muscle relaxants or in the presence of either atracurium (0.008-0.8 mM) or metocurine (0.015-0.85 mM). Atracurium produced a concentration-dependent leakage of LDH. The leakage out of cells obtained from TOTP-pretreated rats was greater than was the leakage out of hepatocytes harvested from animals pretreated only with corn oil (a vehicle for TOTP). Metocurine did not produce a leak of LDH. It is concluded that the LDH leakage was produced by ester-type products of atracurium degradation. Acrylates appear to be the toxic agent.

Acrylates↗
PubMed1986

Comparative toxicity of atracurium and metocurine in isolated rat hepatocytes.

Primary cultures of liver cells isolated from seven rats were used to study the possible toxicity of atracurium and metocurine. The muscle relaxants were separately added to the culture medium and the cells then incubated for 4 hr. The amount of lactic dehydrogenase (LDH) that leaked into the culture medium was determined at the end of incubation. The customary assumption was made that the exudation of LDH reflects the toxic effects of the relaxants. In untreated dishes, approximately 11% of the total intracellular LDH leaked out during the incubation. The net leakage of LDH produced by the relaxants was obtained by subtracting this amount from the LDH activity determined in the media of dishes with the relaxants added. On this basis, metocurine, in concentrations of 12-850 X 10(-6)M, did not cause a net leak of LDH. On the other hand, atracurium, in similar molar concentrations, caused a statistically significant and concentration-dependent leak of LDH that, at its maximum, amounted to more than one half of the intracellular LDH. The results are interpreted in terms of damage to cellular membranes produced by atracurium or its metabolites. Although the exact biochemical process was not identified, we hypothesize that acrylates--produced by Hofmann elimination from atracurium--might be the likely toxic species.

Animals↗
PubMed1985

Enzymatic hydrolysis of atracurium in vivo.

Inactivation of atracurium in vivo has been postulated to proceed along two pathways: Hofmann elimination and ester hydrolysis. Since an end product of Hofmann elimination (acrylate) may be potentially toxic, the authors conducted a study to determine the extent of degradation via enzyme-catalyzed hydrolysis relative to that via Hofmann elimination. The enzyme carboxylesterase was inhibited by the pretreatment of rats with an organophosphorous compound, triorthotolyl phosphate (TOTP). Skeletal muscle relaxation produced either by d-tubocurarine or succinylcholine was not influenced by the pretreatment. This indicates that TOTP does not alter directly the paralyzing properties of either depolarizing or nondepolarizing muscle relaxants. Relaxation produced by atracurium, however, was prolonged markedly and the rate of recovery from relaxation was decreased. The authors conclude: 1) enzyme-catalyzed hydrolysis is probably responsible for the short duration of action of atracurium; 2) Hofmann elimination, at least in rats, probably is not the principal degradation pathway; and 3) the opportunity for in vivo generation of large amounts of potentially toxic end products is less than previously implied.

Animals↗
PubMed1985

Inactivation of atracurium in human and rat plasma.

The contribution of enzyme-catalyzed hydrolysis to inactivation of atracurium in human and rat plasma was determined in vitro by inhibiting the enzyme carboxylesterase with triorthotolyl phosphate. The inhibitor was removed by centrifugation and aspiration. Atracurium was then added to both the control and the inhibited plasma samples, and all samples were incubated at 37 degrees C for 45 min. The amount of atracurium present in aliquots of plasma was determined using a bioassay technique in anesthetized rats. Inactivation of atracurium proceeded rapidly in control rat plasma but was markedly slowed in samples treated with the inhibitor of carboxylesterase. In contrast, the inactivation was slow in control human plasma, and inhibition of carboxylesterase produced only marginal, if any, effects. We conclude that the inactivation of atracurium proceeds, in part, by enzyme-catalyzed ester hydrolysis. In species with high enzyme activity in plasma, e.g., the rat, enzyme-catalyzed hydrolysis is clearly evident. In humans, the level of enzyme activity is low and the contribution of enzyme-catalyzed inactivation is less manifest. By exclusion, Hofmann elimination or other reactions probably represent the major inactivation pathway in humans.

Animals↗
PubMed1984

Succinylcholine, cholinoceptors and catecholamines: proposed mechanism of early adverse haemodynamic reactions.

An hypothesis is proposed to account for the occurrence of adverse haemodynamic reactions to succinylcholine. Interaction of succinylcholine with cholinergic receptors is postulated to result in release of endogenous catecholamines (predominantly norepinephrine). The occurrence and the clinical manifestations of the adverse reactions would be dependent on the extent of the release. Based on literature reports of findings in experimental animals with nicotinic and muscarinic agents, a mechanism for the release of norepinephrine is outlined. Interaction of succinylcholine with muscarinic and nicotinic receptors is proposed to result in an initial activation which is followed by a phase of chemical insensitivity. Activation of the presynaptic nicotinic receptors on the postganglionic sympathetic terminals leads to a short-lasting release of norepinephrine. Activation of the presynaptic muscarinic receptors produces attenuation of the norepinephrine release. In the majority of patients these opposing actions are balanced and the net result is small, variable, and of little clinical importance. An unbalanced response leading to clinical manifestations can be expected if the two types of the presynaptic cholinoceptors are differentially activated.

Animals↗
PubMed1983

Succinylcholine-induced increases in plasma catecholamine levels in humans.

Given the hypothesis that interaction of succinylcholine with nicotinic receptors releases endogenous catecholamines, plasma levels of epinephrine and norepinephrine were determined in anesthetized and manually ventilated patients immediately before and 2 min after intravenous administration of succinylcholine. Anesthesia was induced with intravenous thiopental (3-4 mg/kg) followed by the administration of nitrous oxide and oxygen (1:1) and 0.5-1.0% halothane. Stimulation of the patients was avoided. Succinylcholine (1 mg/kg) or metocurine (0.3 mg/kg) was injected intravenously and ventilation was controlled without intubation. Plasma norepinephrine levels increased from 301 pg/ml to 491 pg/ml (SEM = +/- 19 pg/ml, P less than 0.01, N = 5) 2 min after the injection of succinylcholine; the increase in plasma epinephrine was not statistically significant. The time course of catecholamine elevation was studied in three additional patients. The increase of norepinephrine occurred immediately after the injection of succinylcholine, peaked (647 +/- 67 pg/ml) around the third minute, and disappeared by the 10th min. The increase in epinephrine was less marked. Plasma levels of catecholamines did not change after the injection of metocurine (N = 2). The possibility that succinylcholine stimulates nicotinic receptors on the postganglionic sympathetic terminals is discussed. We propose that the elevation of plasma norepinephrine might contribute to the development of early adverse cardiovascular reactions to succinylcholine.

Adult↗