[Drug-induced liver injury]. / Il danno epatico da farmaci.

Drug-induced liver injury represents the principal cause of acute liver failure and orthotopic liver transplantation in western country. A very large number of different drugs and medicinal herbs has been associated with liver injury but just for few of them we know the process that causes liver disease. All the people which ingest a large number of drugs present a risk of developing liver injury. Diagnosis is very difficult because a specific biomarker of damage is absent and the clinical picture is common to other liver diseases. A therapeutic approach is efficacy only in few cases. When a drug-induced liver injury is suspected, cessation of the drug is the first step in their management.

Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families.

BACKGROUND: Malignant hyperthermia (MH) is a potentially lethal genetic disorder in response to volatile anesthetics and depolarizing muscle relaxants. To support the claim that a novel genetic variant causes MH, it is necessary to demonstrate that it has significant effects on the sensitivity of the ryanodine receptor (RYR1) calcium channel. In this study we focused on 2 Austrian families with strong MH disposition and new RYR1 variants. METHODS: We sequenced the entire coding region of the RYR1 from 2 Austrian MH individuals. Genotype-phenotype segregation and evolutionary conservation of the variants were considered. On a functional level, Ca(2+) release experiments with fura-2-acetoxymethyl ester were performed in cultured skeletal muscle cells derived from individuals carrying the new variants and compared with control cells from nonsusceptible individuals. Caffeine, 4-chloro-m-cresole (4-CmC), and halothane were used as specific Ca(2+) releasing agents. RESULTS: The variant p.A612P in family A segregated with an MH-susceptible phenotype and cells showed an increased sensitivity for all Ca(2+)-releasing substances tested. In family B, 2 variants (p.R2458H/p.R3348C) were identified. While p.R2458H and p.R2458H/p.R3348C segregated with an MH-susceptible diagnosis, p.R3348C alone showed an MH equivocal diagnosis. Ca(2+)-release experiments showed that exchanges of these highly conserved amino acids increased the sensitivities for the substances tested (except 4-CmC with p.R2458H and p.R3348C) when compared with the MH-negative control group. CONCLUSIONS: Our results suggest that these variants are new causative MH variants.

Intramuscular injection of malignant hyperthermia trigger agents induces hypermetabolism in susceptible and nonsusceptible individuals.

BACKGROUND AND OBJECTIVE: A new minimally invasive metabolic test for the diagnosis of susceptibility for malignant hyperthermia measuring intramuscular p(CO(2)) and lactate following local application of caffeine and halothane in humans was recently proposed. The present study tested the hypothesis that a more simplified test protocol allows a differentiation between malignant hyperthermia susceptible (MHS) and malignant hyperthermia nonsusceptible (MHN) and control individuals. METHODS: With approval of the local ethics committee and informed consent, microdialysis and p(CO(2)) probes with attached microtubing were placed into the lateral vastus muscle of six MHS, seven MHN and seven control individuals. Following equilibration, boluses of 500 microl caffeine 80 mmol l(-1) and halothane 10 vol% dissolved in soybean oil were injected locally. p(CO(2)) and lactate were measured spectrophotometrically. RESULTS: The maximal rate of p(CO(2)) increase was significantly higher in MHS than in MHN and control individuals following application of halothane and caffeine, respectively. Intramuscular caffeine injection leads to a significantly higher increase of local lactate levels in MHS than in MHN and control individuals, whereas halothane increased local lactate levels in all investigated groups. Haemodynamic and systemic metabolic parameters did not differ between the investigated groups. CONCLUSION: Local caffeine and halothane injection increased intramuscular metabolism in MHS individuals significantly more than in the two other groups. In contrast to previous investigations, direct injection of the concentrations of halothane described here increased lactate and p(CO(2)) even in MHN skeletal muscle.

Evaluation of drug-induced QT prolongation in a halothane-anesthetized monkey model: effects of sotalol.

INTRODUCTION: Cynomolgus monkeys are used in in vivo models of safety pharmacological studies to evaluate the effects of drug candidates on the cardiovascular system. Models using halothane-anesthetized animals have been used for the detection of drug-induced QT interval prolongation, but few studies with anesthetized monkeys have been reported. METHODS: The electrophysiological changes induced by dl-sotalol, a representative class III antiarrhythmic drug, were assessed in halothane-anesthetized monkeys (n = 4) or conscious and unrestrained monkeys (n = 4). RESULTS: In terms of basal characteristics, the QT interval was longer and the heart rate (HR) was lower under anesthesia than those under conscious conditions. Intravenous administration of 0.1 to 3 mg/kg dl-sotalol to anesthetized monkeys decreased the HR and prolonged the QT interval, monophasic action potential (MAP) duration and ventricular effective refractory period in a dose-dependent manner. In addition, reverse use-dependent prolongation of MAP duration was detected by electrical pacing, whereas the terminal repolarization period was hardly affected at any dose. Oral administration of 3 to 30 mg/kg dl-sotalol to conscious monkeys also decreased the HR and prolonged the QT interval in a dose-dependent manner. When compared at similar plasma concentrations of sotalol, the extent of QT interval prolongation under halothane anesthesia was equal to or greater than that under conscious conditions. DISCUSSION: The sensitivity for detection of drug-induced QT prolongation under halothane anesthesia may be satisfactory compared with that under conscious conditions. The present examinations indicated the usefulness of a model using halothane-anesthetized monkeys for evaluation of drug-induced QT interval prolongation.

Creatine monohydrate supplementation and the quality of fresh pork in normal and halothane carrier pigs.

The objective of this research was to examine the impact of supplementation with creatine monohydrate (CMH) on the quality of various muscles from normal and heterozygous halothane carrier pigs. Twenty-nine crossbred pigs, 16 normal (NN) and 13 halothane carrier (Nn) genotypes, were supplemented with 0 or 25 g x pig(-1) x d(-1) of CMH for 5 d before slaughter. Supplemented pigs gained 2.26 kg more weight (P < 0.05) during 5 d of supplementation. There were trends (P < 0.10) toward higher objective marbling scores and lower cooking loss for supplemented pigs. The 45-min pH was 0.27 units higher (P < 0.05) for supplemented pigs in the semimembranosus; CMH supplementation did not influence (P > 0.05) drip loss or muscle composition. Supplementation with CMH also resulted in lower L* values in two ham muscles, semitendinosus (5.15 units) (P < 0.05) and semimembranosus (1.95 units) (P < 0.10) for Nn carcasses. Genotype had significant effects on most quality indicators, with Nn carcasses producing lower-quality lean as evidenced by less desirable subjective and objective color and higher drip losses. Genotype also affected the composition of several muscles, with the NN carcasses having more fat and less moisture.

Acute canine model for drug-induced Torsades de Pointes in drug safety evaluation-influences of anesthesia and validation with quinidine and astemizole.

An acute in vivo model for drug-induced torsades de pointes (TdP) for use in safety evaluation of drugs was developed using dogs with acute complete atrioventricular (AV) block. In order to study the effects of anesthetic agents on the inducibility of TdP, arrhythmias were induced by programmed electrical stimulation (PES) before and after cumulative intravenous administration of quinidine under anesthesia with sodium pentobarbital, halothane, or isoflurane. Both prolongation of the QTc and the incidence of TdP were greatest in dogs anesthetized with halothane and were smallest in those given pentobarbital, suggesting that halothane is the most suitable anesthetic for this TdP model. To further validate this model, astemizole was administered intravenously to other dogs under halothane anesthesia. Astemizole at 0.3 mg/kg caused slight prolongation of the QT interval but did not induce any arrhythmias. At 1 mg/kg, however, TdP were induced in 5 of 10 animals and in an additional 2 animals at 3 mg/kg. Single and multiple ectopic beats preceded the induction of TdP, and the ectopic beats were observed in a dose-dependent manner. The plasma concentrations of quinidine in dogs with TdP were equivalent to or less than quinidine levels in humans with TdP, while those of astemizole were higher in dogs. In conclusion, this acute canine model of TdP with halothane anesthesia, complete AV block, PES, and simultaneous measurements of plasma drug concentration would be valuable for assessing the risk of drugs, especially I(Kr) blockers, to induce TdP in humans.

Neonatal halothane anesthesia affects cortical morphology.

Neonatal cryoanesthesia has recently been documented to affect morphology and behavior after a single exposure [Dev. Brain Res. 111 (1998) 89; Horm. Behav. 37 (2000) 169]. In the current experiment, we investigated the effect of one-time exposure to halothane inhalant anesthesia on neonatal rats of both sexes. Fifteen minutes of exposure on postnatal day one resulted in detectable changes in the volume of the visual cortex at 3 months. Thus, neonatal halothane alters neural development and its effects are observable in the adult rat.

Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle.

BACKGROUND: General anaesthetics inhibit mitochondrial function in animal models. However, very few studies have been performed in humans, and the results have not been conclusive. METHODS: We prospectively studied the oxygen consumption and the individual enzyme activity of each complex of the mitochondrial respiratory chain of skeletal muscle mitochondria in 54 healthy individuals who underwent general anaesthesia for orthopaedic surgery. The control group (n = 54) was made up of individuals submitted to the same orthopaedic procedure under regional anaesthesia (n = 31), and patients who underwent muscle biopsies for diagnostic purposes by local anaesthesia (n = 23). RESULTS: We found a significant decrease in the oxidation of glutamate (-36%), succinate (-25%) and ascorbate (-29%) in the general anaesthetic group compared with the controls (P < 0.001 for all substrates). The level of such inhibition was similar for volatile anaesthetics with strong (halothane) or weak (isoflurane) negative inotropic effect. By contrast, the enzymatic activity of all individual complexes and the coupling of oxidative phosphorylation did not differ between the two groups. CONCLUSION: We conclude that during general anaesthetic procedures there is an extensive inhibition of substrate oxidation in human muscle mitochondria, and that it is not caused by a direct effect on complexes of the mitochondrial respiratory chain or through uncoupling oxidative phosphorylation.

[The efficacy of using alpha-tocopherol during ftorotan anesthesia]. / Effektivnost' primeneniia al'fa-tokoferola pri anestezii ftorotanom.

Halothane monoanesthesia in hypoxia leads to activation of lipolysis with increase in the content of NEFA and POL products. The administration of alpha-tocopherol in a dose of 50 mg/liter in such cases was conductive to a statistically significant decrease in the content of peroxidation products in the blood.

Dysrhythmias during oral surgery--effect of combined local and general anesthesia.

In two groups, each of 50 patients undergoing pulpectomy or multiple extractions, effects of combining xylocaine nerve block with halothane general anesthesia were studied. Local blockade of surgical stimuli reduced markedly the incidence of dysrhythmias occurring during halothane anesthesia. Recovery was faster and postoperative analgesia was enhanced.

Cardiac dysrhythmias during oral surgery: effect of combined local and general anaesthesia.

In two groups, each of 50 patients undergoing oral surgery, effects of combining lidocaine nerve block with halothane general anaesthesia were studied. Local blockade of surgical stimuli reduced markedly the incidence of cardiac dysrhythmias occurred during halothane anaesthesia. Recovery was faster and post-operative analgesia was enhanced.

Hepatic glutathione S-transferase release after multiple halothane anaesthesia

Halothane is a commonly used anaethetic in paediatric practice. However, it is thought to be hepatotoxic. This study was designed to examine the effects of both single and multiple halothane anaesthesia on liver function. Heaptic glutathione S-transferase (GST) was also examined as a possible index of acute liver damage. The study group consisted of ten children who had consumed corrosive substances. This group was subdivided into two groups, depending on the number of halothane exposures, the single and the multiple halothane group. These children were compared with a surgical (n=5) and a ketamine control group (n=5). All children were studied prospectively over a 24hr. period, and the trend of liver enzyme release following anaesthesia measured. In addition, the children in the multiple halothane group were studied longitudinally. Four children from the study group, exhibited dramatic increases in the B1 subunit of liver specific GST, 24 hours after anaethesia. Twelve studies showed an early transient rise in total plasma GST, between the end of anaesthesia and 6 hrs. after. Six studies exhibited marked secondary rise at 24 hrs. after anaesthesia. These data indicate two possible phases of liver dysfunction following halothane anaesthesia. Significant changes in the level of aminotransferases were observed in the multiple halothane group, suggesting that measurement of these liver enzymes are still useful as indices of liver dysfunction following multiple halothane exposure. Cellular antioxidant systems were also measured to examine the relationship between halothane exposure and oxidative stress. A significant increase (p<0.05) in red cell GST was noted in the multiple halothane group, indicating that these children are in fact subjected to chronic oxidant stress. Collectively, these data indicate a transient impairment of hepatocellular integrity following multiple halothane exposures, despite lack of clinical evidence of hepatotoxicity. It is recommended that children undergoing repeated halothane anaesthesia be examined carefully for possible hepatic dysfunction (AU)

Halothane hepatitis. Detection of a constitutional susceptibility factor.

We studied susceptibility to halothane hepatitis with an in vitro test that detects cell damage from electrophilic drug intermediates. Metabolites of phenytoin were generated by incubation of phenytoin with rat hepatic microsomes in the presence of the epoxide hydrolase inhibitor 1,1,1-trichloropropene oxide (TCPO), which prevents the further metabolism of phenytoin to an inert metabolite. In lymphocytes exposed to this system, cytotoxicity was measured by trypan blue dye exclusion and was expressed as the percentage increase in trypan blue-positive cells after the addition of TCPO. In the presence of TCPO, lymphocytes from 11 patients with halothane hepatitis exhibited an increase in cytotoxicity at 0.06 mM phenytoin that was eight times greater than the increase in healthy controls (54 +/- 10 per cent [mean +/- S.E.M.] vs. 7.1 +/- 2.2 per cent, P less than 0.0001). Patients with other liver diseases and persons recently exposed to halothane without adverse effects did not differ from healthy controls. In three patients with halothane hepatitis who were studied serially, the lymphocyte abnormality was still present after 13 months. Family studies revealed abnormal results on 10 cytotoxicity tests among 19 members of four families. We propose that there is a familial, constitutional susceptibility factor that predisposes persons to halothane hepatitis.

Malignant hyperthermia in a halothane-anesthetized horse.

Malignant hyperthermia developed in a 4-year-old Thoroughbred horse following 3 hours and 15 minutes of halothane anesthesia, with supplementary succinylcholine. Clinical signs included fever, sweating, hyperventilation, tachycardia, and decreased blood pressure followed by a rapid increase in blood pressure. Biochemical aberrations included hypocalcemia, hyperkalemia, hyperphosphatemia, myoglobinuria, and high creatine phosphokinase and ornithine carbamyl transferase activities. Treatment consisted initially of surface cooling with cold water, alcohol and ice, IV administration of cooled balanced electrolyte solutions and sodium bicarbonate, and removal from the anesthetic and rebreathing circuit. Oxygen was given by endotracheal insufflation. The rectum was then packed with ice, the horse was moved to a recovery raft and pool, and his body was packed in ice. Xylazine and dantrolene were given during recovery from anesthesia. Following recovery, treatment consisted of administration of balanced electrolyte solutions, calcium borogluconate, potassium penicillin, meperidine, and additional dantrolene. Muscle biopsy demonstrated exaggerated contracture responses to halothane and caffeine, confirming a diagnosis of malignant hyperthermia. The horse was returned to training following a routine postsurgical convalescent period.

The hepatoprotective effect of oxygen during halothane anesthesia.

The effects of halothane anesthesia on liver function, as reflected by postanesthetic changes in serum glutamic pyruvic transaminase (SGPT) levels, were evaluated in 2 groups of 40 patients. All patients had 2 halothane anesthetics. In 1 group, both anesthetics were administered at 1 atmosphere pressure with 30% O2 in the inspired air. In the 2nd group, both anesthetics were administered at 2 to 3 atmospheres (absolute) of pressure with 97 to 98% O2 in the inspired air. While the SGPT levels remained within the normal range in all cases, there was a significant rise in SGPT levels in patients undergoing surgery under 1 atmospheric pressure. Patients undergoing surgery at 2 to 3 atmospheres pressure (absolute) had SGPT levels which remained at low normal values. The difference in response of SGPT in the 2 groups was statistically significant. We conclude that increased O2 tensions alter the normal response of SGPT to halothane anesthesia and that increased O2 tensions appear to protect the liver from possible adverse responses to halothane or its metabolites.

Pseudocholinesterase changes in anesthesia using pancuronium.

Pseudocholinesterase activity was investigated in three groups of unselected patients. A slight rise of the enzyme was found during surgery under local anesthesia with lidocaine. In general anesthesia with thiopentone and halothane, the pseudocholinesterase activity diminished. The inhibition was more pronounced when pancuronium had been injected. From these data one may conclude that pancuronium must be carefully given in patients with low level of pseudocholinesterase when other drugs inhibiting the enzyme activity, like succinylcholine, procaine and propanidid, are used.

[Mild form of malignant hyperthermia? OR, ABNORMAL REACTION To succinyldicholine?]. / Abortive Verlaufsform der malignen Hyperpyrexie? ODER Abnorme Reaktion auf Succinyldicholin?

In addition to two published cases of malignant hyperthermia (M.H.) 13 more cases have been observed in this institution since 1971, which are probably early reactions of the M.H. type. All 13 patients were children, 3-12 years of age, who developed a rigor of the jaw muscles after succinyldicholine and/or halothane within minutes after the induction of anesthesia. Further symptoms that could be observed regularly were a tachycardia of several hours duration and a marked elevation of the serum CPK-activity with a peak after 24 hours. Since the anesthesia was terminted immediately and the operations postponed as soon as a M.H. reaction was suspected, the rise in body temperature was minimal or absent and exceeded in no case 39 degrees C. Several children were operated upon later in neuroleptanalgesia (NLA) supplemented by nitrous oxide without any muscle relaxants. None of these children developed the aforementioned symptoms rigor, techycardia and CPK-elevation. One child had Alloferin in addition to NLA-nitrous oxide-anesthesia. This child had postoperatively a tachycardia lasting several hours and 24 hours later a serum CPK activity of 1500 U/1. Since this CPK activity is higher than in comparable cases (see fig. 1) it is concluded, that the nitrous oxide-NLA sequence appears to be safe for patients susceptible to M.H. Alloferin however must probably be regarded as a trigger agent for M.H.