This is the 54th report of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). The main objective of ECVAM, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences, and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and of opportunities for the possible incorporation of alternative methods into regulatory procedures. It was decided that this would be best achieved through a programme of ECVAM workshops, each addressing a specific topic, and at which selected groups of independent international experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward.A workshop on Metabolism: a bottleneck in in vitro toxicological test development, was held at
Aims The purpose of the study was to investigate the effects of asimadoline, a new k-opioid agonist, on renal function and on hormones related to body¯uid balance as well as its tolerability in healthy subjects. Methods In a placebo-controlled, randomised, double-blind crossover design we studied the effects of single oral doses of 1, 5, and 10 mg of asimadoline, in 24 healthy volunteers. Two hour control urine collections were followed by 2 h postdose urine collections and subsequently 2.5% saline was given i.v. at a rate of 0.3 ml min x1 kg x1 during another 2 h urine collection. Blood was obtained hourly. Arginine-vasopressin (AVP), atrial natriuretic peptide (a-hANP), endothelin (ET-1) and cAMP were determined by r.i.a. or ELISA.Results GC-MS measurements revealed C max values of asimadoline in plasma ranging from 18 ng ml x1 at the 1 mg dose, 91 ng ml x1 at the 5 mg dose, to 214 ng ml x1 at the 10 mg dose after an average of 1.1±1.4 h. Without effects on blood pressure, heart rate, GFR or urine electrolyte excretion, urine volume increased after 1±2 h after administration of 5 and 10 mg asimadoline from 3.3t1.3 to 5.6t1.4 (P<0.05) and from 3.2t1.6 to 5.5t2.2 ml min x1 (P<0.01), respectively. C H 2 O rose from 0.2t1.5 to 2.0t1.6 (P<0.05) and from 0.6t1.6 to 3.0t1.6 ml min x1 (P<0.01). Urinary excretion of AVP was suppressed only with the 10 mg dose from 46t23 to 25t15 fmol min x1 (P<0.05) without and from 410t206 to 181t125 fmol min x1 (P<0.05) with stimulation by 2.5% saline. Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5% saline infusion.Changes in the a-hANP or ET-1 systems were not affected by asimadoline.Conclusions Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level. Suppression of AVP secretion was observed only at the highest dose level of 10 mg of asimadoline.
Abstract:The fate of acetaminophen after intravenous injection in whole bowel-irrigated rats (n = 40) and the influence of activated charcoal on the kinetics were investigated. After randomization to four groups (n = 10, each group), plasma concentration and the quantities of acetaminophen and metabolites excreted into bile, urine and intestine were determined using an in vivo model with or without orally administered activated charcoal and with or without bile duct cannulation. The cumulative amount of acetaminiphen and metabolites exsorbed into the small intestine within 3.5 hr after intravenous injection was about 20% of dose in the animals with bile duct cannulation and about 7% of dose in the animals without. Correspondingly, about 13% of dose was detected in the externalized bile. Activated charcoal did not influence the amount exsorbed into the small intestine. Terminal half-life in plasma ranged from 35 to 51 min. within the four treatment groups without statistically significant difference (P = 0.152). Correspondingly, the area under the curve did not vary much and ranged between 2.6 and 3.3 g/min./l (P = 0.392). Deposition of acetaminophen and metabolites in liver and kidney after 3.5 hr was marginal and ranged between 0.02% and 0.6% of the dose within all groups. The excretion of acetaminophen and metabolites into urine varied strikingly between 31% and 56% of the dose within all groups and correlated with diuresis. The lack of effect of activated charcoal on the elimination of acetaminophen and metabolites may be due to the small amount of the drug being exsorbed into the intestine or the reduced adsorbent capacity of activated charcoal to acetaminophen and metabolites, which also could be influenced by inadequate luminal stirring.
HLö 7, (pyridinium, 1-[[[4-(aminoarbonyl)pyridinio]methoxy]methyl] -2,4-bis- [(hydroxyimino)methyl] diiodide) has been shown to be efficacious in soman poisoning of mice even in the absence of atropine. To assess possible risks involved in the administration of HLö 7 its degradation products were analyzed at pH 2.5 and pH 7.4, respectively. At pH 2.5, where HLö 7 in aqueous solution was assumed to possess maximal stability, the predicted shelf life (10% decomposition) was about 8 years for 10 mM solutions at 8 degrees C. The apparent energy of activation was 117 kJ/mol. At pH 2.5, attack on the aminal-acetal bond predominated with formation of pyridine-2,4-dialdoxime, 2-cyanopyridine-4-aldoxime, isonicotinamide, and formaldehyde. At pH 7.4, primary attack on the 2-aldoxime group resulted in formation of an intermediate 2-cyano-4-aldoxime derivative which mainly decomposed into cyanide and the corresponding 2-pyridinone, 1-[[[4-(aminocarbonyl)-pyridinio]methoxy]methyl]-4- [(hydroxyimino)methyl] diiodide. In addition, liberated cyanide reacted with the intermediate 2-cyano-4-aldoxime derivative with formation of 2-pyridinone, 1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]methyl]-6-cyano-4- [(hydroxyimino)methyl] diiodide. This cyanide sequestering pathway became significant only at high concentrations (10 mM) of HLö 7, and was marginal at 1 mM HLö 7.
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