Extrapolating from animal studies to the efficacy in humans of a pretreatment combination against organophosphate poisoning

Abstract

The extrapolation from animal data to therapeutic effects in humans, a basic pharmacological issue, is especially critical in studies aimed to estimate the protective efficacy of drugs against nerve agent poisoning. Such efficacy can only be predicted by extrapolation of data from animal studies to humans. In pretreatment therapy against nerve agents, careful dose determination is even more crucial than in antidotal therapy, since excessive doses may lead to adverse effects or performance decrements. The common method of comparing dose per body weight, still used in some studies, may lead to erroneous extrapolation. A different approach is based on the comparison of plasma concentrations at steady state required to obtain a given pharmacodynamic endpoint. In the present study, this approach was applied to predict the prophylactic efficacy of the anticholinergic drug caramiphen in combination with pyridostigmine in man based on animal data. In two species of large animals, dogs and monkeys, similar plasma concentrations of caramiphen (in the range of 60-100 ng/ml) conferred adequate protection against exposure to a lethal-dose of sarin (1.6-1.8 LD(50)). Pharmacokinetic studies at steady state were required to achieve the correlation between caramiphen plasma concentrations and therapeutic effects. Evaluation of total plasma clearance values was instrumental in establishing desirable plasma concentrations and minimizing the number of animals used in the study. Previous data in the literature for plasma levels of caramiphen that do not lead to overt side effects in humans (70-100 ng/ml) enabled extrapolation to expected human protection. The method can be applied to other drugs and other clinical situations, in which human studies are impossible due to ethical considerations. When similar dose response curves are obtained in at least two animal models, the extrapolation to expected therapeutic effects in humans might be considered more reliable.

Isolation of volatiles from Nigella sativa seeds using microwave‐assisted extraction: effect of whole extracts on canine and murine CYP1A

“…Although we did not characterize each extract for secondary metabolites, it might be possible that the inhibitory effect comes from thymoquinone as it did show a similar pattern to various extracts. As the present study was carried out in vitro on two animal models, the extrapolation to the expected pharmacological effects in humans might be considered more reliable (Levy et al ., ). Consequently, attention should be paid to the possible drug interaction in patients who concurrently use N .…”

Caramiphen edisylate as adjunct to standard therapy attenuates soman-induced seizures and cognitive deficits in rats

“…Previously in humans, caramiphen was taken orally at up to 1.15 mg/kg or 3.4 mg/kg over 4 days, which led to peak blood level of 60 ng/ml (Levandoski and Flanagan, 1980;Tallarida, 1982). Levy et al (2007) extrapolated from dogs and monkeys to predict an effective dose of caramiphen against 1.6-1.8 LD 50 sarin in humans to be 70-100 ng/ml. Our study aimed to bring about higher blood levels of caramiphen, in this range, for this later therapeutic intervention against GD exposure in our rodent model.…”

Neuroprotective efficacy of caramiphen against soman and mechanisms of its action

“…However, we do not know the blood and brain concentrations of caramiphen after in vivo injection of 100 mg·kg −1 of body weight. If we attempt to make a very rough estimate based on the blood concentrations of caramiphen after repeated or continuous administration (Levandoski and Flanagan, 1980; Levy et al ., 2007), we would suggest that a single injection of 100 mg·kg −1 caramiphen produced a blood concentration in the micromolar range. It is likely, therefore, that the NMDA receptor‐antagonistic properties of caramiphen contributed to its anticonvulsant efficacy; previous studies have suggested that antagonism of NMDA receptors plays an important role in the termination of nerve agent‐induced seizures (Braitman and Sparenborg, 1989; Dorandeu et al ., 2007).…”