ABSTRACT
Worldwide the application for a drug registration follows three basic principles: the proof of quality, efficacy and safety. In the following the applicability of these three principles on extracts from roots of the medicinal plant Kava (Piper methysticum) will be examined in the light of the current discussion of possible hepatic side effects ratio.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Adverse Drug Reaction Reporting Systems , Anti-Anxiety Agents/adverse effects , Anti-Anxiety Agents/standards , Chemical and Drug Induced Liver Injury/etiology , Clinical Trials as Topic , Humans , Plant Extracts/adverse effects , Plant Extracts/standards , Quality Control , Treatment OutcomeABSTRACT
A national interlaboratory study to validate two alternative methods to the Draize rabbit's eye test, co-ordinated by ZEBET at the German Federal Health Office (BGA), is described. The aim of the study is to classify chemicals according to their irritation potential using the neutral red/kenacid blue (NR/KB) cytotoxicity assay and the hen's egg chorioallantoic membrane (HET-CAM) test. During the last two years 12 toxicology laboratories from industry, universities and other research institutions have tested 32 substances from a variety of chemical classes, characterized by a broad spectrum of locally irritating properties, using the NR/KB cytotoxicity test and the HET-CAM assay. Intra- and interlaboratory reproducibility of the two methods was investigated under standardized conditions. The so-far limited evaluation of the interlaboratory assessment phase of validation indicates that the results of the Draize rabbit's eye test correlate better with the results of the HET-CAM test than with those of the cytotoxicity test as far as false negative results are concerned. However, the intra- and interlaboratory reproducibility of the cytoxicity test is better than that of the HET-CAM test. The validation project has recently entered the stage of database development during which 150 chemicals will be tested in seven laboratories to provide information on whether and to what extent the NR/KB test and the HET-CAM test can replace the Draize rabbit's eye test for the classification and labelling of chemicals with regard to their eye irritation potential.
ABSTRACT
The optical isomers of alpha-phthalimidoadipinimide (1) were synthesized by a route based on D(+)- and L(-)-amino-epsilon-caprolactam (5) as synthon. The isomers of 1 were obtained in high yields by treating D(+)- and L(-)-amino-epsilon-caprolactam (5) with N-carboethoxyphthalimide (4), followed by oxidation with benzeneseleninic anhydride (7). The teratogenic potency of both isomers of 1 was studied by the HET-(Hen's Egg Test); 1 caused distinctly lower teratogenic effects in contrast to thalidomide (2). D(-)-1 and L(+)-1 showed sedative effects with a lower activity than 2. Both are more stable in alkaline solution at the same time with a smaller tendency for racemization.
Subject(s)
Hypnotics and Sedatives/chemical synthesis , Teratogens , Thalidomide/analogs & derivatives , Thalidomide/toxicity , Animals , Chick Embryo , Female , Hydrogen-Ion Concentration , Lethal Dose 50 , Male , Mice , Motor Activity/drug effects , Oxidation-Reduction , Stereoisomerism , Thalidomide/chemical synthesisABSTRACT
N-Hydroxythalidomide (1d), a potential metabolite of thalidomide (1a), was synthesized from N-phthalyglutaminic acid anhydride (1b) and O-tetrahydropyraline hydroxylamine, followed by deprotection. The teratogenicity of 1d was studied using the Hen's-Egg-Test model which had been found applicable for 1a. 1d was more teratogenic to chicken embryos compared to 1a. The percentage of teratogenic malformations in the 1d groups was 28-46%, whereas the percentage in the 1a groups was 20-23%. The oxygen protected precursor N-hydroxythalidomide (1c) was less teratogenic (11-15%).
