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The present study investigates synergistic effects of the TNF-alpha inhibitor thalidomide and the poly(ADP-ribose) polymerase (PARP)-inhibitor nicotinic acid amide (NAA) in male DBA/1 hybird mice suffering from type II collagen-induced arthritis. Parameters including the arthritis index, chemiluminescence and anti-collagen antibody titers were used for the assessment of disease activity: The disease courses demonstrated clearly an inhibitory effect of thalidomide. NAA inhibited established collagen arthritis in a dose-dependent manner. The combined application of thalidomide and NAA caused a powerful synergistic inhibition of arthritis. Furthermore, thalidomide and NAA were tested ex vivo for their inhibition of the NADPH oxidase-dependent generation of reactive oxygen species by activated neutrophils and monocytes in unseparated human blood. Our data show that type II collagen-induced arthritis can be suppressed by the simultaneous inhibition of TNF-alpha, PARP, and NADPH oxidase.

The influence of a single injection of 300 μg oestradiol-benzoate (OeB) or 1.25 mg testosterone-propionate (TP) shortly after birth (day 2 or 4 of life) on the age dependent and sex-specific development of the activity patterns of some liver enzymes involved in steroid metabolism (Δ4-5α-hydrogenase, steroid-hydroxylases, 3α- and 3β-hydroxysteriod-dehydrogenase and 20-keto-reductase) was studied in male and female rats. Female animals: The single neonatal injection of OeB or TP (day 2 or 4 of life) causes the mature animals to exhibit the typical morphological alterations of ovaries, uterus and adrenals. However, no effect on the sex-specific development of the activity patterns of the above mentioned enzymes could be observed, indicating that this treatment with TP cannot abolish the basic tendency of female livers to develop feminine activity patterns. This must be attributed to the antagonizing action of endogenous oestrogens. Male animals: A single injection of OeB on day 2 of life produces persistent feminization of enzyme activity patterns in mature animals. The development with age (day 30–180 of life) of the activities of particular enzymes is in every phase nearly or completely identical with that of sexually normal developed females. When TP is applied on day 2 of life, there is in no instance a complete adjustment of the enzyme activity to a female level, although some tendency to feminization is observed. However, 20-keto-reductase activity remains unchanged at the male level. If OeB is applied on day 4 of life the Δ4-5α-hydrogenase and the steroid-hydroxylases are the only enzymes whose activities show a considerable trend towards feminization.

The aim of our study was to determine the period of maximum sensitivity for the induction of characteristic malformations with thalidomide (TH) in Himalayan rabbits. TH was administered orally in different doses (50, 100, 150 and 200 mg/kg) four times at 24-h intervals starting at 192 h of gestation. The malformations affected various organs: renal defects (dysplasia) and limb anomalies (dysmelia)--which had never occurred spontaneously in this strain--appeared as dose-dependent effects of the drug. By administering single doses of TH (200 and 300 mg/kg body wt) between hours 192 and 264 of gestation, we discovered the different periods of maximum sensitivity for induction of renal dysplasia (clearly prior to the 220th h of gestation) and dysmelia (between hours 230 and 240 of gestation). The types of limb malformations that we observed in the rabbit were identical to those produced in man following the intake of TH. Three doses of TH (300 mg/kg each) given between hours 222 and 228 of gestation produced characteristic limb malformations in 9 of 11 litters treated. These results make it possible to conduct in vivo experiments on a readily available laboratory animal with minor drug exposure of the gravid dam and under avoidance of toxic side effects.

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