Transition metal-catalysed acylation of alpha,beta-unsaturated carbonyl compounds with acylstannanes.

Acylstannanes were found to add to such alpha,beta-unsaturated carbonyl compounds as enones or ynoates in the presence of a nicel or palladium catalyst to give 2-stannyl-4-oxoalk-2-enoates or 1,4-diketones, whereas the three component coupling between acylstannanes, enones and aldehydes provided 2-hydroxymethyl 1,4-diketones.

Mutagenicity test systems for the detection of chromosome aberrations in vivo.

In mutagenicity testing of pharmaceuticals it is advisable, whenever possible, to use in vivo mammalian systems where the pharmacokinetic properties of a drug would be more or less similar to those in man. However, although there are a number of different genetic endpoints which are important in mutagen testing, sufficiently validated, practical and well documented in vivo test systems exist only for structural chromosome aberrations. This paper provides an overview of existing in vivo test systems for the detection of chromosome aberrations. Emphasis has been laid on the functions, advantages and limitations of the three tests recommended in the guidelines of the European Community; first, the metaphase analysis assay, and, as alternatives, the micronucleus test and the dominant lethal test. These three tests are then also discussed from the viewpoint of our own practical experience.

Analysis of chromosome aberrations and sister-chromatid exchanges in human lymphocytes exposed in vitro to Hydergine.

Hydergine (dihydroergotoxine mesylate, Sandoz) was examined for its capability to induce chromosome damage and sister-chromatid exchanges (SCEs) in human lymphocyte in vitro. For the chromosome-aberration study, cultures set up from 6 individuals were divided into 5 groups: negative control, positive control (caffeine, 0.5 mg/ml), and Hydergine (0.1, 0.25 and 0.5 micrograms/ml). For the SCE examination, which used 8 individuals, 4 cultures were made per person in the following way: negative control, positive control (mitomycin C, 0.1 microgram/ml), and Hydergine (0.1 and 0.5 micrograms/ml). Lymphocytes were cultivated for 72 h, being exposed to the respective treatments during the final 24 h. The results showed that Hydergine induced no chromosome damage in human lymphocytes in vitro.

Actions of an antispermatogenic, but non-mutagenic, indenopyridine derivative in mice and Salmonella typhimurium.

This paper describes a new antispermatogenic agent. Following single oral administration to mice, the indenopyridine derivative (4aRS,5SR,9bRS)-2-ethyl-1,3,4,4a,5,9b-hexahydro-7-methyl-5-p-tolyl-2H-indeno(1,2-c)pyridine hydrochloride, code No. 20-438, produced long-lasting inhibition of the spermatogenic process at dose levels of 10 mg/kg (1/40 of the lowest lethal dose) and higher. Testes weights were significantly reduced from days 2--217 after treatment, and no clear-cut evidence of a recovery was found during this time. The fertility of treated males was normal during the initial 2 weeks after treatment, followed by partial or total sterility in weeks 3--6, and incomplete recovery in weeks 7--29 after treatment. The antifertility effects were caused by maturation depletion of the germ cells, leading to oligospermia. The following rank of decreasing "susceptibility" of the germ cells was observed: Spermatocytes greater than early spermatids, intermediate spermatogonia greater than stem cells. Sperm and late spermatids were not affected. Despite the characteristic specific germ-cell pattern of antifertility effects, 20-438 showed neither indications of pre- and post-implantational dominant lethality, nor mutagenic potentiality as measured by cytogenetic analysis of spermatocytes or spermatogonia, the sperm abnormality assay, the micronucleus test, and the Salmonella assay. These data suggest that the action of 20-438, leading to oligospermia, does not involve genetic toxic effects.

Failure to detect dominant-lethal mutations and effects on reproductive capacity in mice exposed to dihydroergotoxine mesylate.

Triethylenemelamine (TEM), a known chemical mutagen, and dihydroergotoxine mesylate (DHETM, Hydergin), an ergot derivative, were tested for mutagenic effects by means of the dominant-lethal test in male mice and the total reproductive capacity test in female mice. In contrast to TEM, which proved to be strongly effective in these test systems, DHETM did not show any effect. It is concluded that this drug, at both subtoxic and pharmacologically active dose-levels, has no potential to affect spermatogenic and oogenic cells.

Q-banding of human chromosomes after BUdR and BCdR treatment.

Two different Q patterns were found in BUdR and BCdR treated chromosomes of human lymphocyte cultures: X-type pattern, in which Giemsa and quinacrine banding both are reversed; Y-type pattern, in which Q-banding remains conventional in spite of reverse G-banding. Possible mechanisms of these findings are discussed.

Effect of an ergot derivative on human lymphocyte chromosomes in vivo.

Chromosome examination was made from 12 healthy adult male volunteers by using human lymphocyte cultures twice before, and 8 and 12 weeks after continuous intake of 3 X 1.5 mg Hydergine, an ergot derivative, per day orally. The mean frequency of cells with aberrations and the number of aberrations per 100 cells after 12 weeks' medication corresponded well with those of control cultures. However, for unknown reasons, significantly different values were found after 8 weeks of medication at a level of 5%, i.e., the values of capillary blood culture C8W were lower than those of CI, CII and C12W.

Irregular phenotypic expression of ring chromosomes.

2 patients with 13- and C9-rings are reported. On reviewing the phenotypical features of the published ring carriers and comparing them with our results we do not find any characteristic similarities. This can be explained by cytogenetical and biological findings. We are therefore inclined to reject the existence of clear-cut ring chromosome syndromes.

Satellite DNA III and alkaline Geimsa staining.

Satellite DNA III visualized by staining chromosomes with Giemsa at pH 10-12. Evidence is presented that besides the secondary constriction of chromosome 9, satellite III contained in considerable amount in the long arms of chromosome 20, giving rise to a clearly visible secondary constriction just below the centromere. The latter finding confirms that reported by Bobrow et al. (1972). The long arms of the Y chromosome also show strong staining with alkaline Giemsa, the region of staining corresponding exactly with the intensely flourescing area. This is interpreted as possible evidence for the presence of satellite DNA III in the distal long arms of the human Y chromosome.