Effects of trifluoromethylaniline isomers on enzyme activities in lymphatic organs and hematology of the rat.

Three isomers of trifluoromethylaniline (TFMA) were investigated for their possible different toxic effects on the hematopoietic system in male Wistar rats. The effects of isomeric 2-, 3- and 4-TFMA were compared with those of aniline, the prototypic drug. Strong leukocytosis manifested by considerable increase in the number of all respective white blood elements was observed in the peripheral blood 1 day after the administration of 4-TFMA. In contrast, erythropoiesis, as ascertained by erythrocyte count and hemoglobin concentration, was inhibited by 4-TFMA. The determination of the ED50 revealed lymphocytes to be the most responsive elements towards 4-TFMA administration. Besides hyperemic and proliferative splenomegaly the histological changes in maturation of immunocompetent cells following the 4-TFMA administration were found also in thymus. In accord with an enhanced incorporation of [3H]thymidine, the specific activity of thymidine kinase (TdK) in spleen was increased after a single dose of 4-TFMA. Activities of the catabolic enzymes adenosine deaminase (ADA) and inosine phosphorylase (IP) decreased in both organs with the exception of IP activity in thymus. The effects evoked by the 3-TFMA isomer were regularly less pronounced, and 2-TFMA was nearly inactive.

Nephrotoxicity of borocaptate after short-term administration in rabbits.

Fifteen Chinchilla rabbits were treated by seven daily i.v. injections of two doses (25 or 50 mg/kg body wt.) of sodium borocaptate (Na2B12H11SH), an agent now widely investigated for potential use in Boron Neutron Capture Therapy (BNCT) of malignant brain tumors. Definite nephrotoxic lesions hyperemic and dilated glomeruli, degenerative necrobiosis with desquamation of tubular epithelium, granular casts in the distal convoluted and collecting tubuli were detected by histopathological examination in the kidneys of all animals without relation to dose of borocaptate. The accumulation of urea in blood and a reduction in red blood cell counts were, however, statistically significant only in rabbits receiving the higher dose (50 mg/kg body wt.) of borocaptate. In the brain the prevalent finding was dilation of perivascular (Virchow-Robin's) spaces. The growth of the animals was retarded and three animals died after injection of the 5th daily dose of borocaptate. With respect to these findings borocaptate sodium can by no means be regarded as an agent which is fully devoid of activity towards healthy non-tumor tissue. Therefore, recent proposals to enhance the effectiveness of BNCT by repeated borocaptate treatment should be considered with caution.

Spontaneous acute lymphoblastic leukemia in Sprague-Dawley rats. II. Clinicopathologic observations.

Spontaneous acute lymphoblastic leukemia (ALL-SD) was diagnosed in a breeding colony of isohistogenic Sprague-Dawley rats. Animals younger than one year of age died approximately 1 to 2 weeks after the onset of the disease and represented approximately 17% of the total rat population. Clinically, the affected rats showed mainly spinal cord paralysis and enlargement of mandibular lymph nodes. Gross lesions were characterized by hepatosplenomegaly and enlargement of visceral lymph nodes. Histological examination of affected tissues and cells revealed generalized infiltration of blast cells accompanied by focal hemorrhages and necrosis. According to the FAB classification, it was concluded that ALL-SD corresponds to ALL type L2 in man. Therefore this leukemia of young rats may be an important model system for the study of human leukemia.

Study of the effect of Edikron on the immune system.

Using the nucleolar test, the authors investigated the effects of the new Czechoslovak cytostatic agent Edikron (gamma, gamma-bis[4-ethylphenyl]-alpha, beta-dibromisocrotonic acid] on Wistar rats. The test showed that Edikron, administered perorally in the dose of 100 mg/kg BW per day for 5 days, affects neither the number of leukocytes nor the proteosynthetic activity of peripheral lymphocytes. The serum levels of Edikron, assessed with the aid of HPLC method 90 min after its last administration, averaged 14.03 +/- 1.63 micrograms/ml serum. Histological examination of the spleen, lymph nodes and thymus of the experimental and control groups also failed to detect any changes. However, the administration of Edikron elicited a statistically significant rise of erythrocytes in the experimental group, but the reason for that has not so far been ascertained.

Arthritogenic activity of a synthetic immunoadjuvant, muramyl dipeptide.

A synthetic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine, dissolved in saline only and applied subcutaneously to rats of the Lewis inbred strain, produced arthritis, clinically manifest by hind feet paresis but without apparent paw swelling in most cases. Histologically, the disease was characterized by edema and hyperemia of connective tissues, joint synovias, and tendon sheaths, with massive accumulation of inflammatory cell infiltrates composed mainly of lymphoplasmocytes and partly of neutrophil leukocytes. Fibrin exudation and fibrinoid necrosis in connective tissues were observed in the most severe cases. Synovial layers of the talocrural joint, especially on their villi, exhibited marked swelling or cell desquamation of the inner zone. Clinical symptoms of the disease disappeared spontaneously within 5 days after cessation of the treatment; also, histological examinations showed that the effects were reversible. Our results prove that (i) muramyl dipeptide is the principal substance involved in the production of arthritis, (ii) there is no necessity for the presence of additional mycobacterial cell wall components, and (iii) the involvement of the oil moiety is not requisite for the production of arthritis.

Pregnancy interrupting effects of some bacterial toxins.

Embryotoxic properties of Shigella dysenteriae and Clostridium perfringens toxins, of E. coli endotoxin, V. cholerase and E. coli enterotoxins were compared in mice. E. coli endotoxin has embryotoxic effects at all stages of pregnancy. E. coli enterotoxin V. cholerae enterotoxin and Shigella dysenteriae toxin are most effective mainly at earlier stages of pregnancy. Clostridium perfringens toxin has no embryotoxic effect.

PIP: Pregnancy interrupting effects of some bacterial toxins were studied in mice. Embryotoxic properties of Shigella dysenteriae and Clostridium perfringens toxins, Escherichia coli endotoxin, Vibrio cholerae, and Escherichia coli interotoxins were compared up to Day 18 of pregnancy following injections on Day 6, 8, or 13 of pregnancy. Escherichia coli endotoxin caused embryotoxic effects in all stages of pregnancy while Escherichia coli enterotoxin, Vibrio cholerae enterotoxin, and Shigella dysenteriae toxin were most effective mainly at earlier stages of pregnancy. Histological studies revealed indirect embryotoxicity at later stages by placental damage. The main site of damage was the fetal side for Shigella dysenteriae toxin and the maternal side for Escherichia coli endotoxin, enterotoxin, and cholera toxin. Clostridium perfringens toxin had no embryonic effect.