Acute toxicity of dimethylnitrosamine in the presence of inhibitors of DMN demethylase

Summary The LD₅₀ of DMN was determined in groups of mice in the presence of inhibitors of DMN demethylase. Piperonyl butoxide, dibutylnitrosamine and nitrososarcosine had no effect on the acute toxicity of DMN. Diethylnitrosamine and DMN were markedly synergistic. All mice treated with 100 mg/kg diethylnitrosamine and 10.7 mg/kg DMN died. These results suggest that DMN demethylase may not be involved in theaacute toxicity of DMN.We thank Dr.D. B. Couch, Mr.E. J. Greene and Dr.A. E. Munson for their technical assistance.     

Anticonvulsant action of YG 19-256 in baboons with photosensitive epilepsy.

YG 19-256, 4-(1,3,4,9b-tetrahydro-5 methyl-2H-indeno[1,2-c]pyridine-2-yl)-2-butanone methane sulphonate, 1-3 mg/kg i.v., abolished or reduced photically-induced myoclonic responses for 1.5-6.5 h in baboons, Papio papio, without producing signs of acute neurological toxicity.     

Blutagglutinierende und toxische Eiweissfraktionen aus Bohnen

Summary Soluble proteins from black beans (Phaseolus vulgaris) have been separated into 4 fractions, one soluble in 1% NaCl-solution and 3 water soluble. The latter were separated by ammonium sulfate fractionation. The haemagglution of these fractions is compared with their toxicity in mice when applied by intraperitoneal injection. The LD₅₀ of the most active fraction was about 50 mg/kg. When used in mice of different strains, the toxicity was not the same while the blood cells were agglutinated by the same final concentration. Crotonoil-induced papilloma-bearing mice were slightly more resistant than normal animals.     

Effect of the synthetic cannabinoid nabilone on spermatogenesis in mice

Chronic treatment of mice with the synthetic cannabinoid nabilone (50 mg/kg, 3 times per week) reduced the number of pachytene spermatocytes. Nabilone did not affect other cell types in the testis or the sex organ weights. Nabilone tended to increase the number of abnormal spermatozoa, but this did not reach statistical significance. It is concluded that nabilone causes less testicular toxicity than the natural cannabinoids.     

Effect on non-steroidal anti-inflammatory drugs on Moloney sarcoma virus inoculated mice

Summary Chronic administration of phenylbutazone, flufenamic acid and a new, potent non-steroidal anti-inflammatory agent ITF (3-methyl-5-benzoyl-amino-isothiazole-4-carboxy-p-ethoxyphenylamine) to BALB/c mice inoculated with a Moloney sarcoma virus resulted in a stimulation of tumor growth and increased severity of disease. This treatment, however, had no effect on the spontaneous regression of tumors. Indomethacin in a dose of 5.0 or 2.5 mg per kg suppressed the MSV-induced tumor growth, but this effect was apparently connected with the high toxicity of this drug for mice.     

Effect of the synthetic cannabinoid nabilone on spermatogenesis in mice

Summary Chronic treatment of mice with the synthetic cannabinoid nabilone (50 mg/kg, 3 times per week) reduced the number of pachytene spermatocytes. Nabilone did not affect other cell types in the testis or the sex organ weights. Nabilone tended to increase the number of abnormal spermatozoa, but this did not reach statistical significance. It is concluded that nabilone causes less testicular toxicity than the natural cannabinoids.PBP was supported by an ORS award and David Livingstone Bursary from the U.K.     

Effect of azimexon (BM 12.531) on mouse granulocyte-macrophage and monocyte-macrophage progenitor cells

Summary Treatment of mice with 25 mg/kg azimexon (BM 12.531) resulted in an increase in granulocyte-macrophage colony-forming cells (GM-CFC) in spleen and bone marrow after a transient depression in the cell populations. Bone marrow monocyte-macrophage colony-forming cells (MM-CFC) increased at 7 days after treatment, and splenic MM-CFC were least affected by azimexon treatment. The increase in granulocytic and monocytic colony-forming cells may play a role in the previously reported protection by azimexon against radiation and drug-induced toxicity.Supported by the Armed Forces Radiobiology Research Institute, Defense Nuclear Agency, under Research Work Unit MJ 00026.     

Dexamethasone protection against the acute lethality of ethanol in mice

Summary The administration of dexamethasone (DXM, 2.00 mg/kg) 1 h prior to the injection of lethal doses of ethanol was found to offer complete protection against ethanol toxicity at doses up to 5.25 g/kg and partial protection using higher doses. It is suggested that DXM central action might be involved in the protection against ethanol toxicity.Supported by a grant from U.S. National Aeronautics and Space Administration.     

Acute toxicity of folic acid in mice

The toxicity of folic acid (PGA) was studied in different inbred strains of mice. LD50 values of PGA by the i.p. route showed a unique toxicity pattern. In some strains, convulsions, ataxia and weakness were observed. Histopathological study in strains S/RVCri, BDF1, DBA/2 and DBA/2fNCri showed acute renal tubular necrosis.     

Ureido-ethyl-imidazolines active against autochthonous diethylnitrosamine-induced epidermoid,papillary and adenocarcinomatous tumors of the respiratory tract of Syrian hamsters and against human bronchogenic carcinomas in nu/nu mice

Summary The detection of a new class of tumor inhibiting substances is described. Employing a chemical reaction discovered several years ago, a series of imidazolinylureas were prepared. It was found that some compounds of this group were active against diethylnitrosamine (DENA)-induced tumours in hamsters. CGP 15 720 A (1-{2-[2-(4-pyridyl)-2-imidazoline-l-yl]-ethyl}-3-(4-carboxy-phenyl)urea,Xb), the most active compound at present, was developed through a series of structural variations. CGP 15 720 A inhibits significantly in oral or parenteral treatment with well tolerated doses (10–30 mg/kg) the progressive growth of autochthonous, DENA-induced papillary, epidermoid and adenocarcinomatous tumors of the respiratory system in Syrian hamsters and prolongs significantly the survival. The substance also inhibits significantly the growth of 2 poorly differentiated human epidermoid or anaplastic bronchogenic carcinomas in nu/nu Balb/c mice and prolongs the mean survival time. In these mice, the substance is also active against the rodent ascites tumors Ehrlich carcinoma, CrSa 180 and Yoshida Sa AH 66, although it is only marginally active or inactive against these tumors in normal mice or rats. — In the therapeutic trials, hamsters tolerated the highest dose administered for 4 weeks, 1000 mg/kg p.o., without signs or symptoms of toxicity.Editorial remarks. There is still an urgent medical need for effective and welltolerated drugs for the treatment of the most common forms of cancer, such as bronchial carcinoma, or for post-operative prophylaxis against relapse and metastasis. — The old-established screening method based on rapidly proliferating acute transplantable lymphatic leukemias in the mouse that is applied in the major cancer research centers has certainly achieved some measure of clinical success, inasmuch as the mean duration of survival of patients with acute lymphatic leukemia has increased from 3 months to about 6 years and similar activity has been found in some rapidly proliferating lymphomas, sarcomas and teratomas.The authors were convinced, however, that chemotherapeutic agents effective against lung cancer could only be found with the help of new specific animal models. They developed a model of an autochthonous tumor in the hamster, applied it in extensive series of experiments, and succeeded in synthesizing and identifying a group of compounds that were both effective and well tolerated. They describe the synthesis and biological activity of CGP 15 720, the compound with the highest therapeutic index and an apparently non-cytotoxic mode of action.     

Protection by chlorpromazine against lethality and renal toxicity of cisplatin in mice

The effect of chlorpromazine on acute lethal toxicity and nephrotoxicity induced by cisplatin was studied in mice. Chlorpromazine given (i.p.) 1 h before cisplatin greatly reduced lethal and renal toxicities of cisplatin. Chlorpromazine did not reduce the antitumor activity of cisplatin against Sarcoma 180 in ddY mice or EL-4 Leukemia in C57BL/6J mice.     

Protection by chlorpromazine against lethality and renal toxicity of cisplatin in mice.

The effect of chlorpromazine on acute lethal toxicity and nephrotoxicity induced by cisplatin was studied in mice. Chlorpromazine given (i.p.) 1 h before cisplatin greatly reduced lethal and renal toxicities of cisplatin. Chlorpromazine did not reduce the antitumor activity of cisplatin against Sarcoma 180 in ddY mice or EL-4 Leukemia in C57BL/6J mice.     

Protective effect of Shigyaku-to,a traditional Chinese herbal medicine,on the infection of herpes simplex virus type 1 (HSV-1) in mice

The antiviral activity of Shigyaku-to (TJS-109), a traditional Chinese herbal medicine, was investigated in mice infected with herpes simplex virus type 1 (HSV-1). TJS-109 is a combination of the medicinal plant extracts fromZingiberis siccatum rhizoma,Aconiti tuber andGlycyrrhizae radix in a specific proportion. Mice infected with a 10 LD₅₀ dose of HSV-1 were treated with TJS-109 orally at doses of 1.25 to 20 mg/kg 2 days before, and 1 and 4 days after the infection. The treated groups had 80% (1.25 mg/kg), 40% (5 mg/kg) and 23% (20 mg/kg) mortality rates 25 days after the infection as compared with a 100% mortality rate in control mice treated with saline. When HSV-1 infected mice (recipients) received CD8⁺T cell fractions derived from spleens of mice treated with TJS-109 (donors), 70% of recipients survived, as compared with 0% survivors in the groups of mice treated with saline, B cell fractions, CD4⁺ T cell fractions or macrophage-enriched fractions prepared from the same donors. TJS-109 did not show any virucidal activities against HSV-1 or any virostatic activities on the growth of HSV-1 in Vero cells. These results suggest that TJS-109 protected mice exposed to lethal amounts of HSV-1 through the activation of CD8⁺ T cells.     

Anticonvulsant action of YG 19-256 in baboons with photosensitive epilepsy

Summary YG 19-256, 4-(1,3,4,9b-tetrahydro-5 methyl-2H-indeno[1,2-c]pyridine-2-yl)-2-butanone methane sulphonate, 1–3 mg/kg i.v., abolished or reduced photically-induced myoclonic responses for 1.5–6.5 h in baboons,Papio papio, without producing signs of acute neurological toxicity.We thank the Medical Research Council, The Wellcome Trust and the British Epilepsy Association for financial support, and Drs D.M. Loew and H. Weber (Sandoz Ltd) for the gift of YG 19-256.     

Cellular changes of adrenal under the acute stress of O-chlorobenzylidene malononitrile (CS).

This investigation describes histological and cytometrical changes of cortical and medullary tissue of adrenal in rats under the acute stress of O-chlorobenzylidene malononitrile (10 mg/kg and 20 mg/kg). It has been observed that after injection of CS, the adrenal gland showed histological changes both in the cortical and medullary region.     

Histological changes in thyroid of rat under the acute exposure of O-chloro-benzylidine malononitrile

Summary This communication describes histological changes in the thyroid gland of rats under the acute stress of O-chlorobenzylidene malononitrile (CS) (10 mg/kg and 20 mg/kg). It has been observed that CS, when injected, causes histological changes in the thyroid of varying degrees, depending on the dose used.     

Effect of ethanol on toxicity and metabolism of amphetamine in the mouse.

Ethanol, 3 g/kg i.p., did not significantly alter the acute toxicity of amphetamine in the mouse. However, the urinary metabolite pattern was changed, suggesting that ethanol suppressed metabolism of the stimulant during the initial 6 h period. After 24 h, the mouse metabolized the same fraction of a given dose of amphetamine, whether it was given as amphetamine alone or amphetamine mixed with 2,3 or 4 g/kg ethanol.     

Induction of microsomal drug-metabolizing enzymes caused by hexobarbital.

Hexobarbital was given to anaesthetized mice for a period of 7 h by repeated i. p. injection, first of 100 mg/kg,then several times of 50 mg/kg. A high level of hexobarbital was maintained in the liver. The activity of microsomal drug-metabolizing enzymes was induced by this treatment with hexobarbital. 30 min after a single i. p. injection of 100 mg/kg of hexobarbital, there was a significant inhibition of aminopyrine N-demethylase but none of cytochrome c and neotetrazolium reductases. Hexobarbital in vitro inhibits aminopyrine N-demethylase but not cytochrome c reductase.     

Acute toxicity of folic acid in mice

Summary The toxicity of folic acid (PGA) was studied in different inbred strains of mice. LD₅₀ values of PGA by the i.p. route showed a unique toxicity pattern. In some strains, convulsions, ataxia and weakness were observed. Histopathological study in strains S/RVCri, BDF₁, DBA/2 and DBA/2fNCri showed acute renal tubular necrosis.Acknowledgment. The authors thank Ms N. Hasgekar for her technical assistance     

Induction of microsomal drug-metabolizing enzymes caused by hexobarbital

Summary Hexobarbital was given to anaesthetized mice for a period of 7 h by repeated i. p. injection, first of 100 mg/ kg, then several times of 50 mg/kg. A high level of hexobarbital was maintained in the liver. The activity of microsomal drug-metabolizing enzymes was induced by this treatment with hexobarbital. 30 min after a single i. p. injection of 100 mg/kg of hexobarbital, there was a significant inhibition of aminopyrine N-demethylase but none of cytochrome c and neotetrazolium reductases.—Hexobarbital in vitro inhibits aminopyrine N-demethylase but not cytochrome c reductase.