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The effects on peritoneal macrophages of some chemotherapeutic agents administered subcutaneously to conventional male AB/Jena mice were studied. beta-[1-ethyl-(5-bis-(beta-chloroethyl)-aminobenzimidazolyl-(2)]-DL-alanine (IMET 2925), beta-[1-phenyl-5-bis-(beta-chloroethyl)-amino-benzimidazolyl-(2)]-DL-alanine (IMET 3164), and gamma-[1-phenyl-5-bis-(beta-chloroethyl)-amino-benzimidazolyl-(2)]-butyric acid (IMET 37/70) evoked a pronounced variation of the cell surface consisting in a shortening, coarsening and reduction in number of the microvili and other projections. Likewise, 1.3-bis(piperidinomethyl)-5-ethyl-5-phenyl-barbituric acid induced a flattening of the surface, but the structures appeared to be increased in number per area. Chlorambucil, 6-mercaptopurine, and 5-fluoro-uracil failed to provoke any obvious change in the threedimensional cell surface structure. These morphological findings are consistent with functional results reported previously.

Three spontaneous lymphomas of 23- to 24-month-old (AB/Jena X DBA/2 Jena)F1 females were serially transplanted into syngeneic hosts. They were histologically classified as malignant lymphoblastic lymphomas (ABDt2 and ABDt5) and as a malignant lymphoma of histiocytic type (ABDt6). All lymphomas disseminated into the liver, spleen, and pancreas, whereas ABDt2 and ABDt5 additionally infiltrated the bone marrow and leptomeninx. None of the tumors showed a leukemic growth form, but extreme granulocytosis was observed in leukemia P388-bearing mice. Since the lymphomas ABDt2 and ABDt5 expressed T-cell differentiation antigens Ly-1, Ly-2, and Ly-3, they are thought to be of T-cell origin. On the contrary to the lymphocytes of parental mouse strain ABDt2 and ABDt5 cells reacted with anti H-2.23 allosera. All tumors have been found to be sensitive to at least 5/7 clinically used anticancer drugs. But only ABDt2- and P388-bearing mice survived longer than 60 days after treatment with the potent anticancer drug 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone). Successful chemotherapy of both tumors was accompanied with resistance of the hosts against the second transplant of the same tumor. Summarizing the characteristics of the newly established transplantation tumors it is concluded that they can be recommended as screening models in the search for new antineoplastic agents.

ABD2F1 mice were infected intraperitoneally (i.p.) or intranasally (i.n.) with Mengo or Sindbis virus and treated with either crude murine alpha/beta interferon (MuIFN-alpha/beta) or quercetin, or both. MuIFN-alpha/beta given i.p. or intramuscularly (i.m.) 1-3 h before the infection had a dose-dependent protective effect regardless of the route of administration. When given after the infection, IFN did not show any effect. Oral quercetin, capable of protecting cardio, i.e. Mengo virus-infected mice, failed to show antiviral efficacy in Sindbis virus-infected animals. Of various combinations of quercetin and MuIFN-alpha/beta, a certain well defined regimen resulted in a significant enhancement of protection in Mengo, but not Sindbis, virus-infected mice. A marginally effective treatment regimen of quercetin (20 mg/kg, given 12 h before Mengo virus infection, and 10 mg/kg given both 1 h before and 12 h after infection) potentiated the activity of a single dose of MuIFN-alpha/beta (5000 IU 3 h prior to infection), giving 85-100% survivors compared to 50% for MuIFN-alpha/beta when applied alone (p less than 0.001).

A mathematical model of the pathogenesis of experimental Mengo virus infection in mice has been developed and fitted using kinetic data of both virus multiplication in different organs and mortality. The behaviour of the model proved to be bistable. In contrast to the widely accepted hypothesis that an acutely virus-infected host dies when virus replication has attained a critical level in the main target organ, the present results showed the following: the maximum virus titre in brain, the main target organ, has been reached already 24 hr post infection (p.i.) but the animals began to die since 60 hr. Hence, it was postulated and confirmed by a good model fit to the experimental data that the so-called AUC (area under the curve) of the virus multiplication kinetics may be a critical quantity. From this finding a hypothesis was deduced assuming that in the presence of high amounts of the virus the antiviral effect of IFN wanes with time. Since this process accounts for death, it may be a potential target of antiviral therapy.

In acute toxicity studies the maximum tolerated dose (MTD), the LD50 and the LD100 of Bendamustin were determined in rats and mice after i.v. and oral administration. In a subchronic study male rats were given Bendamustin for 28 days at oral dose levels of 5, 10, 20 or 40 mg/kg/day. Chlorambucil was used as a standard at dose levels of 1, 5 and 10 mg/kg/day. Bodyweight gain, food and water intake, hematology, clinical chemistry and histopathology were evaluated. With quantitative differences the main target organs for both compounds were the bone marrow, the kidney, the intestine and the lymphatic system. Additionally, Chlorambucil caused a significant atrophy of the testes and a slight atrophy of the pancreas at a dose of 5 mg/kg/day. In conclusion, the data obtained may be used as a base to evaluate the therapeutic range of Bendamustin compared to Chlorambucil for the oral route.

Beta-[1-Phenyl-5-bis(beta-chloroethyl)-amino-benzimidazolyl-(2)]-DL-alanin (ZIMET 3164), a highly immunosuppressive but moderately cytostatic agent, was found to be able to prevent the progression of spontaneous murine immune complex nephritis in a dose-dependent fashion. For experiments, BCG-stimulated conventional female (NMRI X NZB)F1 mice suffering from rapidly progressive nephritis, BCG-stimulated and unilaterally nephrectomized (NMRI X NZB)F1 females, and (AB/Jena X NZB)F1 females characterized by a prolonged course of the disease were used. The beneficial effect was quantified by fluorescence photometry and histometry, and semiquantitatively detected by estimation of the extent of damage of individual glomerular structures when histometric methods were unsuited. Treatment of young adult animals characterized by slight to moderate glomerular lesions was more effective than of older ones with advanced nephritis. At equi-immunosuppressive dose levels ZIMET 3164 was about twice as effective as the reference substance cyclophosphamide.

After daily administration of 1 mg/kg over a period of 4 weeks, hirudin did not influence growth and general behaviour of the animals. There was no indication of treatment-related effects on the liver and the kidneys, on number and function of thrombocytes, on number and differentiation of white cells or on the erythrocytic system. Haemorrhagic complications did not occur. Formation of antibodies was not detectable. Histopathological changes due to application of r-hirudin were not found. LD50 is greater than 50 mg/kg body weight for intravenous application.

Experiences with the three step teratological screening test for selection of teratogenic side effects are described. Step I: The prenatal examination of the foetuses may give indications of embryotoxicity, growth retardation and teratogenicity. Step II: The peri- and postnatal examination includes the duration of pregnancy, the delivery, the viability, the postnatal development and behaviour of the untreated offspring. In special cases the transplacental tumour induction may be studied. Step III: The fertility of the untreated offspring is examined and, in some cases, the generation test should be added.

The influence of increasing doses of various potentially antiviral agents on Mengo virus-and Sindbis virus-infected mice was assessed determining death rates and histologic lesions. All drugs given in abundance showed dose-dependent decrease of antiviral activity following the maximum protective effects in either animal model. From the toxicological point of view the antiviral agents in question could be classified into two groups. High doses of tilorone hydrochloride or 10-carboxymethyl-9-acridanone produced toxic effects in both uninfected and virus-infected animals. In contrast, high doses of quercetin, double-stranded ribonucleic acid (dsRNA), 1-ethylisatin-S-n-butylisothiosemicarbazone or Norakin induced no obvious drug-mediated histologic alterations either in uninfected or in virus-infected individuals, but exerted a decreased protection in virus-infected animals. It is suggested that high doses of the compounds of second group adversely affect early host defence in both Mengo virus and Sindbis virus-infected mice.

Intranasal (i. n.) infection with 10 LD50 of Sindbis virus caused acute encephalomyelitis and death in ABD2F1 mice 3-7 days post infection (p.i.). Histologic lesions were found in the CNS, pancreas. liver, parotid glands, exorbital lacrimal glands, lymphoid organs and kidneys. Repeated oral administration of the anticholinergic anti-Parkinson drug Norakin protected infected animals from death in a dose-dependent manner when treatment was started prior to but not after virus inoculation. The maximum protective effect was achieved when the drug was administered twice daily at doses of 2.5 or 5.0 mg/kg body mass for at least 56 hr; single injections of the full daily dose were ineffective. Daily doses of greater than or equal to 25 mg/kg body mass had a reduced protective effect or failed to prevent mortality. Administration of Norakin up to doses of 300 mg/kg body mass per day to noninfected ABD2F1 mice were tolerated without obvious clinical or histological signs of illness over a period of 104 hr. Replication of sindbis virus in BHK 21/C13 cells was not inhibited by Norakin concentrations up to 10 micrograms/ml. In Mengo virus-infected mice Norakin did not exert any protective effect within the range of 1.25-50.0 mg/kg body mass when treatment started 1 hr before infection and has been continued twice daily over a period of 104 hr.

Four newly synthesized estra-1,3,5(10)-triene-derivatives, --3-methoxy-17 alpha-cyanomethyl-estra-1,3,5(10)-triene-17 beta-ol (I), --3-methoxy-17 alpha-rhodanomethyl-estra-1,3,5(10)-triene-17 beta-ol-tetrahydropyranylether (II), --17 beta-(N',N'-dimethylhydrazinocarbonyloxy)-estra-1,3,5(10)-triene-3-ol (III), --3-methoxy-17 beta-(N-phenylaminocarbonyloxy)-estra-1,3,5(10)-triene (IV), were studied in subchronic toxicity tests in female rats. The drugs were given orally and compared to mestranol (V) which was used as a reference. Special histopathologic examination was performed in each rat with respect to pituitary morphology. Different pituitary responses to the applied estrogens were found with regard to hyperplasia of the adenohypophysis and interstitial haemosiderosis: 17 beta-hydroxy-17 alpha-alkylsubstituted derivatives (I, II, V) were less effective than 17 beta-carbamyloxy-derivatives (III, IV). These findings may be related to differences in pituitary accumulation of the investigated compounds, indicating any disposition-effect-relationships.

Turimycin is characterised by low acute toxicity. Mean lethal doses for mouse and rat are 750 mg/kg body weight for intraperitoneal application of something in excess of 3,000 mg/kg for oral administration. The blood pressure of anaesthetised cats may be reduced by amounts depending on intravenous Turimycin doses (between 10 and 50 mg/kg). The hypotensive effect of Turimycin is attributable to its negative inotropic effect on the heart and its spasmolytic action on the unstriated muscles. Reversible reduction of urine and ion excretion of rat following intraperitoneal application of 50 mg/kg body weight of Turimycin is interpreted as a consequence of such action upon blood pressure. A preliminary study was conducted into dogs which had orally received daily Turimycin doses of 50 or 125 mg/kg body weight over twelve months. No substance-depending functional or morphological damage was recorded.

After single i.v. administration of cis-diammine-platinum(II)-lactate cis-diammine-platinum(II)-lactate, L cis-diammine-platinum(II)-dilactate trans-dihydroxy-cis-dichlorodiammine-platinum(IV), the LD50 values have been calculated to range between 80 and 130 mg/kg in mice, and between 22 and 45 mg/kg in rats. The LD50 of cis-DDP amounted to 17 mg/kg and 6.6 mg/kg, respectively. Likewise, the compounds have been found to be about 3 to 5 times less toxic than the standard cis-DDP when administered daily for 5 consecutive days. Since the kidneys, the bone marrow, the lymphatic tissue and the intestinal tract have been proved to be the main target organs, the profile of the toxic action of the Pt(II)-complexes seems to be similar to that of cis-DDP. Additionally, the Pt(IV) compound has been found to be toxic to the pancreas, the liver and the salivary glands. With regard to the antineoplastic activity the more soluble lactates of cis-DDP showed a smaller therapeutic index compared to cis-DDP.