Growth and conidiation of Trichoderma viride are affected by non-steroidal antiinflammatory agents.

Nonsteroid antiinflammatory agents (NSAIA's) (inhibitors of cyclooxygenase and lipoxygenase) of several structural series inhibited growth of Trichoderma viride. The most potent growth inhibitors were indomethacin and its derivative repanidal which inhibited in the range of 0.1 mmol/L. The weakest inhibitors were acetylsalicylic acid and lysine salicylate which exerted only a weak effect at concentrations above 1 mmol/L. The inhibition of growth was accompanied by a stimulation of conidiation in the dark. A light pulse increased the efficiency of these drugs to stimulate the conidiation. Saccharomyces cerevisiae was as sensitive to NSAIA's as T. viride while Botrytis cinerea was less sensitive. The results indicate that arachidonate metabolism may play a role in the growth of fungi and may participate also in the process of conidiation.

Methyl-alpha-D-mannopyranoside, mannooligosaccharides and yeast mannans inhibit development of rat adjuvant arthritis.

Methyl-alpha-D-mannopyranoside, mannooligosaccharides obtained by acetolysis of yeast mannan, and pure mannans isolated from the cell walls of pathogenic (Candida albicans) and nonpathogenic (Saccharomyces cerevisiae) yeasts were used for treatment of rat adjuvant arthritis. The arthritis was induced by the application of Freund's complete adjuvant into the tail region of rats. The mannose substances were injected into the arthritic rats intraperitonealy at different time intervals. Levels of serum albumin, changes in hindpaws swelling and radiographs were measured in infected rats as variables of the inflammation and destructive arthritic changes. While mannan from C. albicans inhibited both the inflammation and destructive arthritic changes, mannan from S. cerevisiae showed less effect. However, acetolysate of S. cerevisiae mannan as well as simple methyl-alpha-D-mannopyranoside inhibited both inflammation and destructive arthritic changes to a similar degree as mannan isolated from C. albicans. The effect, which is not dose dependent indicates its possible immunoregulatory mechanism. This is the first time a therapeutic effect of simple carbohydrates on rat adjuvant arthritis has been described.

[Immunomodulatory effect of Consupren Sol. Spofa (cyclosporin A). Preclinical study]. / Imunomodulacní úcinky Consuprenu Sol. Spofa (cyklosporinu A). Preklinická studie.

Consupren Spofa was demonstrated in our tests to be a distinguished immunomudulating agent. The preparation did not show any direct lymphotoxicity or myelotoxicity but it markedly influenced maturation of T lymphocytes in the thymus. When testing the functional activity of the immunity system in vivo, the inhibitory effect of Consupren Spofa was manifested only when administering a relatively larger dose of the drug with an antigenic stimulus or shortly after it, i.e., in the period of early activating processes. The use of a suitable time and dosage regimen is therefore decisive to induce an inhibitory effect. On the basis of comparative experiments it can be stated that Consupren Spofa is minimally as much effective as, or in some experiments even more effective than Sandimmun Sandoz.

[New analgesically active derivatives of 1-phenyl-5-mercaptotetrazole]. / Nové analgeticky úcinné deriváty 1-fenyl-5-merkaptotetrazolu.

For the investigation of new anti-inflammatory drugs, 1-phenyl-5-mercaptotetrazole (I) was selected as the principal structure. The purpose itself lay in an alkylation of the mercapto group with different remainders. In some cases at the same time a substituent was introduced on the phenyl nucleus in position 1. An alkylation of 1-phenyl-5-mercaptotetrazole with ethyl bromacetate and a subsequent hydrolysis resulted in (1-phenyl-5-tetrazolylthio)acetic acid (II) as well as its chloride and hydrazide. The reaction of chloride with amino acids gave rise to amides III-VII. From hydrazide and phenylisocyanate, 4-chlorphenylisocyanate and phenylisothiocyanate, semicarbazides VIII and IX and thiosemicarbazide X were prepared. Furthermore, a reaction of substituted anilines and 2,3-expoxypropylchloride yielded the pertinent 3-anilino-2-hydroxypropylchlorides XX-XXIII, by which 1-phenyl-5-mercaptotetrazole in the form of the potassium salt was alkylated to compounds XIV-XIX. 1-Phenyl-5-mercaptotetrazole was also alkylated by 2-chlorethanol and the obtained 1-phenyl-5-(2-hydroxyethylthio)tetrazole was esterified by 4-phenylbenzoylchloride and 2-acetoxybenzoyl-chloride giving rise to esters XII and XIII. Finally, three compounds XXIV-XXVI, resulting from an alkylation of 1-phenyl or 1-allylmercaptotrazole by substituted 3-phenoxy-2-hydroxypropylchlorides. In all compounds an orientational acute toxicity higher than 1 g/1 kg p.o. was found. Pharmacological results are shown in Table 2. None of the above-mentioned compounds showed a significant anti-inflammatory efficacy. Analgetic efficacy was manifested in a more marked way; in compound VIII it is comparable with the used standard aminophenazone.

Reductive effect of lonazolac on lung metastasis formation in mice.

The purpose of this study was to determine the antimetastatic potential of lonazolac. Intravenous inoculation of Lewis lung carcinoma (LLC) or melanoma B-16 (B-16) cells induced macroscopically detectable lung metastases on day 15 after inoculation. After pre- and post-treatment with lonazolac-Ca at oral doses of 1, 25, and 50 mg/kg, the numbers of animals with lung metastases and the score of metastases significantly decreased. Lonazolac-Ca had similar effects also on the formation of spontaneous lung metastases. After treatment with lonazolac-Ca at oral daily doses of 1, 25, and 50 mg/kg during 8 days (LLC) or 10 days (B-16) after inoculation of the tumor cells, the number of animals developing spontaneous lung metastases and the score of metastases also decreased. Intravenous injection of lonazolac natrium was effective in protecting the mice inoculated with 1 X 10(6) melanoma B-16 cells against acute pulmonary embolic death.

[Thymosin fraction 5. Preclinical study]. / Thymosin frakce 5. Preklinická studie.

Thymosin fraction 5 from the Research Institute for Pharmacy and Biochemistry possessed the immunomodulatory activity in performed tests. The activity is manifested mostly by the induction of the maturation and the differentiation of T cell precursors, which are released from thymus to secondary lymphoid organs. Thymosin fraction 5 causes the expression of the surface membrane markers Thy-1.2, Lyt-2 and L3T4 on the immature T lymphocytes as well. The induced cells are immunocompetent and able to exert the complete functional activity. In the intact mice thymosin fraction 5 had not pronounced effect on the functional potency of mature immunocompetent cells, but in MTA influenced mice its stimulatory effect on the proliferative response to mitogens and on the antibody production against the T-dependent antigen was demonstrated. Thymosin fraction 5 influenced positively not only the components of the specific immunity, but also the functional activity of peritoneal macrophages. The toxicity of thymosin fraction 5 was in the battery of tests in vitro and in vivo very low and therefore it can be considered to be harmless for the clinical practice.

Hindering of tumor lung metastasizing with alpha-(4-cyclohexylphenyl)propionic acid in mice.

Alpha-(4-cyclohexylphenyl)propionic acid, a potent inhibitor of platelet aggregation, has appeared to reduce the quantity and size of Lewis lung carcinoma (LLC) tumor nodules in the lungs. The number of animals developing the tumor colonies in the lungs was decreased by 34% to 49% either when the tumor cells were injected i.v. and alpha-(4-cyclohexylphenyl)propionic acid was administered during 3 days, or when the tumor cells were transplanted i.m. The primary tumor was removed 6 days later and the drug administered during 8 or 21 days.

Substances with antineoplastic activity. XCVI. Some pharmacological properties and therapeutic synergism of 6-purinyl-N-(2-chloroethyl)thiocarbamate with cytosine arabinoside.

The cancerostatic effect of 6-purinyl-N-(2-chloroethyl)thiocarbamate (Cloturin VUFB, VUFB-15686) was studied in detail in mice and rats bearing transplantable tumors. The cytotoxic activities were measured by determining the incorporation rate of 5-iodo-2'-deoxy[6-3H]uridine and uniformly labeled [U-14C]amino acid mixture into trichloroacetic acid-insoluble fraction of Yoshida ascites reticulosarcoma cells during a short-term incubation with the drug. From the results obtained it follows that the new substance is therapeutically more effective in comparison with 6-mercaptopurine (NSC-755). A therapeutic synergism of Cloturin with cytosine arabinoside (NSC-63978) was observed.

The possibilities of predicting allergic effects of new antirheumatics.

The new antirheumatic drugs Benzofenac and Flobufen were assessed for their possible influence on various immunological parameters. They were shown to enhance passive cutaneous anaphylaxis (PCA) to ovalbumin in rats and to suppress the numbers of helper and suppressor T-lymphocytes in mice. The effect of Benzofenac in the latter system was found to be more pronounced. The drugs had no effects in any of the other test systems, including the development of delayed hypersensitivity, mitogen-induced lymphocyte proliferation in vitro and the production of antisera (as tested by PCA).

Inhibitory action of flurbiprofen and mopidamole on tumor lung metastasis formation in mice.

Flurbiprofen, 0.25 mg/kg, administered to mice orally once daily during 3 days prior to an iv transplantation of Lewis lung carcinoma cells, protected 50%-57% of experimental animals from the formation of lung tumor colonies. With the daily dose of 1.0 mg/kg, this effect was less pronounced. Mopidamole, twice daily 90 mg/kg orally during 3 days, did not have this effect.

To what extent can results of experimental studies be extrapolated in predicting adverse side effects of drugs in man?

A new potential antiinflammatory substance serves as an example that substantiates the necessity of carrying out concurrent comparative pharmacokinetic and biotransformation studies of new drugs in experimental animals and man during the preclinical research stage, with adherence to all safety precautions. Such a procedure will facilitate the choice of an animal model that approaches human metabolism and pharmacokinetics as closely as possible. This serves in the further development of the test drug, and thus enhances the validity of the transfer of experimental data to man, especially from the toxicological aspect.

Antimetastatic effect of flurbiprofen and other platelet aggregation inhibitors.

In the present study, we have examined the antimetastatic effect of flurbiprofen, a nonsteroidal antiinflammatory drug, on spontaneous metastases formation in mice bearing Lewis lung carcinoma and these results were compared with effects of other inhibitors of platelet function (mopidamole, dipyridamole, pentoxifylline). Flurbiprofen decreased significantly spontaneous metastases formation in a dose-depending manner. From the results obtained, it appears that the treatment with flurbiprofen, either on days 1-8 or days 1-21, was similarly effective. In mopidamole treated groups the number of animals with lung metastases was significantly decreased. This effect was not observed after treatment with dipyridamole or pentoxifylline.