Effective prevention of lethal acute graft-versus-host disease by combined immunosuppressive therapy with prodigiosin and cyclosporine A.

Prodigiosin (PDG), a bacterial metabolite, is a known T cell-specific immunosuppressant. Here, we compared its inhibitory potency and mode of action with cyclosporine A (CsA) in a mouse model. PDG efficiently inhibited T cell proliferation with an IC(50) of 3.37 ng/ml, a similar dose to that of CsA (IC(50) of 2.71 ng/ml). PDG inhibited only IL-2Ralpha expression, but not IL-2 expression, whereas CsA inhibited both. Exogenously added IL-2 reversed the suppressive activity of CsA, but not that of PDG. Moreover, although both PDG and CsA markedly reduced mortality rates in lethal acute graft-versus-host disease (GVHD), the combined treatment was more effective than either drug alone. These results demonstrate that PDG and CsA have similar inhibitory potencies, but different modes of action, and suggest that PDG has potential use as a supplementary immunosuppressant in combination with CsA for the treatment of GVHD.

Janus kinase 3: a novel target for selective transplant immunosupression.

Existing immunosuppressants inhibit lymphocyte activation and T cell cytokine signal transduction pathways, reducing the rate of acute rejection episodes to < 10%. However, the widespread tissue distribution of their molecular targets engenders pleiotropic toxicities. One strategy to address this problem seeks to identify compounds that selectively inhibit a target restricted in distribution to the lymphoid system. Janus kinase (Jak) 3 is such a molecule; it mediates signal transduction via the gamma common chain of lymphokine surface receptors. Disruption of this lymphoid-restricted enzyme would not be predicted to produce collateral damage in other organ systems. Development of selective Jak3 inhibitors has been difficult due to crossreactivity with its homologue, Jak2. In contrast to all other putative antagonists, which are discussed in detail herein, one Jak3 inhibitor, NC1153, shows at least 40-fold greater selective inhibition for Jak3 than for Jak2, is robustly synergistic with calcineurin antagonists, and, either alone or in combination with cyclosporin, produces no adverse effects in rodents preconditioned to be at heightened risk for nephrotoxicity, bone marrow suppression, or altered lipid metabolism.

Evaluating new antimalarial drugs against trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys.

An antimalarial drug testing system is described which utilizes trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys. The schizonticidal activity of standard antimalarial drugs in this system is reported. The system accurately predicted antimalarial activity in man of 8 of 9 compounds selected for clinical trials.

[Effect of prodigiozan on the course of candidiasis of the oral mucosa clinically and in an experiment]. / Vliianie prodigiozana na techenie kandidoza slizistoi obolochki polosti rta v klinike i éksperimente

The effect of various doses of prodigiozan on Candida infection was studied under experimental and clinical conditions. Hamsters and guinea pigs were used in the experiments. Prodigiozan was administered intramuscularly to the hamsters in doses of 100 gamma/kg of the body weight 1 hour before the infection and intracutaneously to the guinea pigs in doses of 50 gamma/kg 2 days before the infection. The results showed that the drug accelerated the recovery of the animals. In complex therapy of a group of 22 patients with candidosis of the mouth mucosa of various localization prodigiozan was administered thrice in doses of 50 gamma/kg. This provided faster elimination of the pathological process.

[Effect of carbenicillin and its combination with prodigiozan and lysozyme on the course of an experimental inflammatory process of Proteus etiology]. / Vliianie karbenitsillina i ego sochetaniia s prodigiozanom i lizotsimom na techenie vospalitel'nogo protsessa proteinoi étiologii v éksperimente

Biological properties of 142 Proteus strains isolated from patients were studied. Sensitivity of Proteus to II antibiotics was tested. The isolates were resistant to most of the antibiotics. The highest number of the isolates was sensitive to ampicillin (77.1 minus or plus 7.16) and especially to carbenicillin (82.6 plus or minus 6.16). This provided the use of carbenicillin for the treatment of experimental septicemia in albino mice and wound processes in rabbits with Proteus complications. The high therapeutic effect of the antibiotic was shown in experiments with 210 albino mice and 44 rabbits. The therapeutic effect of carbenicillin increased when it was used in combination with prodigiozan and especially in combination with prodigiozan and lysozyme.