3-4-5-trihydroxybenzamidoxime and Disease-Models--Animal

Clinically, the vascular pathobiology of human sickle cell disease includes an abnormal state of chronic inflammation and activation of the coagulation system. Since these biologies likely underlie development of vascular disease in sickle subjects, they offer attractive targets for novel therapeutics. Similar findings characterize the sickle transgenic mouse, which therefore provides a clinically relevant inflammation model.. The authors tested two polyhydroxyphenyl hydroxamic acid derivatives, didox and trimidox, in sickle transgenic mice. Animals were examined by intravital microscopy (cremaster muscle and dorsal skin fold preparations) and by histochemistry before and after transient exposure to hypoxia, with versus without preadministration of study drug. Previous studies have validated the application of hypoxia/reoxygenation to sickle transgenic mice as a disease-relevant model.. Animals pretreated with these agents exhibited marked improvements in leukocyte/ endothelial interaction, hemodynamics and vascular stasis, and endothelial tissue factor expression. Thus, these drugs unexpectedly exert powerful inhibition on both the inflammation and coagulation systems.. Each of these changes is expected to be therapeutically beneficial in systemic inflammatory disease in general, and in sickle disease in particular. Thus, these novel compounds offer the advantage of having multiple therapeutic benefits in a single agent.

Topics: Anemia, Sickle Cell; Animals; Benzamidines; Blood Coagulation; Cell Communication; Chronic Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelial Cells; Enzyme Inhibitors; Humans; Hydroxamic Acids; Inflammation; Leukocytes; Mice; Mice, Transgenic; Thromboplastin

Inhibition of ribonucleotide reductase (RR) has gained attention as a potential strategy for HIV-1 therapy through the success of hydroxyurea (HU) to potentiate the activity of the nucleoside reverse transcriptase inhibitor (NRTI) didanosine (ddI) in clinical trials. However, the use of HU has been limited by its development of hematopoietic toxicity. In this study, the novel RR inhibitors didox (DX; 3,4-dihydroxybenzohydroxamic acid), and trimidox (TX; 3,4,5-trihydroxybenzamidoxime) were evaluated along with HU for anti-retroviral efficacy in LPBM5-induced retro-viral disease (MAIDS) both as monotherapeutic regimens and in combination with the guanine containing NRTI abacavir (ABC). Anti-retroviral drug efficacy was determined by measuring inhibition of splenomegaly, hypergammaglobulinemia, and splenic levels of proviral DNA. In this study, all RRIs tested showed the ability to improve the efficacy of ABC in the MAIDS model by reducing splenomegaly, hypergammaglobulinemia, and splenic proviral DNA levels.

Topics: Animals; Antiviral Agents; Benzamidines; Bone Marrow Cells; Dideoxynucleosides; Disease Models, Animal; Drug Therapy, Combination; Hematopoietic Stem Cells; Hydroxamic Acids; Hydroxyurea; Mice; Mice, Inbred C57BL; Murine Acquired Immunodeficiency Syndrome; Ribonucleotide Reductases; Spleen; Splenomegaly

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Benzamidines; Disease Models, Animal; Drug Resistance, Microbial; Humans; Hydroxamic Acids; Immunity, Cellular; Mice; Ribonucleotide Reductases; Sensitivity and Specificity

Recent information on the compounds that inhibit cellular enzymes to suppress HIV and increase the antiviral activity of nucleoside analogs, such as AZT or ddI, is examined. Specific drugs addressed include didox, trimidox, fluorouracil, floxuridine, ribavirin, and dipyridamole. Also addressed are the promising combination therapies of ribavirin with ddI, and AZT with dipyridamole.

Topics: Animals; Antiviral Agents; Benzamidines; Dipyridamole; Disease Models, Animal; Floxuridine; Fluorouracil; Humans; Hydroxamic Acids; Hydroxyurea; Mice; Murine Acquired Immunodeficiency Syndrome; Ribonucleotide Reductases