PubMed · 4924371
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J B Wyngaarden. 1965. Gout.. https://doi.org/10.1016/b978-1-4831-6750-3.50006-8
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BACKGROUND: Leishmaniasis is a major tropical and subtropical parasitic disease. Sodium stibogluconate, N-methyl -D-glucamine antimoniate, amphotericin B, pentamidine, and ketoconazole are drugs used to treat this disease. Some of these drugs cause severe adverse side effects and treatment failures are common. Allopurinol, a purine analog, has been used to treat leishmaniasis, alone or combined with the previously mentioned drugs. Low cost, ease of administration (oral), and lack of toxicity make allopurinol a particularly appealing candidate. METHODS: The effect of allopurinol on Leishmania infantum (MCAN/ES/89/IPZ229/1/89, zymodeme MON1) wild-type promastigotes (wt-p229), and an altered form of these promastigotes (allo-p229) resulting from long term in vitro exposure to allopurinol, was determined by [(3)H]-thymidine incorporation assays and by diverse flow cytometric approaches. RESULTS: Allopurinol arrested the proliferative capacity of wt-p229 promastigotes, reduced the proportion of viable cells, and decreased their total protein content. In contrast, allo-p229 promastigote proliferation was only slightly decelerated and the proportion of viable cells and the protein content were not affected by the allopurinol treatment. CONCLUSIONS: The flow cytometry approach allowed us to demonstrate differences in allopurinol susceptibility of the two promastigote forms, expanding the spectrum of flow cytometry applications in studies of parasite resistance.
Reperfusion of tissues after interruption of their vascular supply causes free-radical generation that leads to tissue damage, a scenario referred to as "reperfusion injury." Because sickle disease involves repeated transient ischemic episodes, we sought evidence for excessive free-radical generation in sickle transgenic mice. Compared with normal mice, sickle mice at ambient air had a higher ethane excretion (marker of lipid peroxidation) and greater conversion of salicylic acid to 2,3-dihydroxybenzoic acid (marker of hydroxyl radical generation). During hypoxia (11% O(2)), only sickle mice converted tissue xanthine dehydrogenase to oxidase. Only the sickle mice exhibited a further increase in ethane excretion during restitution of normal oxygen tension after 2 hours of hypoxia. Only the sickle mice showed abnormal activation of nuclear factor-kappaB after exposure to hypoxia-reoxygenation. Allopurinol, a potential therapeutic agent, decreased ethane excretion in the sickle mice. Thus, sickle transgenic mice exhibit biochemical footprints consistent with excessive free-radical generation even at ambient air and following a transient induction of enhanced sickling. We suggest that reperfusion injury physiology may contribute to the evolution of the chronic organ damage characteristic of sickle cell disease. If so, novel therapeutic approaches might be of value.
Virus-induced elaboration of proinflammatory cytokines is mediated by virus-induced oxidative stress. The purpose of these studies was to determine the source of the virus-induced oxidative stress. Inhibition of viral replication with antibody to intercellular adhesion molecule-1 had no effect on virus-induced oxidative stress or interleukin-8 (IL-8) response (597+/-88 vs. 668+/-78 pg/mL in control cells). Treatment of cells with diphenylene iodonium inhibited virus-induced oxidative stress and IL-8 elaboration, but allopurinol, ibuprofen, and rotenone had no effect. Studies in cell lines produced from a patient with gp91-phox deficiency revealed normal responses. In contrast, the oxidative response was decreased and the IL-8 concentration was 227+/-36 pg/mL in cells from a patient with p47-phox deficiency, compared with 664+/-48 pg/mL in control cells. These studies suggest that the stimulation of reactive oxygen species by viral challenge occurs at the cell surface even in the absence of viral replication and involves a flavoprotein that may act in concert with p47-phox.