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Preincubation of CD4 lymphocytes with pentamidine isethionate at a concentration of 1.5 mg/L then removal from incubation medium prior to addition of HIV-1, or incubation of cells with the drug and virus simultaneously, increased HIV-1 DNA load but reduced p24 antigen release. The number of syncytia generated was not affected by the presence of pentamidine. The extent of balloon degeneration of cells was greater, however, although this was not associated with a discernable increase in cellular necrosis or reduction in cell viability. This suggests that drug-treatment resulted in an increased load of intracytoplasmic (but not necessarily integrated) forms of HIV- 1; this may explain the lower levels of antigen produced and also the balloon degeneration of treated cells, a phenomenon previously observed with other retroviruses.

Therapeutic concentrations (0.3-1.5 mgL-1) of pentamidine isethionate, normally obtainable in-vivo after parenteral administration of the drug, did not affect the in-vitro activity of the enzymes lysozyme, beta-glucuronidase or myeloperoxidase released from zymosan-activated human neutrophilic granulocytes. At concentrations of 0.7, 1.1 and 1.5 mgL-1, activity of cytosolic enzymes lactate dehydrogenase and glucose-6-phosphate dehydrogenase were reduced relative to untreated cells (P < 0.001 and P < 0.01, respectively), but not in a dose-dependent fashion. Cell viability, as determined by dye-exclusion remained unaffected.

Both pentamidine isethionate and pentamidine mesylate induced a depression in activity of the NADPH-dependent oxidase system of stimulated human neutrophilic granulocytes. This drug-induced effect occurred at concentrations of 0.7, 1.1 and 1.5 mg/l, values within the therapeutic range after parenteral administration of a standard dose of either pentamidine salt, and was dose-related. There was no significant difference between the two salts with regard to this suppression in neutrophilic granulocyte function. The reduced activity of the NADPH-dependent oxidase system, after incubation with pentamidine salts, may be associated with the previously observed depression in candidacidal capacity of human neutrophilic granulocytes treated with these drugs.

Therapeutic concentrations (0.3-1.5 mg/l) of pentamidine isethionate and pentamidine mesylate, obtained after parenteral administration of either drug, did not affect oxygen consumption in the stimulated neutrophilic granulocyte. At concentrations of 0.7, 1.1 and 1.5 mg/l, superoxide production, hydrogen peroxide production, myeloperoxidase (MPO)-mediated iodination and hexose monophosphate shunt activity were suppressed relative to untreated cells (P less than 0.001 in each case). The depression in each activity was dose-related. There was no significant difference between the drugs with regard to these impairments in neutrophilic granulocyte function. This lowered respiratory burst activity, which would lead to a depression of MPO-dependent and MPO-independent processes in stimulated neutrophilic granulocytes, may be due to drug induced dysfunction of NADPH-oxidase.

Therapeutic concentrations (0.3-1.5 mg/l) of pentamidine isethionate and pentamidine mesylate, obtained after parenteral administration of the drugs, did not influence neutrophilic granulocyte adherence, random and chemotactic migration or phagocytosis of Candida albicans spores in vitro. At concentrations of 0.7, 1.1 and 1.5 mg/l, the ability of neutrophilic granulocytes to kill C. albicans spores was depressed (P less than 0.001); at all concentrations used, their ability to reduce nitroblue tetrazolium was decreased (P less than 0.001). There was no significant difference between the drugs with regard to these impairments in neutrophilic granulocyte function. It is likely that pentamidine salts inhibit superoxide radical formation in the stimulated neutrophilic granulocyte and that this dysfunction leads to depressed intracellular killing of C. albicans spores.