Monitoring antithyroid therapy.

Patients with severe granulocytopenia are more susceptible to severe infections and sepsis. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1 alpha), and IL-1 beta play an important role in the pathophysiology of sepsis. The profile of these proinflammatory cytokines after lipopolysaccharide (LPS) challenge in cyclophosphamide-induced neutropenic mice was assessed, and possible mechanisms responsible for the modified cytokine production were studied. After LPS, both circulating concentrations of TNF and IL-1 alpha in neutropenic mice were 50% to 200% higher than those of controls, whereas IL-1 beta concentrations were not modified. The kinetics of cytokine production were similar in neutropenic and control animals. The susceptibility of neutropenic mice to an LPS challenge was increased. The observed overproduction of TNF and IL-1 alpha was not due to a direct effect of cyclophosphamide treatment. Because circulating concentrations of uric acid were increased in the neutropenic mice, the effect of hypouricemic treatment with allopurinol and sodium bicarbonate was investigated; such treatment in neutropenic mice challenged with LPS was followed by an improved survival and a reduced proinflammatory cytokine production towards the concentrations in control mice. Hyperuricemia induced by repeated administrations of uric acid in normal mice led to an increased TNF production after LPS. In conclusion, neutropenic mice respond with enhanced cytokine production and increased susceptibility to an LPS challenge, and hyperuricemia probably plays an important role in this phenomenon.

Agranulocytosis↗

PubMed1997

Activation of CGS 12094 (prinomide metabolite) to 1,4-benzoquinone by myeloperoxidase: implications for human idiosyncratic agranulocytosis.

Many marketed pharmaceuticals are known to cause idiosyncratic agranulocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinical trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its parahydroxy metabolite, CGS 12094. To investigate mechanisms for this human specific toxicity, experiments were conducted to study the metabolism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophils and leukocyte progenitor cells. Although prinomide was not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90%; 2 min); this reaction was dependent on H2O2 and MPO and was inhibited by azide. During the MPO-catalyzed metabolism of CGS 12094, reactive intermediates that irreversibly bound to protein and cysteine were generated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a compound implicated in the myelotoxicity associated with benzene. Thus during conditions which lead to elevated levels of H2O2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced agranulocytosis.

Agranulocytosis↗