IFN-gamma is effective in reducing infections in the mouse model of chronic granulomatous disease (CGD).

Chronic granulomatous disease (CGD) is a genetic disorder characterized by recurrent bacterial and fungal infections and tissue granuloma formation. CGD phagocytes are unable to generate superoxide because of mutations in any of four proteins of the phagocyte NADPH oxidase. Prophylactic recombinant human interferon-gamma (IFN-gamma) has been shown to reduce the frequency and severity of infections in CGD patients, but its mechanism(s) remains undefined, and its benefit has been questioned. We investigated the prophylactic effect of IFN-gamma in the mouse model of the major autosomal recessive (p47(phox)) form of CGD. In a prospective, randomized, placebo-controlled study, we compared IFN-gamma, 20,000 U administered subcutaneously (s.c.) three times weekly, to placebo in 118 p47(phox-/-) mice. By 6 weeks of study, there were 3 infections in the IFN-gamma group compared with 13 infections in the placebo group (77% reduction in infections, p<0.01). By 18 months of study, there were 7 infections in the IFN-gamma group compared with 18 infections in the placebo group (39% reduction in infections, p<0.01). Two animals receiving IFN-gamma had seizures after 7 months in the study. No other toxicities were observed. Peripheral blood phagocytes from IFN-gamma treated p47(phox-/-) mice produced no superoxide, excluding restoration of the oxidative burst as a mechanism for the IFN-gamma effect. There were no differences in either peritoneal macrophage nitrate production or thioglycollate-induced peritoneal exudate between treatment groups. This animal model demonstrates a prophylactic benefit of IFN-gamma similar to that seen in humans and provides an opportunity to investigate the mechanism(s) of action for IFN-gamma in CGD.

Hepatic safety of erythromycin acistrate in 1549 patients with respiratory tract or skin infections.

Erythromycin acistrate is a new 2'-acetyl esther prodrug of erythromycin, whose structure resembles that of erythromycin estolate. However, in toxicological studies, it does not have the problems of hepatotoxicity. To assess its effects on hepatic functions in clinical practice, the liver parameters of patients with respiratory tract or skin infections were monitored during therapy. In total 1549 patients were treated for 7-14 days. In addition, 127 patients with suspected viral infections served as controls. There were no significant differences in serum aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyltransferase (gamma-GT) or alkaline phosphatase (APHOS) values between the erythromycin acistrate or control groups at the beginning or end of therapy. ASAT values increased moderately in 2.4% and clearly in 0.3% of patients treated, but also decreased in 2.0%. ALAT values were moderately increased in 9.9%, clearly increased in 0.6% and normalized in 3.5% of the patients. gamma-GT values increased moderately in 3.5% and and clearly in 0.3%, but decreased to normal in 3.3% of the patients. APHOS was moderately elevated in 1.0% of the patients and normalized in 1.3%. The correlation of changes between the different liver enzymes was poor. Only ten patients (0.6%) had two or more clearly elevated liver enzyme values by the end of the therapy, of whom five had increased liver enzyme activities before the treatment, two had underlying disease explaining the changes and in only three patients out of 1549 (0.2%) could hepatic changes be attributed to erythromycin acistrate therapy. These changes were reversible. The results demonstrate the hepatic safety of erythromycin acistrate in clinical practice. Concomitant food intake did not affect the safety profile.