Influence of pentoxifylline and its derivatives on antibiotic uptake and superoxide generation by human phagocytic cells

Abstract

Pentoxifylline modulates multiple activities of stimulated polymorphonuclear neutrophils (PMNs), including the respiratory burst response and membrane transport of certain substances (e.g., nucleosides). We found that several weakly basic antibiotics are highly concentrated by human PMNs and that these drugs also inhibit the respiratory burst response (by a mechanism different from that of pentoxifylline). Since both pentoxifylline and antibiotics will be administered to some patients with serious infections, we have evaluated several types of interactions between these drugs and human PMNs and have attempted to identify the mechanisms that produce alterations in cellular function. Roxithromycin, dirithromycin, and clindamycin were avidly concentrated by PMNs. Pentoxifylline and two derivatives (HWA-448 [torbafylline] and HWA-138 [albifylline]) increased the uptake of these antibiotics by PMNs, both in the resting state and during phagocytosis. Pentoxifylline, HWA-448, HWA-138, and the highly concentrated antibiotics each exerted an inhibitory effect on the stimulated respiratory burst response in PMNs. The combination of both pentoxifylline and a modulatory antibiotic (roxithromycin or clindamycin) inhibited superoxide production to a greater extent than either agent alone. This additive effect might be expected, since pentoxifylline and the modulatory antibiotics influence the respiratory burst activation pathway at different sites. The ability of pentoxifylline to augment the entry of antibiotics into neutrophils has important therapeutic implications. The consequences of this phenomenon might include improved intracellular bactericidal activity as well as efficient antibiotic delivery and release at sites of infection.

Intracellular accumulation, subcellular distribution and efflux of tilmicosin in swine phagocytes

“…In the present study LPS and pentoxifylline caused a significant increase in tilmicosin uptake. This result is similar to the results obtained by Hand & Hand (1995) with dirithromycin in human neutrophils. Thus, tilmicosin uptake by swine phagocytes is enhanced by stimulation of the phagocyte’s lipid membrane but the exact mechanism remains to be elucidated.…”

Effects of pentoxifylline and polymyxin B on the acute‐phase‐response to Escherichia coli endotoxin in dwarf goats

“…E. coli LPS is a potent inducer of pro-inflammatory cytokines including TNF-a, IL-1b and IFN-g (Dinarello et al, 1988;Jotwani et al, 1995). These cytokines are proximal mediators in the cytokine cascade, appearing in the circulation as brief, early peaks after infusion of LPS ( .…”

Inhibition of LPS and Plasmodium falciparum Induced Cytokine Secretion by Pentoxifylline and Two Analogues

“…The PTX analogues HWA 138 and HWA 448 have previously been shown to inhibit LPS induced TNF production and cAMP phosphodiesterase activity but had no effect on IL-1b production [12]. The PTX analogues increase the uptake of antibiotics in neutrophils and inhibit the stimulated respiratory burst response in neutrophils [26].…”