Dose-dependent and temporal effects of pentoxifylline in a rat model of acute hepatic failure

Introduction

The methylxanthine pentoxifylline (PTX) is known to increase intracellular cAMP concentrations by inhibiting phospodiesterases. Despite beneficial in vitro effects its role in acute hepatic failure (AHF) is controversial. Several studies have demonstrated no benefit in the use of PTX in AHF, sepsis or shock.

Aims

To investigate three hypotheses: (1) the use of PTX leads to improved outcome in AHF; (2) this effect is dose dependent; and (3) improved outcome is limited by temporal constraints. We will compare PTX administration pre and post hepatic injury.

Methods

We have previously described a robust and reproducible model of AHF in the Wistar rat. The animals were randomly allocated into five groups (each n = 10): Group I received 2 × intra-peritoneal injections of thioacetamide (TAA) 8 hours apart (500 mg/kg). Groups II and III were pretreatment groups: Group II was pretreated with low-dose PTX (25 mg/kg body weight) and Group III was pretreated with high-dose PTX (300 mg/kg) and received the TAA protocol as in Group I. Groups IV and V were post-treatment groups. All followed the protocol for Group I; however, 30 min prior to receiving the second dose of TAA they received low-dose PTX (Group IV) and high-dose PTX (Group V). Clinical, biochemical and pathological analysis occurred at 24-hour time points.

Results

Encephalopathy, blood ammonia levels and transaminitis is significantly reduced by pretreatment with low-dose PTX (Group II) (P < 0.05). A significant reduction in mortality is seen in Group II where mortality at 96 hours is 30% compared with greater than 90% in the other pretreatment group (P < 0.005) and 70% in the TAA-treated animals (P < 0.005). This reduction in clinical and biochemical parameters is not seen in the post-treated groups.

Conclusion

Low-dose pretreatment with PTX significantly improves encehalopathy, biochemical markers of AHF and mortality compared with controls (TAA only). Beneficial effects are, however, negated if PTX is administered at high dose pretreatment or any dose post-treatment with TAA, exacerbating hepatic injury, increasing mortality and therefore demonstrating dose-dependent and temporal constraints.