Evaluation of amphotericin B-cyclosporine interaction in the rat.

Although a significant interaction between cyclosporine and amphotericin-B (AmpB) has been observed clinically, these findings have not been duplicated in animal studies. A total of 64 male albino rats were used in single- and multiple-dose experiments with AmpB and CsA in the absence or presence of systemic Candida infection. No significant differences in glomerular filtration rate were found in rats given single i.v. doses of AmpB 1 mg/kg compared with AmpB and CsA. Furthermore, rats given i.p. AmpB 1 mg/kg and CsA 10 mg/kg daily for 10 days showed no significant differences in GFR compared with animals given CsA alone. Morphology and CsA whole-blood pharmacokinetics were not different between groups administered single-dose CsA, AmpB, or the combination; similarities also existed with multiple-dose studies. In an attempt to mimic the clinical setting, 2 groups of rats were administered i.p. CsA 10 mg/kg/day for 10 days followed by inoculation of Candida albicans. After 48 hr, a single i.v. dose of AmpB 1.0 mg/kg was associated with a 33% decline in GFR compared with those given sterile water (P less than 0.05). Systemic clearance of CsA was markedly reduced in candidiasis rats administered AmpB compared with controls given sterile water. A significant reduction in renal Candida colony-forming units was found in rats given CsA and AmpB compared with those administered CsA alone. These data suggest that the presence of systemic Candida highlights the interaction of CsA and AmpB in the rat model.

Advantages of the Papillon protocol in the preoperative treatment of rectal carcinoma.

Standard treatment for advanced rectal carcinoma currently includes surgery, radiotherapy, and chemotherapy. Although there are theoretic advantages to preoperative irradiation, it is often not performed because of the prolonged delay of surgery and the purported increase in perioperative complications. A pilot study was undertaken at our institution to evaluate a treatment protocol advocated by Dr. Papillon that offers a shorter treatment time and less patient morbidity than conventional preoperative therapy for rectal carcinoma. Twenty patients with rectal cancer underwent the preoperative regimen that consisted of 3,000 cGy delivered in 10 fractions over 12 days with concomitant 5-fluorouracil and mitomycin-C. Complications were acceptable. Local recurrence was lower than in most reported trials, and survival rates were comparable. Additional benefits of the protocol include lower radiation morbidity to the patient and a decreased delay between diagnosis and surgery.

Influence of pentoxifylline and related analogues in endotoxemic renal failure.

Acute kidney dysfunction, manifested by reductions in renal blood flow and glomerular filtration rate with increased renal vascular resistance, is a common finding in septic shock. In an attempt to halt the progressive renal dysfunction, the hemorheologic methylxanthines, pentoxifylline (1, 5, or 10 mg/kg of PTX) and 2 structurally-related analogues, 5 mg/kg of HWA-138 and 5 mg/kg of HWA-448, or saline wee given 7.5 hr after endotoxin infusion in the rat. Renal function, assessed by single-dose inulin clearances (CIN), was measured at 6 hr after the infusion of endotoxin and also 1 hr following the drug treatment. The mean CIN at 6 and 9 hr after endotoxin infusion were 2- and 3-fold decreased compared with control rats given either saline or 5 mg/kg of PTX. Although renal function declined in all rats throughout the study period, the reduction in renal function was markedly slowed in endotoxemic rats given 10 mg/kg of PTX or 5 mg/kg of HWA-448 compared with untreated controls (74 +/- 9% and 77 +/- 9 vs. 47 +/- 12% of 6 hr CIN at 9 hr, respectively; P less than 0.01). Similar results were found with single doses of 5 mg/kg of PTX or HWA-138; PTX 1 mg/kg had a modest beneficial effect on renal function. There was no evidence of vascular congestion in endotoxemic kidneys upon histologic examination. These data suggest the potential benefit of PTX and related methylxanthines in stopping progressive renal damage associated with septic shock.