The effect of aldose reductase inhibition and dietary protein restriction on renal function in experimental diabetes mellitus.

The effects of aldose reductase inhibition on renal function in hyperphagic diabetic rats were examined at 3 months. To prevent a high dietary protein intake from influencing renal function, protein intake in the diabetic animals was reduced to that of nondiabetic animals. To determine the influence of renal prostaglandins, clearance studies were performed before and after indomethacin infusion. Experiments were performed in uninephrectomized sorbinil-treated and -untreated streptozocin-diabetic and sorbinil-treated and -untreated control rats. Despite normalization of protein intake, the mean value of the insulin clearance (CIn, mL/min/100 g BW) was 83% greater in the untreated diabetic rats when compared to the untreated control rats (1.06 +/- 0.15 vs. 0.58 +/- 0.07; p less than 0.05). In contrast, the mean value of the CIn in the sorbinil-treated diabetic rats was significantly less than that in the untreated diabetic rats and only 38% greater than the mean value in the sorbinil-treated control rats (0.84 +/- 0.17 vs. 0.61 +/- 0.05; p less than 0.05). In a similar fashion, without sorbinil treatment the mean value of renal blood flow (RBF, mL/min/100 g BW) was greater in the diabetic than the control rats (6.58 +/- 2.03 vs. 3.70 +/- 0.68; p less than 0.05); whereas the mean values of RBF in the sorbinil-treated diabetic and control rats were not significantly different (4.75 +/- 0.73 vs. 4.17 +/- 0.64; NS). Indomethacin infusion failed to cause changes in the CIn and RBF in any group of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary renovascular effects of erythromycin in the rat: relationship to cyclosporine nephrotoxicity.

Erythromycin is known to exacerbate cyclosporine nephrotoxicity. This has been attributed to the potential of erythromycin to reduce the hepatic microsomal metabolism and clearance of cyclosporine. Erythromycin may also be nephrotoxic. We tested the hypothesis that erythromycin may have direct effects on the renal vasculature which are additive or synergistic with the effects of cyclosporine. Sprague-Dawley rats were administered graded doses of either erythromycin, 2.5, 5, 7.5, and 10 mg/kg BW/min i.v. over consecutive 10-min intervals; cyclosporine, 1, 2, 3, and 4 mg/kg BW/min i.v. over consecutive 10-min intervals; or both drugs simultaneously. In separate experiments, identical doses of erythromycin or cyclosporine were infused intravenously following acute unilateral renal denervation. Infusion of erythromycin led to an initial decline in arterial blood pressure whereas infusion of cyclosporine resulted in a dose-related increase in arterial blood pressure. Despite these different systemic effects, each drug alone produced a striking decrease in renal blood flow. This effect was more pronounced when the drugs were infused concomitantly. The reduction in renal blood flow occurred in an additive manner as a direct consequence of increased renal vascular resistance. Prior renal denervation did not modify the response to either erythromycin or cyclosporine. These results demonstrate that cyclosporine-induced vasoconstriction is exacerbated by erythromycin and suggest that the decline in renal function observed in patients coadministered these drugs may be due in part to additive renovascular toxicity.

Influence of the rate of infusion on cyclosporine nephrotoxicity in the rat.

The effect of the rate of infusion of single and multiple doses of cyclosporine (CsA) on renal function was evaluated in Sprague-Dawley rats. CsA was dissolved in cremophore (Crem) or Tween 80 (Tween) and infused over consecutive 10-min periods at doses of 10, 20, 30 and 40 mg/kg. CsA-Crem and CsA-Tween produced similar and progressive changes in MAP, RBF, and RVR. By the end of the infusion, the mean values (% of control) of MAP (122 +/- 16% and 131 +/- 22%), RBF (56 +/- 11% and 66 +/- 20%), and RVR (222 +/- 38% and 232 +/- 134%) were significantly different from their respective preinfusion values. Infusion of Crem alone resulted in renal vasodilation at low doses and renal vasoconstriction at high doses. Vasoconstriction was not produced by infusion of Tween alone. In addition, animals were treated with vehicle alone (Gp 1), CsA 10 mg/kg/day by injection (Gp 2), or CsA 20 mg/kg/day by i.v. infusion over 4 hr (Gp 3), and were studied at 1 week. Systemic toxicity was greater with the 4-hr infusion as judged by an increase in MAP. The mean values of MAP were 107 +/- 8 (Gp 1), 101 +/- 13 (Gp 2), and 135 +/- 5 mm Hg (Gp 3; p less than 0.05). However, renal function was less severely affected with the 4-hr infusion. The mean values of CIn were 434 +/- 99 (Gp 1), 298 +/- 101 (Gp 2; p less than 0.05), and 425 +/- 114 microL/min/100 g BW (Gp 3); and the mean values for RBF were 2.72 +/- 0.74 (Gp 1), 2.08 +/- 0.17 (Gp 2; p less than 0.05), and 3.35 +/- 0.61 mL/min/100 g BW (Gp 3), respectively. Microangiograms showed marked abnormalities in the intrarenal perfusion pattern in the rats injected with CsA, 10 mg/kg BW. In rats infused over 4 hr with CsA, 20 mg/kg BW, the microangiographic pattern was normal. These studies demonstrate that the acute hemodynamic effects of CsA are directly related to the rate of infusion. Furthermore, the renal toxicity which follows repetitive injection of CsA can be minimized or avoided by administering CsA as a slow infusion. In addition to the total dose administered, the rate of infusion is an important determinant of nephrotoxicity.

Medication discharge consultation program in a small community hospital.

The development of a medication discharge consultation program in a 113-bed, acute-care hospital is described. Patients with cardiac or hypertensive disease who are being treated with at least three medications are counseled by a pharmacist at the time of discharge. In addition to providing information orally, the pharmacist gives the patient written monographs on each of the patient's drugs, a sheet of general guidelines on medication administration, and a calendar noting administration schedules. Two pharmacists are responsible for the project and counsel about four patients weekly. The average time to complete a consultation, including documentation in the patient's medical record, is 30 minutes. The medication discharge consultation program improves patient compliance by increasing the patient's knowledge of drug therapy and enables the hospital to meet current practice standards.