Assessment of nutrient supplement to reduce gentamicin-induced ototoxicity.

Gentamicin is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Treatment with this antibiotic carries the potential for adverse side effects, including ototoxicity and nephrotoxicity. Ototoxic effects are at least in part a consequence of oxidative stress, and various antioxidants have been used to attenuate gentamicin-induced hair cell death and hearing loss. Here, a combination of nutrients previously shown to reduce oxidative stress in the hair cells and attenuate hearing loss after other insults was evaluated for potential protection against gentamicin-induced ototoxicity. Guinea pigs were maintained on a nutritionally complete standard laboratory animal diet or a diet supplemented with ß-carotene, vitamins C and E, and magnesium. Three diets with iterative increases in nutrient levels were screened; the final diet selected for study use was one that produced statistically reliable increases in plasma levels of vitamins C and E and magnesium. In two separate studies, significant decreases in gentamicin-induced hearing loss at frequencies including 12 kHz and below were observed, with less benefit at the higher frequencies. Consistent with the functional protection, robust protection of both the inner and outer hair cell populations was observed, with protection largely in the upper half of the cochlea. Protection was independently assessed in two different laboratories, using two different strains of guinea pigs. Additional in vitro tests did not reveal any decrease in antimicrobial activity with nutrient additives. Currently, there are no FDA-approved treatments for the prevention of gentamicin-induced ototoxicity. The current data provide a rationale for continued investigations regarding translation to human patients.

Regional pharmacokinetics of 5-fluorouracil in dogs: role of the liver, gastrointestinal tract, and lungs.

The purpose of this study was to determine the presence and extent of pulmonary elimination for 5-fluorouracil (FUra). A secondary aim was to characterize the relative importance of the liver, gastrointestinal tract, splanchnic region, and lungs toward the overall elimination of FUra. A total of 10 mixed-breed male and female dogs were used in these acute studies in which FUra was administered through a cephalic vein. Six dogs were studied at sequentially escalated dose rates of 0.125, 0.250, 0.500, 0.750, and 1.00 micromol/min/kg (8-fold range); four dogs were studied at sequentially escalated dose rates of 0.0625, 0.250, 0.750, 1.50, and 2.00 micromol/min/kg (32-fold range). Each infusion lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, and pulmonary artery), perfusion rates were measured (hepatic artery, portal vein, and cardiac output), and pharmacokinetic parameters were directly assessed. Pulmonary elimination of FUra was conclusively demonstrated. Although only 17% of the drug was extracted by the lungs at the lowest dose rate, pulmonary clearance (16.0 ml/min/kg) was on the order of splanchnic clearance (13.5 ml/min/kg), or larger. As the dose rate increased, pulmonary clearance was more easily saturated than splanchnic clearance. Thus, it appears that at increasing dose rates, the splanchnic region becomes a more significant pathway, whereas the lungs have a reduced role in the overall elimination of FUra.

Regional pharmacokinetics of 5-bromo-2'-deoxyuridine and 5-fluorouracil in dogs: hepatic arterial versus portal venous infusions.

The purpose of this study was to determine the effect of route of hepatic administration of drug on the regional pharmacokinetics and systemic exposure of 5-fluorouracil (FUra) and 5-bromo-2-deoxyuridine (BrdUrd). A total of 13 mixed-breed male and female dogs were used in these acute studies. Each dog was administered hepatic arterial and portal venous infusions of a single drug, in a cross-over fashion, at two dose rates for a total of four sequential infusions. BrdUrd was studied at 0.250 and 0.500 micromol/min/kg, and FUra was studied at 0.125 and 0.500 micromol/min/ kg. Each infusion lasted 2 h, at which time steady-state plasma concentrations were obtained (ie., gastroduodenal artery, portal vein, hepatic vein, and femoral artery), perfusion rates in hepatic artery and portal vein were measured, and hepatic extraction (as opposed to extraction across the splanchnic region) was directly assessed. BrdUrd and FUra were found to be highly extracted across the liver (E(H) > or = 0.65) at the regional dose rates studied, resulting in low values for the fraction of drug escaping presystemic hepatic elimination (F(H) < or = 0.35). In addition, the regional kinetics (ie., hepatic extraction, fraction escaping first-pass elimination in the liver, and hepatic clearance) and systemic exposure (i.e., CFA) of FUra and BrdUrd were not significantly different following hepatic arterial versus portal venous infusions of drug. Thus, it appears that regional chemotherapy may be applied to halogenated pyrimidines following hepatic arterial, portal venous, and alternating regional dosing routes with no additional risk of systemic toxicity.

Mutual kinetic interaction between 5-fluorouracil and bromodeoxyuridine or iododeoxyuridine in dogs.

The pharmacokinetics of 5-fluorouracil (FUra) were studied alone and in the presence of either bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd) in five mixed breed hounds. FUra was administered intravenously over 1 min as a 5 mg/kg dose in all three treatments. BrdUrd or IdUrd was infused intravenously at 2.5 mg/hr.kg x 6 hr and FUra was given 3 hr into the 6-hr infusion of thymidine analog. Serial blood samples were obtained for 3 hr prior to and after FUra dosing. Plasma concentrations of FUra, BrdUrd and bromouracil (BrUra), and IdUrd and iodouracil (IUra) were measured by reversed-phase HPLC. Concomitant administration of BrdUrd or IdUrd resulted in substantial changes in the kinetics of FUra. In particular, the total plasma clearance of FUra was decreased and area under the plasma concentration-time curve was increased. There were also significant changes in the volume of distribution steady-state, and in the mean residence time and half-life of FUra. The data show that FUra had little or no effect on the disposition of BrdUrd or IdUrd. In contrast, FUra had a significant effect on the disposition of BrUra and IUra going to form catabolic products. The observed pharmacokinetic interaction in dogs is probably due to a competition between BrUra (or IUra) and FUra for the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase. This kinetic interaction was mutual and of a smaller magnitude for FUra + BrdUrd than for FUra + IdUrd.

A balloon-dilatable pulmonary artery band in the dog. Results at one year.

Increased pulmonary blood flow and pulmonary hypertension are frequent problems in infants with congenital heart disease. Although the use of pulmonary artery banding to limit pulmonary blood flow has decreased, the procedure may still be beneficial in certain forms of complex heart disease. The ability to noninvasively relieve the obstruction caused by the band may significantly reduce later operative complexity or even avoid reoperation entirely. The present study evaluated the effectiveness of a balloon-dilatable pulmonary artery band. Twenty 1-week-old dogs had a band of an absorbable suture material (Vicryl; Ethicon, Inc., Somerville, N.J.) placed around the main pulmonary artery. Eight dogs underwent angioplasty 6 months after band placement and also underwent follow-up catheterizations 3 and 6 months after angioplasty. Balloon angioplasty acutely reduced both the right ventricle-pulmonary artery pressure gradient (from 37 +/- 7 mm Hg to 3 +/- 1 mm Hg, p less than 0.001) and the right ventricular systolic pressure (from 62 +/- 8 mm Hg to 32 +/- 2 mm Hg, p less than 0.01). At follow-up the gradient remained low, measuring 4 +/- 1 mm Hg at 3 months and 3 +/- 1 mm Hg at 6 months. Twelve dogs did not undergo balloon dilatation until 12 months after band placement to determine whether any obstruction persisted and whether the band could be relieved after long-term placement. These 12 dogs had progressive increases in right ventricle-pulmonary artery gradient, from 27 +/- 3 mm Hg at 6 months to 43 +/- 4 mm Hg at 12 months. Ten of these dogs underwent dilation 1 year after pulmonary artery band placement. This dilation significantly reduced the right ventricular outflow tract gradient (from 43 +/- 4 mm Hg to 1 +/- 1 mm Hg, p less than 0.001). The remaining two dogs underwent successful partial dilation of the band 12 months after placement. This study demonstrated that a pulmonary artery band of absorbable suture material maintains effective right ventricular outflow tract obstruction for at least 1 year. Additionally, the effect of the pulmonary band can be successfully and persistently relieved.