PubMed · 840287
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C Lawyer, A Pond. 1977-04-07. Problems with terbutaline.. https://doi.org/10.1056/nejm197704072961422
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Prior studies have obtained conditioned preferences for flavors paired with intragastric (IG) infusions of Polycose (hydrolyzed starch) at concentrations of 1-32% over a different flavor paired with IG water. The present study determined if rats would also learn to prefer a flavor paired with concentrated Polycose infusion over a flavor paired with a more dilute Polycose infusion. In Experiment 1, adult female rats were food-deprived and trained during alternating one-bottle sessions (30 min/day) to associate one flavored solution (the CS + 8) with IG infusions of 8% Polycose, a second flavored solution (the CS + 16) with IG infusions of 16% Polycose, and a third flavored solution (the CS-) with IG water infusions. In subsequent choice tests, the rats displayed similar preferences for the CS + 8 and CS + 16 over the CS-, but preferred the CS + 16 to CS + 8 in a direct choice test. A similar preference pattern was obtained in 22 h/day tests with the rats nondeprived. In Experiment 2, new rats were similarly trained and tested but with CS + 16 and CS + 32 solutions paired with 16% and 32% Polycose infusions, respectively. The rats preferred both CS+ solutions over the CS- solution in the short- and long-term tests. However, the CS + 16 was preferred over the CS + 32 by the food-deprived rats in the short-term tests. The two CS+ solutions were equally preferred in the long-term tests with food ad lib. These and other findings indicate that the postingestive reinforcing action of Polycose increases as concentration increases from 1% to 16% but does not increase further, and may actually decrease, at a 32% concentration. The rapid satiating effect of concentrated carbohydrate solutions may limit their reinforcing consequences.
The remedial investigation/feasibility studies conducted at certain Army installations showed a need to clean up contaminated sites, where high levels of ammunition chemicals such as 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB), 1,3-dinitrobenzene (DNB), and their degradation products/metabolites were detected in surface soil and groundwater. TNB is a photodegradation product of TNT; it is not easily degraded, and persists in the environment. The toxicity data on TNB are scanty. Hence the U.S. Environmental Protection Agency in 1988 (U.S. EPA, 1997) developed a reference dose (RfD) for TNB (0.00005 mg/kg/d for chronic toxicity) based on the toxicity of DNB, which is structurally similar to TNB. Since then we have completed acute, subacute, subchronic, chronic, reproductive, and developmental toxicity studies and toxicokinetics studies. We have reviewed the mammalian toxicity data for TNB and have determined the no observed adverse effect levels (NOAEL) and low observed adverse effect levels (LOAEL) for subchronic, chronic, reproductive, and developmental toxicity. Based on the newly determined NOAEL and LOAEL values, we have now developed a new RfD for TNB (0.03 mg/kg/d), based on the chronic toxic effects on hematology and histopathological changes in testes and kidney.
FK506 (tacrolimus), a potent immunosuppressant, is used for inhibiting allograft rejection in the organ transplantation field. In a preclinical toxicity study in rats, FK506 induced various toxicities, including renal and pancreatic injuries. One of these toxic findings was cataract, and we have found that cataract appeared in rats dosed orally with FK506 for 13 weeks and more. Therefore, to better elucidate the onset mechanism of FK506-induced cataract, we measured biochemical parameters, such as sorbitol, Na,K-ATPase and glutathione in the lens of rats. Rats were dosed with FK506 in oral daily doses of 0.2, 1 or 5 mg/kg for 13 weeks, the lowest dose of which approximated the expected clinical dosage. Cataract developed in the 5-mg/kg/day group, with an incidence of 25%, whereas no cataract formation was observed in the 0.2- or 1-mg/kg/day groups. Five mg/kg/day led an increase of sorbitol and a decrease of reduced type glutathione, but did not affect Na,K-ATPase activity of the lens. FK506 is known to have diabetogenicity mediated through pancreatic injury, which appears as vacuolation of islet cell in rats. Five mg/kg/day of FK506 induced an elevation of blood glucose associated with glucose intolerance, and decrease of both basal insulin level and insulin content in the pancreas, and the changes were in parallel with the cataract development in the present study. On the other hand, diabetic parameters did not change in the 0.2- or 1-mg/kg/day groups. These observation suggest that diabetes developed in the rats dosed with 5 mg/kg/day of FK506. Coadministration of a novel aldose reductase inhibitor, Zenarestat, at an oral dose of 50 mg/kg/day resulted in a reduction of incidence of the FK506-induced cataract and a decrease of sorbitol levels in the lens when compared to that in the lens of rats dosed with 5 mg/kg/day of FK506. These results suggest that FK506-induced cataract in rats is due to an accumulation of sorbitol in the lens, secondary to the diabetogenic effect of FK506. FK506 treatment at the doses of 0.2 and 1 mg/kg/day neither affected parameters indicative of diabetes nor induced cataract in rats, suggesting that the cataract would not develop with FK506 if diabetic parameters were kept under control.