Drug-nutrient interactions最新文献

The effects of various high-fat diets (20% w/w) containing commercially available fats and oils (butter, corn oil, corn oil margarine, canola oil, canola oil margarine, soybean oil, soybean oil margarine, sunflower oil, sunflower oil margarine) on myocardial contractility and morphology and on plasma lipids were investigated in male Sprague-Dawley rats fed the diets for 16 weeks. Diets containing corn oil caused significantly (P less than or equal to .05) higher plasma total cholesterol levels than diets containing butter. Significant differences were also determined in lipoprotein levels. Plasma triglyceride levels were significantly (P less than or equal to .05) higher with butter than with sunflower oil or sunflower margarine. No significant differences among the groups occurred in blood pressure, heart rate, or myocardial contractility. Histological evaluation revealed that animals fed canola oil had the highest incidence and severity of myocarditis and fibrosis and that the degree of cardiac lipidosis was not correlated to the erucic-acid content of the diet. Myocardial damage was significantly (P less than or equal to .05) negatively correlated with stearic and palmitic acids and positively correlated with oleic acid. The results indicate that diets low in saturated fats may have adverse long-term effects on the heart.

Excessive ethanol intake during pregnancy can cause birth defects in humans and is referred to as fetal alcohol syndrome (FAS). Because of the characteristic changes that are similar in FAS and zinc (Zn) deficiency, we have examined the role of Zn nutriture in the teratogenicity of ethanol in Sprague-Dawley rats. Female Sprague-Dawley rats were adapted to liquid diets containing Zn at 2 micrograms/ml (LZn), 30 micrograms/ml (AZn), or 300 micrograms/ml (HZn); ethanol contributed either 0% or 36% of kilocalories. Ethanol consumption resulted in reduced fetal growth and retarded skeletal development. Ethanol had no effect on whole body fetal Zn concentrations; however, copper (Cu) deficiency was induced in the HZn fetuses. Ethanol consumption resulted in higher than normal fetal liver CuZnSOD activity in the LZn and AZn groups. Fetuses from HZn dams showed no ethanol effect on CuZnSOD activity, suggesting that the low availability of Cu to the fetus prevented the increase in CuZnSOD activity in response to ethanol. The increase in the activity of fetal CuZnSOD in LZn and AZn groups is consistent with the concept that the metabolism of ethanol results in free radical generation in fetal tissue. Because excessive free radical levels may result in tissue damage, this may be one mechanism contributing to the expression of FAS.

The status of vitamins A, B1, B2, B6, B12, C, D, and E as well as that of beta-carotene, biotin, and folate in the blood of over 500 epileptics was compared with that of a normal population. Male and female epileptics showed a poorer supply of vitamins B2, biotin, folate, and 25-hydroxycholecalciferol; the males, of only vitamin B6, B12, and E, and the women, of only vitamin A. Concentrations of beta-carotene and vitamin E in female epileptics were higher. The evaluation of relations between vitamin concentrations and mean daily dose, total dose of anticonvulsants, and duration of therapy suggested a possible influence of anticonvulsant medication on vitamins B1, B2, B6, C, D, E, beta-carotene, biotin, and folate. Concentrations of B vitamins as well as of folate were distinctly lower in patients under monotherapy with enzyme-inducing drugs than in those under valproate sodium. There was no relationship between bone mineral content and 25-hydroxycholecalciferol levels and between the neurographic parameters and the neurotropic vitamins of the B group, which also had no influence on concentration performance. Patients with poorer results in tests of the function of the central and the peripheral nervous system displayed a tendency towards lower vitamin-C levels. There were indications of potential links between immunological status and vitamin B6 and biotin. Males and females with a poorer supply of vitamin C, as well as males with lower riboflavin levels, showed a tendency towards macrocytic anaemia. Cerebellar disturbances were associated with lower concentrations of folate, of vitamin C or D, and possibly of biotin. The incidence of gingival hyperplasia could be linked to riboflavin, to biotin, and possibly also to vitamin C, D, or folate status.

Weanling male CD-1 mice were fed low-iron or iron-supplemented diets for 31 days. Mice fed the low-iron diet exhibited typical signs of iron deficiency, which included reduced weight gains (P = 0.0041) and anemia (P less than 0.0001). The effect of iron deficiency on antibody production, lymphocyte blastogenesis, and sensitivity to endotoxin were evaluated. Antibody production against sheep red blood cells, a T-lymphocyte dependent response, was reduced in iron-deficient mice (P = 0.0067). In contrast, antibody production against dinitrophenyl-ficoll, a T-lymphocyte-independent response, was not affected by iron deficiency (P = 0.291). Iron deficiency reduced T-lymphocyte blastogenesis induced by concanavalin A (P = 0.011), but had no effect on B-lymphocyte blastogenesis induced by Escherichia coli lipopolysaccharide (P = 0.662). These results indicate that the immunosuppressive effects of iron deficiency are related to T-lymphocyte function associated with lymphocyte proliferation and antibody production. A significantly increased susceptibility to endotoxin, a T-lymphocyte-independent response involving nonspecific defense mechanisms, was not observed in iron-deficient mice. Mortality associated with endotoxin was 14.2% in the iron-deficient mice as compared to 35% in the iron-replete mice (P = 0.079).

The present randomized study compared the influence of a gel-forming wheat bran with a nongel-forming bulk cathartic (an ispaghula formulation, Vi-Siblin S) on the steady state concentrations of digoxin in plasma in 30 geriatric in-patients treated with either combination (16 with wheat bran + digoxin, 14 with ispaghula + digoxin) for 4 weeks. After 2 but not after 4 weeks, wheat bran reduced the digoxin levels, although the levels were still within the therapeutic range. Ispaghula had no influence at any time. It is concluded that neither wheat bran nor the ispaghula formulation has any clinically relevant influence on therapeutic digoxin levels in geriatric patients.

The glucose effect on hepatic drug metabolism (decreased) of barbiturates was maximum after 2 days of increased glucose intake as indicated by increased barbiturate sleep time in mice. However, this effect was not observed after 5 days of glucose treatment, and barbiturate sleep time was similar to the control after 6 days of treatment. Serum glucose and liver glycogen were, in general, not significantly different from control, even after chronic glucose intake, indicating that neither hypoglycemia nor alteration of liver glycogen levels were required for the glucose effect on drug action. However, in contrast to the decreased metabolism of barbiturate, there was increased metabolism of glucose in the glucose-treated animals. Brain levels of barbiturate in 48 hours glucose-treated mice were higher and declined at approximately half the rate of controls (Ke(G) 0.009 vs Ke(C) 0.015). A similar trend in barbiturate blood concentration indicated decreased metabolism of the barbiturate and/or decreased clearance of drug and metabolites. The glucose treatment altered the pentobarbital dose response curve, but there appeared to be no alteration of the sensitivity to insulin; exogenase insulin still produced significant hypoglycemia and prolonged barbiturate S.T. after 7 days of glucose treatment. Other factors may be involved in the glucose effect; increased permeability of the brain to barbiturate, decreased permeability to outflow so that brain concentrations remain higher for a long period of time.

The effect of administration of glucose on methotrexate-induced body weight loss and gastrointestinal toxicity in mice was investigated. Using the everted sac technique, control rates (mumol/g/hr) of transport of D-glucose and L-tyrosine were 35.0 and 10.0, respectively. In animals pretreated with methotrexate (25 mg/kg/day i.p. for 4 days), these rates decreased to 10.9 and 6.3 mumol/g/hr, respectively. However, when intestinal sacs from untreated mice were exposed to MTX (10(-3) M), the drug had no significant effect on rates of transport of D-glucose or L-tyrosine. Methotrexate pretreatment in vivo also caused a 15% loss in animal body weights. Administration of glucose (0.5/g/kg. i/p.) 1 hour prior to methotrexate prevented the inhibition of transmucosal transport of both glucose and tyrosine. Glucose also reduced the body weight loss caused by methotrexate. Similar treatment with the nonmetabolizable sugar, 3-O-methylglucose, had no significant effect on the methotrexate-induced toxicity. The data suggest that coadministration of glucose with methotrexate may have a potential clinical value, since glucose may alleviate the toxic effects of methotrexate in patients receiving this drug.

The single-dose kinetics of the neuroleptic thioxanthene zuclopenthixol was assessed in 12 healthy volunteers who ingested 10 mg of the drug orally, both on an empty stomach and together with a standardized breakfast of 1840 kj (440 kcal). The serum concentrations of zuclopenthixol were measured by HPLC. Concomitant food intake did not influence the peak concentration nor the time to reach the peak concentration or the elimination half-life of zuclopenthixol, but the AUC values were significantly increased. Hence it seems likely that concomitant food intake enhances the bioavailability of zuclopenthixol, without influencing its absorption rate. The most likely mechanism is that food reduces the presystemic clearance of the drug. As the increase in AUC was only 26%, it is doubtful whether zuclopenthixol has to be administered in a standardized relation to meals.

These studies were undertaken to assess the effect of dietary selenium on glutathione-related enzyme activities in the liver and kidney and on hepatic drug metabolism. The intent was to study underlying mechanisms of selenium-induced beneficial effects in some models of hepatoxicity and carcinogenesis. Dietary selenium, as sodium selenite, was incorporated into a torula yeast basal diet (0.02 ppm selenium) and fed to male rats at supplementation levels of 0.0-5.0 ppm selenium for periods of three or six weeks. Additionally, a commercial cereal-based diet (CD, 0.05-0.08 ppm selenium) was compared to the experimentally defined diet (DD) supplemented with approximately the same amount of selenium. Liver and kidney glutathione peroxidase activity essentially plateaued at levels of selenium of 0.1 ppm and greater. CD- and DD-fed animals had hepatic and renal glutathione peroxidase activities which were similar. Glutathione S-transferase activity in liver, but not kidney, increased with increasing supplements of selenium. Glutathione S-transferase activities in CD- and DD-fed rats were not different. Cytochrome P-450 content and associated oxidative drug metabolism activities were relatively unmodified by selenium. Overall, dietary selenium appeared to act by enhancing potential conjugative detoxication pathway, rather than by decreasing the potential activation of chemicals via the hepatic cytochrome P-450 system.

Sprague-Dawley rats were raised by dams (mother reared, MR) or artificially reared from day 4 to day 11, using chronic intragastric cannulas, and infused with one of four diets: control (AR); or supplemented with nicotinamide-low (LN, 300 mg/l), medium (MN, 750 mg/l), or high (HN, 1500 mg/l). Liver to body weight ratios were higher in all artificially reared groups (AR, LN, MN, HN) compared to MR pups. The amount of recovered hepatic microsomal protein was lower in all artificially reared groups when compared with MR pups. Uridine diphosphoglucuronyl transferase activity with para-nitrophenol as the substrate (UDPGT-PNP) was greater in all of the artificially reared groups compared to the MR group. UDPGT-PNP activity in the HN group was greater than in the AR, LN, or MN groups. Cytochrome P-450 concentration was highest in the MR group, whereas there were no differences among the artificially reared groups. It was concluded that the artificial rearing process stimulated hepatic UDPGT-PNP activity and depressed cytochrome P-450 concentrations, whereas dietary supplementation with nicotinamide during the preweanling period resulted in a further increase in UDPGT-PNP activity.