Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination.

Diltiazem and hydrochlorothiazide are widely used to treat cardiovascular disease, often in combination. The purpose of this investigation was to determine whether a drug-drug pharmacokinetic interaction exists between diltiazem and hydrochlorothiazide. In a randomized, crossover, open study, multiple doses of diltiazem (60 mg four times daily for 21 doses) and hydrochlorothiazide (25 mg twice daily for 11 doses) were administered alone and in combination on three separate occasions to 20 healthy male volunteers. Trough and serial blood samples were collected and plasma was assayed for diltiazem, hydrochlorothiazide, and diltiazem metabolites (desacetyldiltiazem and N-desmethyldiltiazem) using HPLC. Total urine was also collected and quantified for hydrochlorothiazide. Coadministered hydrochlorothiazide did not significantly (p > 0.05) alter diltiazem (alone versus combination) steady-state maximum plasma concentration (Css(max); 145 versus 158 ng mL(-1), respectively), time to maximum plasma concentration (t(max); 3.0 versus 2.8 h, respectively); area under the plasma concentration-time curve (AUCss; 688 versus 771 ng x h mL(-1)), oral clearance (Cl(oral); 96.2 versus 88.0 L h(-1)), or elimination half-life (t(1/2); 5.2 versus 5.2 h). Similarly, administration of diltiazem did not significantly (p > 0.05) influence hydrochlorothiazide (alone versus combination) Css(max) (221 versus 288 ng mL(-1)), t(max) (1.8 versus 2.0 h), AUCss (1194 versus 1247 ng x h mL(-1)), Cl(oral) (22.4 versus 21.2 L h(-1)); t(1/2) (9.8 versus 9.6 h), or renal Cl (15.5 versus 15.2 L h(-1)). In conclusion, a clinically significant pharmacokinetic interaction between diltiazem and hydrochlorothiazide does not exist.

Effect of supplemental vitamin E on the immune system of calves.

The effect of vitamin E on immune responses of Holstein calves was investigated. Treatments were: 0,1400, and 2800 mg of dl-alpha-tocopheryl acetate given orally at weekly intervals or 1400 mg of dl-alpha-tocopherol weekly by injection. Calves were fed milk for 6 wk and then fed a complete calf starter ad libitum. Calves were on experiment until they were 12 wk of age. Lymphocyte stimulation indices were significantly higher for calves given the high amount of oral supplementation and for injected calves than for unsupplemented calves. There were no significant differences at any of the individual weeks between unsupplemented and orally supplemented calves. Injected calves showed significantly higher values than unsupplemented calves at wk 4 and than all other calves at wk 8. There were no significant differences in the concentrations of immunoglobulins G1 and G2 among treatments. Immunoglobulin M was significantly higher at wk 6 in calves given the high amount of oral supplementation than in all other calves. At wk 12, serum from calves given the high amount of oral supplementation and calves given injections inhibited infectious bovine rhinotracheitis viral replication in tissue cultures as compared with those of unsupplemented calves. In supplemental experiments serum alpha-tocopherol and lymphocyte stimulation indices of yearling heifers determined 7 d after a single injection of 2000 IU of dl-alpha-tocopherol were significantly higher than preinjection values. In vitro addition of vitamin E to lymphocyte cultures did not increase phytohemagglutinin-induced blastogenesis.

Effects of supplemental vitamin E on the performance and metabolic profiles of dairy calves.

Twenty-eight Holstein heifer calves were allotted at birth to one of four treatments: 1) 0 mg, 2) 1,400 mg, or 3) 2,800 mg of dl-alpha-tocopherol acetate given orally at weekly intervals, or 4) 1,400 IU of dl-alpha-tocopherol weekly by intramuscular injection in order for us to study their performance and metabolic profile. Calves were fed milk at 8% of birth weight until they were weaned at 6 wk of age and fed a complete calf starter ad libitum from birth. Calves were on experiment for 12 wk. There were no significant differences in weekly weight gains, starter consumption, and fecal scores among treatments. However, there was a trend toward greater starter consumption and weight gains in supplemental calves. Serum alpha-tocopherol concentration measured after 7 d of each administration was significantly higher at wk 4 in calves given the high oral supplementation and at wk 2, 4, 6, and 8 higher in injected calves than in unsupplemented calves. Creatine kinase activity was higher in unsupplemented calves and negatively correlated with serum alpha-tocopherol until wk 8, suggesting preclinical muscular dystrophy. Alkaline phosphatase activity was higher with the high oral supplementation. Serum carbon dioxide values showed a trend toward positive correlation with those for serum tocopherol; however, the values were within normal range. There were no significant differences in creatinine, glucose, phosphorus, calcium, urea nitrogen, chloride, sodium, potassium, albumin, and total protein among treatments. Serum glucose was higher in all calves at wk 10 and 12 than at wk 4, 6, and 8. Calves may not get enough vitamin E with conventional calf starters, and supplementation may be essential to obtain maximum performance.