Improved control of non-insulin-dependent diabetes mellitus by combined halofenate and chlorpropamide therapy.

Combined halofenate-chlorpropamide was evaluated for the treatment of NIDDM. Four subjects treated with 500 mg/day chlorpropamide were given 500-1000 mg halofenate daily for 48 wk or longer. Fasting plasma glucose fell from 210 +/- 16 (+/- SEM) (11.67 +/- 0.89 mM) to 107 +/- 10 mg/dl (+/- SEM) (5.94 +/- 0.55 mM), P less than 0.005. Twelve additional subjects were entered into a 16-wk double-blind study testing chlorpropamide plus either placebo or halofenate. In the halofenate group, the mean fasting glucose fell from 227 +/- 27 (+/- SEM) (12.61 +/- 1.50 mM) and reached 107 +/- 19 mg/dl (+/- SEM) (5.94 +/- 1.06 mM) during the fourth month, whereas the placebo groups showed a decrease from 242 +/- 22 (+/- SEM) to 208 +/- 29 mg/dl (+/- SEM) (P less than 0.005). In addition, halofenate reduced the height of postprandial glycemic excursions by lowering fasting plasma glucose. When halofenate was used as the only therapy, reduction in fasting plasma glucose was small [179 +/- 12 reduced to 142 +/- 8 mg/dl (+/- SEM); 9.94 +/- 0.67 mM and 7.89 +/- 0.44 mM], P less than 0.05.

Potentiation of hypoglycemic effect of sulfonylureas by halofenate.

We investigated the possibility of a drug interaction between the antilipemic agent halofenate and sulfonylureas. Twelve young, healthy men were given 1 g of tolbutamide by mouth before and after 12 days of double-blind treatment with 1 g per day of halofenate, or placebo. There was a significant increase in serum tolbutamide at eight, 10 and 12 hours (P less than 0.01) and a significant (P less than 0.01) decrease in serum glucose at one, four and six hours after halofenate treatment, but not after placebo. In a long-term, double-blind study of halofenate or clofibrate treatment of patients with Type IV hyperlipoproteinemia, diabetic patients receiving a sulfonylurea and halofenate either required a reduction in the dose of the sulfonylurea or demonstrated significantly improved control of hyperglycemia (P less than 0.05) or both. No appreciable decrease in serum glucose levels was noted in diabetic patients receiving sulfonylurea and clofibrate. This interaction between halofenate and sulfonylureas is clinically important, especially in view of the association of hyperlipemia and diabetes.

Alterations in the effects of warfarin in dogs by halofenate: an influence upon the kinetics of prothrombin.

The interaction between warfarin and the new lipid lowering agent halofenate (MK 185) [2- acetamidoethyl (p-chlorophenyl) (m-trifluoromethylphenoxy) acetate] was studied in dogs in both short- and long-term experiments. Our data suggest that halofenate potentiates the anticoagulant effect of warfarin by increasing the degradation of prothrombin (factor II) (Kdeg on placebo = 211 +/- 32 X 10(-4) X Hr-1 mean +/- SEM; on halofenate = 268 +/- 39 X 10(-4) X Hr-1 mean +/- SEM; P less than 0.01). However, a concomitant increase in factor II synthesis of 34% results in resistance to warfarin's effect if halofenate is administered prior to warfarin. The mean prothrombin time of 4 dogs on 2 mg of warfarin following halofenate pretreatment for 8 weeks was 74.8% +/- 17.3 (SE) of the anticoagulated control dog. On 2 mg of warfarin alone, it was 133.7% +/- 42.0 (P less than 0.001). Cessation of halofenate from combined therapy resulted in a delayed augmentation of warfarin effect. These data suggest that the nature of the interaction between warfarin and drugs such as halofenate which alter the kinetics of prothrombin may depend on the sequence of administration.

Anomalous results of studies on drug interaction in man. II. Halofenate (mk-185) and antipyrine, bishydroxycoumarin, and warfarin.

Three highly reproducible experiments on drug interaction in normal human volunteers provided anomalous results: chronic halofenate administration shortened plasma antipyrine and bishydroxycoumarin half-lives but prolonged plasma warfarin half-lives. This dissociation in the effect produced by a chronically administered drug on the metabolism of test drugs has not previously been reported in man. Chronic halofenate administration to rats, mice and dogs stimulated several hepatic microsomal drug-metabolizing systems, including those responsible for bishydroxycoumarin warfarin hydroxylation.

Halofenate versus clofibrate in the management of true diabetes insipidus.

The antidiuretic effect of two chemically related drugs, clofibrate and halofenate, was tested in a patient with pitressin-sensitive diabetes insipidus. The conventional daily dosage of 2 g clofibrate failed to control the symptoms of this patient; in order to obtain an adequate response the dosage had to be increased to 4 g daily.Halofenate at a dosage of 2 g daily, an amount equivalent in hypolipidemic activity to 4 g per day of clofibrate, significantly reduced water intake and output, while urinary osmolarity was markedly increased.It is concluded that (1) the antidiuretic effect of clofibrate may be dose-related, and that (2) halofenate also possesses some antidiuretic activity.