Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review.

OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosing of rosiglitazone, the second thiazolidinedione approved for the treatment of type 2 diabetes mellitus. METHODS: Background information for this article was obtained from searches of MEDLINE , Iowa Drug Information Service, and International Pharmaceutical Abstracts, as well as from data on file with the manufacturer of rosiglitazone. RESULTS: Rosiglitazone is indicated for use alone or in combination with metformin or sulfonylureas for the maintenance of glycemic control in patients with type 2 diabetes mellitus. Rather than stimulation of insulin secretion, rosiglitazone's primary mechanism of action is sensitization of tissues to insulin through activation of the peroxisome proliferator-activated receptor gamma and increasing expression of the glucose transporter-4 receptor. Rosiglitazone is administered orally, is absorbed almost completely, and is 99.8% bound to plasma proteins. The majority of a dose is metabolized by the cytochrome P-450 2C8 isozyme, with the inactive metabolites excreted primarily in the urine. Four to 8 mg/d of rosiglitazone given alone or in combination with metformin, sulfonylureas, or insulin has produced reductions in baseline fasting plasma glucose and glycosylated hemoglobin in studies of up to 1 year's duration. Common adverse effects (occurring in > or = 5.0% of patients) include upper respiratory tract infection, injury, and headache. Edema, weight gain, and increased low-density lipoprotein cholesterol concentrations have also been observed. It is recommended that rosiglitazone be avoided in patients with alanine aminotransferase levels >2.5 times normal. No clinically relevant drug interactions have been documented with rosiglitazone to date. The initial starting daily dose of rosiglitazone is 4 mg in single or divided doses, without regard to meals, to a maximum of 8 mg. CONCLUSIONS: No direct comparative trials of the efficacy and safety of rosiglitazone versus those of the other available thiazolidinedione, pioglitazone, have yet been performed. The role of rosiglitazone as a single agent and in combination with other antidiabetic agents remains to be clarified as additional comparative and long-term data become available.

Raloxifene hydrochloride.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and therapeutic role of raloxifene hydrochloride are reviewed. Raloxifene is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. A SERM interacts with estrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of estrogen without the possible stimulatory effects on the breasts or uterus. Raloxifene is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass glucuronidation. Approximately 60% of a dose is absorbed; however, absolute bioavailability is only 2%. The volume of distribution is 2348 L/kg for a single oral dose of 30-150 mg, and the elimination half-life averages 32.5 hours. In clinical trials in postmenopausal women, raloxifene had an estrogen-like effect on bone turnover and increased bone mineral density. It reduced the risk of fractures in women with osteoporosis. Raloxifene also seemed to reduce the risk of breast cancer and positively influenced blood lipid markers of cardiovascular disease. Raloxifene is generally well tolerated; the most common adverse effects are hot flashes and leg cramps. A serious adverse effect is venous thromboembolism. The recommended dosage is 60 mg/day orally without regard to meals. Ultimately, it will be information on cardiovascular or breast cancer benefits that will determine the future role of raloxifene. Raloxifene is an alternative to traditional hormone replacement therapy for the prevention and treatment of osteoporosis in selected postmenopausal women. More study is needed to verify possible benefits related to heart disease and breast cancer.

Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, interactions, and formulary considerations of atorvastatin relative to other hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are discussed. Atorvastatin calcium, a synthetic stereoisomer of a pentasubstituted pyrrole, prevents the conversion of HMG-CoA by competitive and selective inhibition of HMG-CoA reductase. This limits cholesterol formation. Atorvastatin undergoes extensive first-pass metabolism; the first-pass effect is saturable at higher doses. Time to maximum plasma concentration ranges from one to four hours. The plasma elimination half-life is considerably longer than for other statins. Like other statins, atorvastatin reduces low-density-lipoprotein cholesterol (LDL-C) and total cholesterol in patients with hypercholesterolemia. However, the reductions achieved with atorvastatin exceed those for other statins. Atorvastatin recipients are more likely to achieve LDL-C goals and to do so more quickly. Atorvastatin also moderately reduces triglyceride levels in patients with hypertriglyceridemia and may play a role in the management of familial hypercholesterolemia. Adequate lipid control with atorvastatin monotherapy may preclude the need for combination drug therapy in some patients. The adverse effects of atorvastatin include mild gastrointestinal disturbances, increased liver enzyme levels, and myalgia. Drug interactions involving atorvastatin can be expected to parallel those of other statins metabolized via CYP3A4. Atorvastatin has become a popular addition to hospital formularies, even though formal pharmacoeconomic analyses are lacking. Atorvastatin effectively reduces blood lipids and may offer some advantages over other statins, but more studies are needed to clarify its optimal role in pharmacotherapy.