Atypical antipsychotic treatment has been associated with serious metabolic adverse events, such as glucose dysregulation and development of type 2 diabetes. As part of our studies on possible underlying mechanisms, we investigated the acute effects of various typical and atypical antipsychotics on plasma glucose and insulin in FVB/N mice, a strain that showed a more pronounced hyperglycemic response to clozapine than C57BL/6 and CD-1 mice. Acute administration of high doses of clozapine, olanzapine, quetiapine, perphenazine, or chlorpromazine significantly increased plasma glucose by 100%-140% above basal levels without significant effects on insulin levels. In contrast, risperidone reduced plasma glucose (-30%) and markedly enhanced plasma insulin levels. Doses of ziprasidone that gave 50-fold higher free plasma concentrations than therapeutic plasma levels, as well as high doses of aripiprazole and haloperidol, did not significantly alter either glucose or insulin levels. Clozapine- and olanzapine-induced hyperglycemia occurred at free plasma concentrations that were within, or one order of magnitude above, the range of therapeutic plasma levels. Pretreatment with either the ganglionic blocker hexamethonium, or the alpha(2) adrenergic receptor antagonist yohimbine, blocked the clozapine- and chlorpromazine-induced increase in glucose levels. Taken together, these results suggest that typical and atypical antipsychotics with known metabolic liability produce acute hyperglycemia in mice and that this effect is likely driven by activation of the sympathetic autonomic nervous system via a central mechanism.

41%, of all deaths in the United States in 1998 (1). As a consequence of atherosclerosis, coronary heart disease (CHD) is the most common cause of cardiovascular morbidity and mortality, with an estimated 12 million people suffering from CHD in the United States alone (1). Elevated total and LDL cholesterol are both accepted primary risk factors for atherosclerosis (1-3). An estimated 101 million United States adults have elevated blood cholesterol ( Ͼ 200 mg/dl) and are candidates for LDL cholesterol lowering through dietary intervention (1, 4, 5). Of these, 41 million are considered high risk, having blood cholesterol greater than 240 mg/dl, and drug therapy is recommended (1, 4, 5).Epidemiological studies have shown that elevated triglycerides and reduced HDL cholesterol are also contributing factors for the development of CHD (2, 3, 6-8). Among the adult United States population, 19% of people have low HDL cholesterol ( Ͻ 40 mg/dl) (3, 9, 10) and 21% have hypertriglyceridemia ( Ͼ 150 mg/dl) (3, 10). Thus, as important as elevated LDL cholesterol is as a risk factor for CHD, it is important to recognize that the most common spectrum of lipid abnormalities is atherogenic dyslipidemia, which is present in 45-50% of men with CHD (11, 12) and includes borderline high-risk LDL cholesterol (e.g., 130-159 mg/dl), elevated triglycerides, small dense LDL particles, and low HDL cholesterol.The HMG-CoA reductase inhibitors (statins) are very effective in lowering LDL cholesterol and somewhat effective in reducing triglycerides, but they have only minimal effects on HDL cholesterol (2, 5, 13-15). Indeed, although numerous clinical trials have demonstrated that LDL cholesterol reduction can significantly reduce CHD risk, a great number of treated subjects who achieve substantial LDL cholesterol reduction still experience a clinical event (2,3,(13)(14)(15)(16)(17)(18). Therefore, with the goal of developAbbreviations: CETP, cholesterol ester transfer protein; CHD, coronary heart disease; ER, endoplasmic reticulum; MTP, microsomal triglyceride transfer protein.

The hypocholesterolemic activities of pamaqueside and tiqueside, two structurally similar saponins, were evaluated in cholesterol-fed rabbits. The pharmacological profiles of the saponins were virtually identical: both dosedependently decreased the intestinal absorption of labeled cholesterol 25-75%, increased fecal neutral sterol excretion up to 2.5-fold, and decreased hepatic cholesterol content 10-55%. High doses of pamaqueside ( Ͼ 5 mg/kg) or tiqueside ( Ͼ 125 mg/kg) completely prevented hypercholesterolemia. Decreases in plasma and hepatic cholesterol levels were strongly correlated with increased neutral sterol excretion. Ratios of neutral sterol excreted to pamaqueside administered were greater than 1:1 at all doses, in opposition to the formation of a stoichiometric complex previously suggested for tiqueside and other saponins. Ratios in tiqueside-treated rabbits were less than unity, a reflection of its lower potency. Pamaqueside-treated rabbits exhibited a more rapid decline in plasma cholesterol concentrations than control animals fed a cholesterol-free diet, indicating that the compound also inhibited the absorption of biliary cholesterol. Intravenous administration of pamaqueside had no effect on plasma cholesterol levels despite plasma levels twice those observed in rabbits given pamaqueside orally. These data indicate that pamaqueside and tiqueside induce hypocholesterolemia by blocking lumenal cholesterol absorption via a mechanism that apparently differs from the stoichiometric complexation of cholesterol hypothesized for other saponins. -Morehouse, L.

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