Objective-The ability of the potent cholesteryl ester transfer protein (CETP) inhibitor torcetrapib 414) to raise high-density lipoprotein cholesterol (HDL-C) levels in healthy young subjects was tested in this initial phase 1 multidose study. Methods and Results-Five groups of 8 subjects each were randomized to placebo (nϭ2) or torcetrapib (nϭ6) at 10, 30, 60, and 120 mg daily and 120 mg twice daily for 14 days. Torcetrapib was well tolerated, with all treated subjects completing the study. The correlation of plasma drug levels with inhibition (EC50ϭ43 nM) was as expected based on in vitro potency (IC50 Ϸ50 nM), and increases in CETP mass were consistent with the proposed mechanism of inhibition. CETP inhibition increased with escalating dose, leading to elevations of HDL-C of 16% to 91%. Total plasma cholesterol did not change significantly because of a reduction in nonHDL-C, including a 21% to 42% lowering of low-density lipoprotein cholesterol at the higher doses. Apolipoprotein A-I and E were elevated 27% and 66%, respectively, and apoB was reduced 26% with 120 mg twice daily. Cholesteryl ester content decreased and triglyceride increased in the nonHDL plasma fraction, with contrasting changes occurring in HDL. studies, the inverse correlation between high-density lipoprotein (HDL) levels and premature coronary heart disease (CHD) has been strengthened. A 1% decrease in HDL cholesterol (HDL-C) has been associated with a 1% to 2% increase in risk for CHD, 3 and lipid intervention trials have demonstrated that increases in HDL-C 4 and its main apoprotein, A-I, 5 contribute to reduced CHD, even in the absence of any change in low-density lipoprotein cholesterol (LDL-C). 6 However, current therapies for raising HDL are limited. The fibrates and statins produce only modest elevations in HDL, and the use of niacin, although somewhat more effective, has been hampered by side effects. 7 In a recent study, the combination of lovastatin and extended-release niacin (Advicor) was able to increase HDL levels by 20% to 32%, 8 but withdrawal rates for incidents of flushing and other adverse events were relatively high. Conclusions-TheseThe marked increase in HDL associated with human deficiency of cholesteryl ester transfer protein (CETP) 9 has See page 387 and cover suggested CETP inhibition as a means of elevating HDL. Expression of CETP in transgenic mice under different metabolic settings has produced mixed results regarding its atherogenicity, whereas inhibition of endogenous CETP in rabbits has more consistently been antiatherogenic. 10 With regard to human CETP mutations and the associated reduction in CETP levels, recent analysis of prospective data from the Honolulu Heart Study 10 is consistent with the results of a previous study of Japanese subjects 11 in concluding that CETP deficiency is protective when associated with HDL-C levels Ն60 mg/dL.The results for a phase 2 study testing the synthetic CETP inhibitor JTT-705 in subjects with mild hyperlipidemia have been reported. 12 At 900 mg daily, JTT-705 led to ...

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Glipizide-GITS was significantly more effective than immediate-release glipizide in reducing FPG levels. Both formulations reduced postprandial plasma glucose levels equally; however, glipizide-GITS exerted its control in the presence of lower plasma glipizide concentrations in addition to significantly lower insulin and C-peptide levels. This suggests that glipizide-GITS improves insulin sensitivity.

Active hydroxy metabolites of imipramine (IMI) and desipramine (DMI) have been quantified in plasma and cerebrospinal fluid (CSF) from patients at steady-state. In plasma of prepubescent boys and adults the concentration of unconjugated 2-hydroxyimipramine is only 15% to 25% that of IMI; 2-hydroxydesipramine (OH-DMI) concentration, however, is usually 50% that of DMI and in some cases OH-DMI is the predominant compound. In CSF from adult patients the ratio of concentrations of OH-DMI/DMI is higher than in plasma. Judging from the CSF/plasma ratio 12% of DMI exists in the free form at steady state, whereas 16% of OH-DMI is free (P less than 0.02). There is no evidence for saturation of hydroxylation within the therapeutic dose and concentration ranges investigated. On the basis of a steady-state OH-DMI/DMI ratio of less than 1/30 in plasma 5% of the population studied could be classified as deficient DMI hydroxylators. This in the same as the incidence of deficient debrisoquine hydroxylators reported in other populations.

This study was designed to compare the pharmacokinetic and short-term pharmacodynamic profile of extended-release glipizide GITS (Glucotrol XL) given in a dosage of 20 mg once daily with that of immediate-release glipizide (Glucotrol) 10mg twice daily in patients with type II diabetes mellitus. In an open-label, randomized, two-way crossover study, each glipizide formulation was administered for 5 days. Serial blood samples were drawn at baseline and on the 5th day of each treatment phase for measurement of glipizide, glucose, insulin, and C-peptide concentrations. At steady state, the mean Cmax after immediate-release glipizide was significantly greater than after glipizide GITS, and the tmax was considerably shorter. Although the mean Cmin with glipizide GITS was about 80% higher than with immediate-release glipizide, the mean AUC0-24 was significantly lower. Despite the lower plasma concentrations with glipizide GITS in this short-term study, the two formulations had similar effects on serum concentrations of glucose, insulin, and C-peptide. The absence of a pronounced peak plasma concentration with the GITS formulation might confer advantages in terms of maintaining clinical effectiveness and reducing the potential to cause adverse effects.

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Single oral and intramuscular (i.m.) doses of imipramine (IMI) were administered to four normal males. Serum and urine concentrations of IMI, desipramine (DMI) and their unconjugated 2-hydroxy metabolites were measured by high-pressure liquid chromatography (HPLC). Urinary conjugated 2-hydroxy metabolites were also measured after enzyme hydrolysis. Computer analysis of serum concentration and urinary excretion rate data allowed confirmation of drug and metabolite kinetics, and calculation of pharmacokinetic parameters. The rapid appearance of the metabolites in serum indicates that sequential first-pass metabolism of IMI involves both hydroxylation and demethylation. However, the dose-normalized areas under the serum concentration-time curves indicate that the fractions of the doses converted to metabolites were similar after both routes of IMI administration. Similar total fractions of the i.m. and oral doses recovered in urine indicate complete absorption of the oral doses. Inclusion of the metabolites increased the apparent availability of active components after oral IMI from 22%-50% to 45%-94%. Both the 2-hydroxy metabolites exhibited formation rate-limited kinetics, whereas DMI kinetics were elimination rate-limited. The t1/2 of IMI and 2-hydroxyimipramine (2-OH-IMI) was 6-18 h, while that of DMI and 2- hydroxydesipramine (2-OH-DMI) was 12-36 h. The t1/2 of these compounds was 1.5-2 times longer after the i.m. doses. The metabolite/parent ratios and the disposition of the individual metabolites confirm findings that chronic dosing results in only limited accumulation of hydroxy metabolites.

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