Objective-To examine the hypothesis, in a community not studied before, that insulin resistance associated with centralised adiposity is the mechanism underlying the predisposition of Asian immigrant communities to both ischaemic heart disease and diabetes mellitus.Design-Cross sectional study within one socioeconomic stratum.Setting-Two factories in the textile sector in Bradford, West Yorkshire.Subjects-Male manual workers of Asian (110) and non-Asian origin (156) aged 20-65 years.Results-Diabetes was almost three times more prevalent in the Asian group. Two hours after an oral glucose load Asian men had double the serum insulin concentrations of non-Asian men (p < 0 0001). Asian men also had significantly lower concentrations of plasma total cholesterol (p < 0 03), high density lipoprotein cholesterol (HDL) (HDL2, p < 0-0001; HDL3, p < 0-0001), and apolipoprotein AI (p < 0 0001). Fasting plasma triglyceride concentrations were slightly higher (p = 0 072) in the Asian men; thus the ratio of triglyceride cholesterol was higher (p = 0 006). The interrelation between serum insulin and plasma lipid concentrations indicated metabolic differences between the ethnic groups. Insulin concentrations were associated with cholesterol concentrations in the Asian men only and there was a lack of association between triglyceride, low density lipoprotein cholesterol, and HDL cholesterol in this group. The risk marker profile in the Asian men was therefore quite different to that of their non-Asian counterparts and was associated with a greater tendency to centralised adiposity.Conclusion-These data support the insulin resistance hypothesis and thus have important implications for

Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending-dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross-linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis. ß

AimsThe primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed. MethodsTwelve healthy volunteer subjects (age range 22-48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full 'cocktail' as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUC last (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events. ResultsOverall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67-1.10), midazolam, 0.96 (0.74-1.24), tolbutamide, 0.86 (0.72-1.03), debrisoquine 1.04 (0.97-1.12) and chlorzoxazone, 0.95 (0.86-1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone. ConclusionsThe five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically impor tant drugdrug interactions during drug development. Assessment of the interactions of five co-administered probe drugsBr J Clin Pharmacol 57:2 163

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