Tanya T.W. Chu

Cardiovascular risk profile of patients with psoriatic arthritis compared to controls—the role of inflammation

OBJECTIVE To examine the distribution of traditional and novel risk factors of cardiovascular disease (CVD) in patients with PsA compared with healthy controls. METHODS We compared risk factors for CVD between 102 consecutive PsA patients and 82 controls, adjusting for BMI. We also assessed the role of inflammation on the CVD risk factor by using a BMI and high-sensitivity CRP (hsCRP)-adjusted model. RESULTS The BMI of PsA patients were significantly higher than healthy controls. After adjusting for the BMI, PsA patients still have a higher prevalence of diabetes mellitus (DM) [odds ratio (OR) 9.27, 95% CI 2.09, 41.09) and hypertension (OR 3.37, 95% CI 1.68, 6.72), but a lower prevalence of low high density lipoprotein (HDL) cholesterol (OR 0.16, 95% CI 0.07, 0.41). PsA patients have significantly increased systolic and diastolic blood pressures, insulin resistance and inflammatory markers (hsCRP and white cell count) compared to controls. PsA patients have higher HDL cholesterol and apolipoprotein (Apo) A1 levels; and lower total cholesterol (TC) and low density lipoprotein cholesterol levels; and a lower TC/HDL ratio. However, the Apo B level (P < 0.05), and the Apo B/Apo A1 ratio (P = 0.07) were higher in PsA patients. Further adjustment for hsCRP level rendered the differences in the prevalence of hypertension and DM; the TC, and sugar levels; and white cell count non-significant between the two groups; while the differences in other parameters remained significant. CONCLUSION These data support the hypothesis that PsA may be associated with obesity, hypertension, dyslipidaemia and insulin resistance because of the shared inflammatory pathway.

ABCG2 Polymorphism Is Associated With the Low‐Density Lipoprotein Cholesterol Response to Rosuvastatin

The ATP‐binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low‐density lipoprotein cholesterol (LDL‐C)‐lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL‐C level, in a gene‐dose‐dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL‐C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.

Effect of Panax ginseng supplementation on biomarkers of glucose tolerance, antioxidant status and oxidative stress in type 2 diabetic subjects: results of a placebo-controlled human intervention trial

American ginseng (Panax quinquefolius L.) and Asian ginseng (Panax ginseng C.A Meyer) have been reported to have an insulin-stimulating or insulin-sensitizing effect [1–3]. The aim of this study was to investigate the effect of supplementation with P. ginseng on type 2 diabetic subjects in relation to glycaemic control and cardiovascular risk. As P. ginseng is promoted as having potent antioxidant properties, effects on biomarkers of oxidative stress and antioxidant defence were also studied, and the in vitro antioxidant capacity of the P. ginseng supplement used was measured. This was a randomized, placebo-controlled, doubleblinded crossover study in 20 consenting type 2 diabetic subjects. Mean s.e.m. of the age was 51.5 1.9 years, HbA1c 7.4 0.4%, bodymass index (BMI) 28.5 1.3 kg/ m. Subjects’ diabetes was controlled with diet and/or oral hypoglycaemic agents, which were continued unchanged throughout the study. After a 2-week placebocontrolled run-in period, subjects were randomized to take ginseng (2 369 mg capsules, three times daily, n 1⁄4 10) or placebo (n 1⁄4 10) for 4 weeks. Placebo capsules were then taken for 2 weeks as washout, after which subjects crossed over to the other treatment for 4 weeks. At the end of the run-in and each 4-week treatment, subjects underwent a 75 g oral glucose tolerance test (OGTT). Plasma glucose, insulin and biomarkers of oxidative stress and antioxidant status were measured. The study was approved by the Ethics Sub-Committee of the Hong Kong Polytechnic University and the Clinical Research Ethics Committee of the Chinese University of Hong Kong. This trial was registered with the Centre for Clinical Trials of the Chinese University of Hong Kong (registration # CUHK_CCT00021). Plasma glucose was measured on the day of collection using a commercial enzyme-linked spectrophotometric kit method. Total antioxidant capacity [as the ferric reducing/antioxidant power (FRAP) value] and the ascorbate (vitamin C) concentration of fresh heparinized plasma were measured following our established protocol [4]. Plasma (stored at 70 °Cand thawed once only for measurement) was measured for insulin (enzyme-linked immunosorbent assay) and oxidative stress markers [malondialdehyde (MDA) [5] and allantoin [6] and tocopherol [7]] by }-high performance liquid chromatography methods and urate by commercial uricase kit method. Homeostatic model assessment (HOMA) was used to assess insulin resistance (HOMA-IR) and beta cell function (as HOMA-%B) [8]. The total antioxidant content (as the FRAP value [4]) of the powdered P. ginseng supplement (dissolved in hot water, cooled and filtered) was measured. Paired t-test was used to compare the differences in biomarker responses at each time point during OGTT after placebo and after ginseng treatment [i.e. (postplacebo minus baseline) compared with (post-ginseng minus baseline)] values. Comparison across OGTT time intervals (0–120 min) following glucose ingestion was performed in the full datasets by ANOVA for repeated measures (with Tukey-Cramer multiple comparisons post-test). Statistical significance was sought at the 5% level (two-sided analysis). Data were also analysed for period and order effects by unpaired t-test. Results are presented in table 1. There was a significantly (p < 0.05) greater decrease in HOMA-IR after ginseng treatment (;45%decrease in HOMR-IR after ginseng treatment comparedwith;12%decrease inHOMRIR after placebo), partly because of a significantly (p < 0.05) lower fasting plasma glucose after ginseng treatment compared with after placebo, and a tendency (p > 0.05) to reduced fasting insulin levels after ginseng treatment. The insulin response to the OGTT tended to be reduced after ginseng treatment, but this did not reach significance. There were no significant changes in the biomarkers of antioxidant defence or oxidative stress (FRAP, ascorbate,

Pharmacogenetic analysis of lipid responses to rosuvastatin in Chinese patients.

Lipid changes with statin treatments vary greatly between individuals for reasons which are largely unknown. This study was performed to examine the genetic determinants of lipid responses to rosuvastatin in Chinese patients. A total of 125 polymorphisms in 61 candidate genes from 386 Chinese patients were analyzed for association with the lipid responses to rosuvastatin 10 mg daily. The polymorphisms most highly associated with the low-density lipoprotein cholesterol (LDL-C) response were 421C>A in the ATP-binding cassette G2 gene (P=9.2×10−7), followed by 18281G>A (V257M) in the flavin-containing monooxygenase 3 gene (P=0.0002), 1421C>G in the lipoprotein lipase gene (P=0.002), and rs4420638 in the apolipoprotein E/C-I/C-IV/C-II gene cluster (P=0.004). Patients with familial hypercholesterolemia had 2.6% smaller reductions in LDL-C compared with patients without familial hypercholesterolemia. This study identified some genetic determinants of LDL-C response to rosuvastatin in Chinese patients, which need to be replicated in other populations.

Study of potential cardioprotective effects of Ganoderma lucidum (Lingzhi): results of a controlled human intervention trial

Previous studies have suggested that Lingzhi (Ganoderma lucidum) has antioxidant effects and possibly beneficial effects on blood pressure, plasma lipids and glucose, but these have not been confirmed in subjects with mild hypertension or hyperlipidaemia. The objective of the present study was to assess the cardiovascular, metabolic, antioxidant and immunomodulatory responses to therapy with Lingzhi in patients with borderline elevations of blood pressure and/or cholesterol in a controlled cross-over trial. A total of twenty-six patients received 1·44 g Lingzhi daily or matching placebo for 12 weeks in a randomised, double-blind, cross-over study with placebo-controlled run-in and cross-over periods. Body weight, blood pressure, metabolic parameters, urine catecholamines and cortisol, antioxidant status and lymphocyte subsets were measured after each period. Lingzhi was well tolerated and data from twenty-three evaluable subjects showed no changes in BMI or blood pressure when treated with Lingzhi or placebo. Plasma insulin and homeostasis model assessment-insulin resistance were lower after treatment with Lingzhi than after placebo. TAG decreased and HDL-cholesterol increased with Lingzhi but not with placebo in the first treatment period, but significant carry-over effects prevented complete analysis of these parameters. Urine catecholamines and cortisol, plasma antioxidant status and blood lymphocyte subsets showed no significant differences across treatments. Results indicate that Lingzhi might have mild antidiabetic effects and potentially improve the dyslipidaemia of diabetes, as shown previously in some animal studies. Further studies are desirable in patients with hyperglycaemia.

Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects.

Abstract Background: Although flecainide is thought to be metabolized predominantly by cytochrome P450 (CYP) 2D6, it shows pharmacokinetic interactions with drugs, such as verapamil and digoxin, which may suggest other CYP pathways or ATP-binding cassette (ABC) transporters might be involved. This study evaluated effects of common polymorphisms in Chinese in CYP2D6, CYP3A5, CYP1A2, and ABCB1 on flecainide pharmacokinetics. Methods: Single oral 100-mg doses of flecainide were given to 15 healthy male Chinese subjects who were genotyped for the CYP2D6*2, *5, *10, CYP3A5*3, CYP1A2*1F and ABCB1 C1236T, G2677T/A, and C3435T polymorphisms. Results: There was no significant difference in the pharmacokinetics of flecainide among CYP2D6 (mainly involving *10) genotypes. The CYP3A5*3/*3 subjects (n=8) had a 26% higher systemic exposure (AUC0–∞) and 17% lower apparent oral clearance of flecainide than the combined group of CYP3A5*1/*1 (n=6) and CYP3A5*1/*3 (n=1) subjects (p<0.05). Subjects homozygous for CYP1A2*1F tended to have lower systemic exposure and increased clearance of flecainide compared to those with CYP1A2*1A/1F in subjects with at least one CYP2D6 variant allele. Conclusions: The disposition of flecainide appeared to be influenced by the CYP3A5*3 and possibly the CYP1A2*1F polymorphisms, particularly in subjects with CYP2D6 variant alleles.

Pharmacokinetic Properties of Single-Dose Lamivudine/Adefovir Dipivoxil Fixed-Dose Combination in Healthy Chinese Male Volunteers

BACKGROUND Both lamivudine and adefovir dipivoxil are approved for the treatment of chronic hepatitis B (CHB) and have established safety profiles. A fixed-dose combination (FDC) formulation of lamivudine/adefovir dipivoxil for the treatment of CHB may provide dosing convenience and improve adherence. OBJECTIVE This study compared the pharmacokinetic profiles of an FDC capsule containing lamivudine/adefovir dipivoxil 100/10 mg and conventional lamivudine 100-mg + adefovir dipivoxil 10-mg tablets to determine bioequivalence. METHODS This randomized, open-label, single-dose, 2-period crossover study was conducted in healthy male Chinese subjects. The study included a screening visit, 2 treatment sessions, and a follow-up visit. Subjects who met the inclusion/exclusion criteria were assigned to receive, in randomized order, 1 FDC capsule or 1 tablet each of lamivudine and adefovir dipivoxil. After a 7- to 10-day washout period, alternate treatment was given to the subjects during the second treatment session. Blood samples were collected immediately before and after dosing for 48 hours for plasma drug concentration measurement. Data on adverse events (AEs) were collected from the start of dosing until the follow-up visit. Tolerability assessments included physical examinations with vital sign measurements and clinical laboratory evaluations throughout the study. RESULTS Forty subjects were enrolled into the study (mean age, 22.4 years [range, 19-28 years]; weight, 63.8 kg [range, 54-78 kg]). The pharmacokinetic profiles of lamivudine and adefovir were similar between the FDC and reference formulations. The geometric mean ratios (GMRs) for lamivudine C(max) and AUC(0-last) were 1.02 (90% CI, 0.92-1.12) and 0.99 (90% CI, 0.95-1.04), respectively; adefovir, 0.94 (90% CI, 0.89-0.99) and 0.95 (90% CI, 0.91-1.00). A limited number of mild AEs were reported, with no clinically significant changes in vital signs or laboratory results. CONCLUSIONS The FDC capsule was bioequivalent to the concurrent administration of lamivudine + adefovir dipivoxil tablets based on the 90% CIs of the GMRs for C(max), AUC(0-∞), AUC(0-last), and t12 (all were between 0.80 and 1.25). Both treatments were well-tolerated.