Guidance on the management of familial hypercholesterolaemia in Hong Kong: an expert panel consensus viewpoin.

In 2016, meetings of groups of physicians and paediatricians with a special interest in lipid disorders and familial hypercholesterolaemia were held to discuss several domains of management of familial hypercholesterolaemia in adults and children in Hong Kong. After reviewing the evidence and guidelines for the diagnosis, screening, and management of familial hypercholesterolaemia, consensus was reached on the following aspects: clinical features, diagnostic criteria, screening in adults, screening in children, management in relation to target plasma low-density lipoprotein cholesterol levels, detection of atherosclerosis, lifestyle and behaviour modification, and pharmacotherapy.

Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6ß-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese.

WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6ß-hydroxycortisol (6ß-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6ß-OHF/F in healthy Chinese. METHODS: Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6ß-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6ß-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6ß-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6ß-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6ß-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.

Effect of whole soy and purified daidzein on ambulatory blood pressure and endothelial function--a 6-month double-blind, randomized controlled trial among Chinese postmenopausal women with prehypertension.

BACKGROUND/OBJECTIVES: Although observational studies suggest that soy foods or isoflavones are cardio-protective, clinical trials on whole soy or isoflavone daidzein (one major isoflavone and the precursor of equol) on blood pressure (BP) and endothelial function (EF) are few and have not been specifically conducted among equol producers, a population most likely to benefit from soy treatment. SUBJECTS/METHODS: We performed a 6-month double-blind, randomized, placebo-controlled trial to examine the effect of whole soy (soy flour) or purified daidzein on BP and EF in prehypertensive or untreated hypertensive postmenopausal women verified to be equol producers. A total of 270 eligible women were recruited and randomized to either one of the three treatment groups, 40 g soy flour (whole soy group), 40 g low-fat milk powder+63 mg daidzein (daidzein group) or 40 g low-fat milk powder (active control group) daily, each given as a solid beverage powder for 6 months. The primary outcome measures were 24 h ambulatory BP (ABP) and EF assessed by flow-mediated dilation using brachial artery ultrasound. RESULTS: A total of 253 subjects completed the study according to protocol. Urinary isoflavones indicated good compliance with the interventions. Intention to treat and per-protocol analysis indicated that there was no significant difference in the 6-month changes or % changes in parameters of ABP and brachial flow-mediated dilation among the three treatment groups. A further subgroup analysis among hypertensive women (n=138) did not alter the conclusions. CONCLUSIONS: Whole soy and purified daidzein had no significant effect on BP and vascular function among equol-producing postmenopausal women with prehypertension or untreated hypertension.

A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections.

BACKGROUND: It is unclear if higher-dose oseltamivir provides benefit beyond the standard dose in influenza patients who require hospitalization. METHODS: A prospective intervention study was performed in 2 acute care general hospitals in Hong Kong over 4 seasonal peaks (2010-2012). Adults (≥18 years) with laboratory-confirmed influenza (85 A/H3N2, 34 A/H1N1pdm09, 36 B) infections who presented within 96 hours were recruited. Study regimen of either 150 mg or 75 mg oseltamivir twice daily for 5 days was allocated by site, which was switched after 2 seasons. Subjects with preexisting renal impairment (creatinine clearance, 40-60 mL/minute) received 75 mg oseltamivir twice daily. Viral clearance by day 5 and clinical responses were compared between groups. Plasma steady-state trough oseltamivir carboxylate (OC) concentration was measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Altogether, 41 and 114 patients received 150 mg and 75 mg twice-daily oseltamivir, respectively; their enrollment characteristics (mean age, 61 ± 18 vs 66 ± 16 years) and illness severity were comparable. Trough OC levels were higher in the 150-mg group (501.0 ± 237.0 vs 342.6 ± 192.7 ng/mL). There were no significant differences in day 5 viral RNA (44.7% vs 40.2%) or culture negativity (100.0% vs 98.1%), RNA decline rate, and durations of fever, oxygen supplementation, and hospitalization. Results were similar when analyzed by study arm (all cases and among those without renal impairment). Subanalysis of influenza B patients showed faster RNA decline rate (analysis of variance, F = 4.14; P = .05) and clearance (day 5, 80.0% vs 57.1%) with higher-dose treatment. No oseltamivir resistance was found. Treatments were generally well tolerated. CONCLUSIONS: We found no additional benefit of higher-dose oseltamivir treatment in adults hospitalized with influenza A, but an improved virologic response in influenza B. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT01052961.

A high incidence of exanthematous eruption associated with niacin/laropiprant combination in Hong Kong Chinese patients.

WHAT IS KNOWN AND OBJECTIVE: Niacin commonly causes cutaneous flushing, which is partially alleviated by laropiprant, a selective antagonist of prostaglandin D2 at the DP1 receptor. Here we report an unusually high incidence of exanthematous eruption associated with the use of the extended-release (ER) niacin/laropiprant combination treatment in Hong Kong Chinese patients. CASE DESCRIPTION: Among 201 patients treated with ER niacin/laropiprant 1000/20 mg over 7 days to assess flushing symptoms and 166 of the patients who continued the treatment for 12 weeks (doubling the dose after 4 weeks), 28 patients (14%) developed a highly pruritic cutaneous eruption at a mean of 5 days after starting the treatment or 4 days after increasing the dose. This resolved over several days after drug withdrawal with symptomatic treatment. Compared with the subjects who completed 12-weeks treatment uneventfully, those who developed cutaneous eruption were older, had significantly lower body weight, were taking background lipid-lowering treatment more frequently and had greater flushing responses in the first few days of treatment. WHAT IS NEW AND CONCLUSION: The relationship of the exanthematous eruption with lower body weight and the increase in dosage suggests a pharmacokinetic effect that may be related to increased exposure to niacin or its metabolites and provoked by inhibition of the DP1 receptor with laropiprant, as we have not seen this rash with niacin used alone. This may suggest that the southern Chinese population may have some genetic predisposition; as such, a high frequency of exanthematous reactions has not been reported in other populations.

Development and validation of a sensitive method for simultaneous determination of rosuvastatin and N-desmethyl rosuvastatin in human plasma using liquid chromatography/negative electrospray ionization/tandem mass spectrometry.

A sensitive and specific liquid chromatography tandem mass spectrometric method was developed and validated for the simultaneous determination of rosuvastatin (ROS) and N-desmethyl rosuvastatin (NOR-ROS) in human plasma using deuterium-labeled internal standards. The plasma samples were prepared using liquid-liquid extraction with diethyl ether. Chromatographic separation was accomplished on an Xterra MS C18 column. The mobile phase consisted of a gradient mixture of 15 µmol/L ammonium acetate in water and in methanol, maintained at a flow rate of 0.4 mL/min. Mass spectrometric detection was carried out in negative electrospray ionization mode and monitored by quantification and qualification transitions for each analyte. Using 300 µL plasma samples, the lower limits of quantification of ROS and NOR-ROS were 0.05 and 0.02 µg/L respectively. The linearity of ROS and NOR-ROS ranged from 0.05 to 42 and 0.02 to 14 µg/L respectively. The relative standard deviations of ROS and NOR-ROS were <13 and 9%, respectively, while the deviations from expected values were within -4.7-9.8 and -5.2-4.6%, respectively. The present method offered high sensitivity and was successfully applied to a 24 h pharmacokinetic study of ROS and NOR-ROS in healthy subjects receiving a single dose of 10 mg ROS.

Association between HLA-B*58:01 allele and severe cutaneous adverse reactions with allopurinol in Han Chinese in Hong Kong.

BACKGROUND: Allopurinol has been reported as a common cause of severe cutaneous adverse reactions (SCARs). Recent studies in various populations suggest that HLA-B*58:01 is a strong genetic marker for allopurinol-induced SCAR, especially in populations with a high frequency of HLA-B*58:01. OBJECTIVES: To confirm the association link between HLA-B*58:01 and hypersensitivity reactions attributed to allopurinol use in Han Chinese patients in Hong Kong. METHODS: We performed a case-control study to investigate whether the HLA-B*58:01 allele predisposes to allopurinol-induced SCAR in Han Chinese patients in Hong Kong. The HLA-B*58:01 genotyping was performed in 20 patients with allopurinol-induced SCAR or erythema multiforme major (EMM; n = 1) and in 30 patients tolerant to allopurinol. RESULTS: All of the 19 patients with allopurinol-induced SCAR examined but not the patient with EMM carried HLA-B*58:01 whereas only four (13%) of the control patients had this allele. The positive rate of the HLA-B*58:01 was significantly higher in the cases than in the allopurinol-tolerant control group [odds ratio (OR) 123·5, 95% confidence interval (CI) 12·8-1195·1; P < 1 × 10(-4) ] and was even higher after removal of the patient with EMM (OR 229·7, 95% CI 11·7-4520·4). The sensitivity and specificity of the HLA-B*58:01 allele for prediction of allopurinol-induced SCAR were 100% and 86·7%, respectively. CONCLUSIONS: This study confirmed the strong association between the HLA-B*58:01 and allopurinol-induced SCAR in Hong Kong Han Chinese patients. A screening test for the HLA-B*58:01 allele should effectively reduce the risk for allopurinol-induced SCAR in Chinese populations.

Herb-drug interactions: methods to identify potential influence of genetic variations in genes encoding drug metabolizing enzymes and drug transporters.

Herbal supplements are often used concomitantly with conventional medications resulting in considerable potential for herb-drug interactions. These interactions, which are generally through interfering with pharmacokinetic and/or pharmacodynamic pathways, may result in beneficial effects or more often adverse reactions such as toxicity or treatment failure and may be influenced by multiple environmental and/or genetic factors. The pharmacogenetic approach may help to identify some interactions which may be more pronounced or only occur in specific groups of subjects although the complex nature of the herbal medicines may limit the discovery of such an interaction. Preclinical studies such as gene expression profiling in rodent liver may help to define metabolic pathways influenced by herbal medicines and facilitate more accurate targeting of human in vivo studies. This review discusses the mechanisms of herb-drugs interaction and the potential influence of genetic variation on herb-drug interactions based on available clinical evidence.

Effects of rosuvastatin on subclinical atherosclerosis and arterial stiffness in rheumatoid arthritis: a randomized controlled pilot trial.

OBJECTIVE: To ascertain the effect of rosuvastatin on carotid atherosclerosis and arterial stiffness in patients with rheumatoid arthritis (RA). METHODS: Fifty RA patients were randomized in a double-blind placebo-controlled trial to receive 10 mg rosuvastatin (n = 24) or placebo (n = 26). Patients were followed prospectively every 3 months for 12 months. Intima-media thickness (IMT), augmentation index (AIx), and subendocardial viability ratio (SEVR) were measured at baseline, 6 and 12 months. RESULTS: Rosuvastatin resulted in statistically significant reductions of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and urate levels vs. placebo. However, rosuvastatin had no significant effect on changes in inflammatory markers, including C-reactive protein (CRP) levels [from 2.9 (1.4-11.0) to 3.1 (0.9-13.3) mg/L in the rosuvastatin group compared with from 5.8 (2.6-14.2) to 4.4 (1.2-12.3) mg/L in the placebo group]. Nonetheless, a significant improvement in the Disease Activity Score (DAS) and a reduction in fibrinogen level was observed at 6 and 12 months compared with baseline in the rosuvastatin group. The treatment group exhibited a significant increase in SEVR (from 157 ± 28% to 163 ± 33% in the rosuvastatin group compared with from 143 ± 18% to 143 ± 26% in the placebo group, p = 0.023), but no significant effect was observed in the changes in IMT and AIx. CONCLUSION: Our data suggest that rosuvastatin has a modest anti-inflammatory effect in RA patients with low disease activity in terms of reduction in DAS and fibrinogen level. Rosuvastastin may also improve subendocardial perfusion and lower the urate level.

Simvastatin-induced myopathy, the role of interaction with diltiazem and genetic predisposition.

WHAT IS KNOWN AND OBJECTIVE: Diltiazem shows a pharmacokinetic interaction with statins that are CYP3A substrates but this may not result in myopathy unless additional genetic or clinical factors are present. Subsequent changes in treatment or underlying disease may result in a delayed onset of this adverse affect. Our objective is to report on two cases of statin-induced myopathy associated with concomitant use of diltiazem and other contributing factors, and to briefly review the related literature. COMMENT: A 63-year-old Chinese woman with hypertension and familial hypercholesterolaemia (FH) taking diltiazem 90 mg twice daily had elevation of creatine kinase (CK) to 4016 U/L and alanine aminotransferase (ALT) to 165 IU/L 4 weeks after increasing the dose of simvastatin from 40 to 80 mg daily. Another 80-year-old Chinese woman with FH, mild vascular dementia and hypertension was hospitalized with bilateral lower limb weakness associated with raised CK (8869 IU/L), lactate dehydrogenase (1384 IU/L) and ALT (288 IU/L) after taking diltiazem 60 mg twice daily with simvastatin 40 mg for 11 months. Statin-associated myopathy was suspected and simvastatin was stopped in both cases, and symptoms resolved and all laboratory parameters returned to normal in 2 weeks. The myopathy in both cases is likely to have resulted from an interaction of higher doses of simvastatin with diltiazem through inhibition of CYP3A enzymes and drug transporters. The strength of simvastatin-diltiazem interactions in the two cases estimated by the Drug Interaction Probability Scale (DIPS) indicated a possible association. WHAT IS NEW AND CONCLUSION: The two cases reported here and the brief literature review emphasize the potential interaction between two drugs frequently coadministered, simvastatin and diltiazem and we suggest that diltiazem should not be used with higher doses of those statins metabolized by CYP3A such as simvastatin or atorvastatin and even with lower doses caution should be exercised in patients who may have cause for impaired metabolism.

The role of ß-blockers in the management of hypertension: an Asian perspective.

Following publication of the National Institute of Clinical Excellence (NICE) Guidelines in 2006, the use of ß-blockers as first-line therapy in hypertension has been somewhat controversial. However, a recent reappraisal of the European Society of Hypertension guidelines highlights that these agents exhibit similar BP lowering efficacy to other classes of agents, prompting a re-examination of the utility of these agents in various patient populations. The authors felt that it is important to address this controversy and provide an Asian perspective on the place of ß-blockers in current clinical practice and the benefits of ß-blockade in selected patient populations. In addition to their use as a potential first-line therapy in uncomplicated hypertension, ß-blockers have a particular role in patients with hypertension and comorbidities such as heart failure or coronary artery disease, including those who had a myocardial infarction. One advantage which ß-blockers offer is the additional protective effects in patients with prior cardiovascular events. Some of the disadvantages attributed to ß-blockers appear more related to the older drugs in this class and further appraisal of the efficacy and safety profile of newer ß-blockers will lend support to the current guideline recommendations in Asian countries and encourage increased appropriate use of ß-blockade in current clinical practice within Asia.

ACE inhibitor use was associated with lower serum dehydroepiandrosterone concentrations in older men.

CONTEXT: Angiotensin converting enzyme (ACE) activity may influence the production of adrenal androgen precursors and testosterone. Use of ACE inhibitors may therefore have an influence on serum sex hormone concentrations in older men. DESIGN AND METHODS: 1486 out of 2,000 community-dwelling Chinese men aged 65years who participated in a cohort study were randomly selected to have archived fasting morning serum analyzed for androgen precursors and sex hormones. DNA was extracted from whole blood and analyzed for ACE gene I/D polymorphism. RESULTS: Subjects with the ACE gene D allele (higher ACE activity) had higher serum dehydroepiandrosterone (DHEA) sulphate and DHEA than those with I/I genotype (P=0.014 and 0.018 respectively, Mann Whitney test). These differences were not significant after Bonferroni correction. Among those with history of hypertension, but without diabetes mellitus or cardiac failure, users of ACE inhibitors had significantly lower serum DHEA (median 1.78 versus 1.49ng/ml in non-users, P=0.0074, Mann Whitney test) and also tended to have lower serum androstenedione and androst-5-ene-3beta,17beta-diol (0.68 versus 0.72ng/ml in non-users; 552.4 versus 624.1pg/ml respectively, both P values <0.05). Serum testosterone and estradiol were not significantly changed. CONCLUSIONS: ACE inhibitor use was associated with lower serum DHEA in older men.

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.

An overview of the Guangzhou biobank cohort study-cardiovascular disease subcohort (GBCS-CVD): a platform for multidisciplinary collaboration.

The Guangzhou Biobank Cohort Study (GBCS, n=30 519, age >or=50 years) was established to examine the effects of genetic and environmental influences on health problems and chronic disease development. Guangzhou is undergoing massive economic development, but from a baseline that had remained unchanged for millennia. The Cardiovascular Disease Subcohort (GBCS-CVD) consists of 2000 participants who have been intensively phenotyped including a range of surrogate markers of vascular disease, including carotid artery intima-media thickness, cerebral artery stenoses, arterial stiffness, ankle-to-brachial blood pressure index and albuminuria, as well as coagulatory and inflammatory markers. Plasma and leukocytes are stored in liquid nitrogen for future studies. Preliminary demographic data show the female volunteers are younger than the male ones, but present with greater levels of adiposity including central obesity (31 vs 16%). Women had more body fat (33 vs 24%) and associated levels of adipokines. Despite this, body mass index and hip circumferences were similar, which contrasts with Caucasian populations. Men had more physician-diagnosed vascular disease (6.1 vs 2.5%), hypertension (42 vs 34%) and hyperglycaemia (36.6 vs 29.6%) than the women, but were less insulin resistant. In men, smoking (40 vs 2%) and drinking alcohol (67 vs 50%) was more common and they also had lower energy expenditures. The genotype distributions of the 15 typed single nucleotide polymorphisms were all in Hardy-Weinberg equilibrium. This article describes the rationale and methodology for the study. Given the comprehensive characterization of demographic and psychosocial determinants and biochemistry, the study provides a unique platform for multidisciplinary collaboration in a highly dynamic setting.