Chi-Keung Cheung

Comparison of enalapril and nifedipine in treating non-insulin dependent diabetes associated with hypertension : one year analysis

OBJECTIVES--To compare the efficacy, safety, and tolerance of enalapril and nifedipine in hypertensive patients with non-insulin dependent diabetes. DESIGN--One year double blind follow up of patients randomly allocated to either enalapril or nifedipine with matching placebos for the alternative drug. SETTING--Metabolic Investigation Unit, Hong Kong. SUBJECTS--102 patients were randomised: 52 to nifedipine and 50 to enalapril. At baseline 44 patients had normoalbuminuria, 36 microalbuminuria, and 22 macroalbuminuria. MAIN OUTCOME MEASURES--Blood pressure, albuminuria, and parameters of renal function and glycaemic control. RESULTS--In patients who completed one years treatment the median dose required by the nifedipine group (n = 49) was 60 mg/day; seven (14%) required additional diuretics. Of 41 patients given enalapril, 37 required the maximum dose (40 mg/day) and 27 (76%) required diuretics. At one year mean arterial blood pressures were similar in both groups. Albuminuria fell by 54% in the enalapril group and 11% in the nifedipine group (p = 0.006). Fractional albumin clearance ratio fell by 47% in the enalapril group and increased by 3% in the nifedipine group (p = 0.009). Creatinine clearance fell similarly in both groups but plasma creatinine concentration was increased by 20% in the enalapril group versus 8% in the nifedipine group (p = 0.001). CONCLUSION--Patients taking enalapril often required diuretics to control blood pressure. Enalapril reduced proteinuria significantly more than nifedipine in the microalbuminuric and macroalbuminuric patients but increased plasma creatinine concentrations. Longer follow up is required to clarify the importance of enalaprils antiproteinuric effect.

Obesity, albuminuria and hypertension among Hong Kong Chinese with non-insulin-dependent diabetes mellitus (NIDDM).

A total of 412 Hong Kong Chinese diabetic patients were studied on at least two occasions 8-16 weeks apart. Although 28% were insulin-treated, only 3.6% had insulin-dependent diabetes (IDDM). In the remaining 397 patients with non-insulin-dependent diabetes (NIDDM), the mean (s.d.) body mass index (BMI) was 24.4 +/- 3.2 kg/m2 in females and 24.2 +/- 3.2 kg/m2 in males. Obesity was present in 17% of males (BMI > 27 kg/m2) and 40% of females (BMI > 25 kg/m2). Established hypertension was present in 49%. Abnormal albuminuria, defined as a mean urinary albumin/creatinine (UA/Cr) ratio greater than 5.4 mg/mmol based on two random spot urine samples, was present in 47%. On stepwise multiple regression analysis, UA/Cr ratio (R2 = 0.34, F = 65.4, P < 0.001) showed significant associations with systolic blood pressure (standardized regression coefficient beta = 0.40, P < 0.001), plasma creatinine concentration (beta = 0.27, P < 0.001) and glycosylated haemoglobin (beta = 0.20, P < 0.001). While the prevalence of hypertension increased with increasing severity of proteinuria, 40% of normoalbuminuric patients had hypertension. Among patients diagnosed before the age of 35 (n = 67), 52% were insulin-treated although only 10% were insulin-dependent. Among these NIDDM patients of young onset (n = 59), obesity was present in 25% of males and 56% of females. Overall, 18% of these patients had a blood pressure greater than 140/90 mmHg and 27% had abnormal albuminuria. In Hong Kong Chinese, diabetes mellitus is predominantly non-insulin-dependent even in the young. Obesity is more prevalent among females. Abnormal albuminuria is relatively common and is closely associated with hypertension and glycaemic control. In the light of increasing prevalence of diabetes among overseas Chinese, our findings may have important implications in the management of Chinese diabetic patients.

Abnormal Albuminuria as a Predictor of Mortality and Renal Impairment in Chinese Patients With NIDDM

OBJECTIVE Microalbuminuria predicts mortality in non-insulin-dependent diabetes mellitus (NIDDM), but its association with deterioration of renal function remains more controversial than in insulin-dependent diabetes mellitus (IDDM). Using albumin-to-creatinine ratios (ACRs) in random spot urine samples is a convenient method for evaluating albuminuria. We studied prospectively the predictive values of albuminuria in NIDDM when assessed by this urine measurement. RESEARCH DESIGN AND METHODS Between 1991 and 1992, we restudied the clinical and biochemical status of 403 Chinese NIDDM patients recruited in 1989 after a follow-up period of 26.6 ± 3.2 months (mean ± SD). Spot urine ACR was measured on two occasions and microalbuminuria was defined as a mean ACR between 5.6 and 38 mg/mmol. RESULTS From the original cohort, 29 patients had died mostly because of cardiovascular events with or without renal failure. The overall relative risk of death in patients with abnormal albuminuria was 7.1 (P < 0.001) (microalbuminuria: 3.7, P = 0.04; macroalbuminuria: 11, P < 0.001). On multivariate analysis, the independent predictive factors for mortality were plasma creatinine (wald = 12.1, P < 0.001) and glucose concentrations (wald = 10.4, P < 0.001) in the normo- and microalbuminuric patients (n = 11) and age (wald = 4.4, P = 0.03) and plasma creatinine (wald = 8.2, P < 0.01) in the macroalbuminuric group (n = 18). In the survivors (n = 374), baseline spot urine ACR was independently associated with 2-year spot urine ACR in the normo- (P < 0.001), micro- (P < 0.01), and macroalbuminuric groups (P = 0.01). In addition, baseline spot urine ACR was independently related to 2-year plasma creatinine (P = 0.01) in the macroalbuminuric group. The rates of change of the reciprocal of plasma creatinine (Δ [Cr]−1) were −27.3 ± 62.5, −43.4 ± 68.6, and −108.8 ± 98.81·μmol−1·months−1 in the normo-, micro-, and macroalbuminuric groups, respectively (P < 0.001). The Δ [Cr]−1 was independently and inversely related to the baseline spot urine ACR (P < 0.001) and 2-year systolic blood pressure (P < 0.001). CONCLUSIONS Abnormal albuminuria as indicated by a random spot urine ACR > 5.6 mg/mmol predicts increased mortality and is associated with the progression of albuminuria and deterioration of renal function in Chinese NIDDM patients.

Accuracy, precision and user-acceptability of self blood glucose monitoring machines

The performance of six self-monitoring blood glucose (SMBG) machines (Accutrend, Reflolux S, Companion 2, Glucometer GX, Glucometer IV and One Touch II) were examined using venous blood samples from 88 patients. Whole blood glucose (BG) values were measured by four machines from each brand. Machine-generated whole blood glucose (BG) values were corrected before comparison with laboratory plasma glucose values, measured by a glucose oxidase method. Based on error grid analysis, most of the corrected machine-generated BG values were clinically acceptable. Accutrend, Glucometer IV and Companion 2 showed the greatest consistency between machines of the same brand. Over 80% of corrected BG values generated by Glucometer IV fell within +/-10% of the reference values. One Touch II yielded the most reproducible results with a mean CV of 2.7% and was considered the most user friendly machine. More studies are required to examine the performance of these machines in the hands of patients.

Albuminuria, Insulin Resistance and Dyslipidaemia in Chinese Patients with Non-insulin-dependent Diabetes (NIDDM)

In order to examine the relationships between albuminuria, insulin resistance, and dyslipidaemia in non‐insulin‐dependent diabetes (NIDDM), we studied 164 Chinese patients (68 men, 96 women), treated with diet or oral hypoglycaemic agents, on three occasions during a 6‐week period. Antihypertensive treatment, if previously prescribed, was withdrawn for at least 2 weeks before the study period. Insulin resistance was calculated from simultaneous fasting plasma glucose and insulin concentrations using the homeostasis model assessment (HOMA) method. Based on two of three 24 h urinary collections, 87 (53 %) patients had normoalbuminuria, 46 (28 %) microalbuminuria, and 31 (19 %) macroalbuminuria. Despite similar glycaemic control, patients with abnormal albuminuria had higher mean arterial pressure, fasting plasma total cholesterol, triglyceride and serum apo B concentrations and were more insulin resistant than normoalbuminuric patients. Albuminuria correlated with mean arterial pressure (r = 0.31, p < 0.001), triglyceride (r = 0.36, p<0.001), total cholesterol (r = 0.28, p = 0.001), apolipoprotein B (apo B) (r = 0.25, p = 0.003), and insulin resistance (r = 0.25, p < 0.002). These close associations may contribute to the increased cardiovascular risk in Chinese NIDDM patients with abnormal albuminuria.

Estimated net endogenous acid production and intake of bone health-related nutrients in Hong Kong Chinese adolescents

Background/Objectives: To examine the daily intake of bone health-related nutrients and to explore the association between diet composition and estimated net endogenous acid production (estimated NEAP) in Hong Kong Chinese adolescents.Subject/Methods: In total, 171 boys and 180 girls aged 10–12 years of Chinese origin from nine primary schools from the Hong Kong Adolescent Bone Health Cohort Study. The study design used food frequency questionnaire. Mean daily intakes of foods and selected nutrients were estimated. Mean percentage of nutrient intake contributed by different food groups was presented. Frassettos method was used to calculate the estimated NEAP from the diets protein to potassium ratio.Results: There was no significant difference in the energy-adjusted intakes of most nutrients between boys and girls, except for intakes of vitamins C and D. Mean protein, sodium and potassium intakes were higher than the Chinese dietary reference intake (DRI), whereas mean intakes of magnesium, calcium and vitamin D were lower than the DRI. Boys had significantly higher estimated NEAP than girls (P=0.0051). Estimated NEAP was significantly positively correlated with meat intake and negatively associated with the consumption of fruits, vegetables, legumes, beverages and dairy products.Conclusions: The results highlight the importance of considering whole diet quality when interpreting the effects of single nutrient or diets net acid load on bone. The effect on high protein intake and low fruit and vegetable intake on the long-term bone health of Hong Kong Chinese adolescents warrants attention.

Factors Determining the Blood Pressure Response to Enalapril and Nifedipine in Hypertension Associated With NIDDM

OBJECTIVE To examine the factors that determine the blood pressure response to enalapril and nifedipine monotherapy in the treatment of hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS After a 6-week placebo baseline period, 102 hypertensive NIDDM patients were randomly assigned, double-blindly, to treatment with nifedipine retard (slow release) (n = 52) or enalapril (n = 50). The daily dosage of enalapril was increased, if required, from 10 to 20 to 40 mg and that of nifedipine from 40 to 60 to 80 mg at 4-week intervals during the 12-week titration period. Blood pressure, 24-h urinary albumin excretion (UAE), biochemical data, and serum angiotensin-converting enzyme (ACE) activity were measured at weeks −6, −4, 0, 4, 8, and 12. At week 0, venous blood was also sampled for baseline plasma atrial natriuretic peptide, renin, aldosterone, and serum insulin concentrations. RESULTS At week 12, the mean daily dose of enalapril was 35 ± 11.4 mg, and 27 (57%) patients were receiving the maximum daily dose of 40 mg. In the nifedipine group, the mean daily drug dose was 50 ± 12.9 mg, and 4 (8%) were receiving the maximum daily dose of 80 mg. Despite a dose-dependent fall in the serum ACE activity in the enalapril group, the mean arterial pressure (MAP) was reduced by only 8 mmHg throughout the 12-week titration period compared to a decline of 15, 18, and 19 mmHg at weeks 0, 4, and 12, respectively, in the nifedipine group (P = 0.01 between groups). In the enalapril group, changes in MAP between weeks 0 and 12 correlated significantly with baseline plasma glucose (r = 0.45, P = 0.001) and aldosterone concentrations (r = −0.32, P = 0.02) and UAE (r = 0.3, P = 0.04). There was no statistically significant correlation between the changes in MAP and baseline plasma renin concentration. On multivariate analysis, the baseline renal function, glycemic control, and plasma aldosterone and serum insulin concentrations were all independently related to the changes in blood pressure in the enalapril-treated patients. No such statistical associations were observed in the nifedipine group. CONCLUSIONS In hypertensive NIDDM patients, the activity of the renin-angiotensin-aldosterone system, the level of serum insulin, glycemic control, renal function, and proteinuria may be important determinants of the blood pressure response to ACE inhibition. Good glycemic control may optimize the antihypertensive efficacy of concomitant ACE inhibitor therapy.

The inter-relationships between albuminuria, plasma albumin concentration and indices of glycaemic control in non-insulin-dependent diabetes mellitus

We studied the relationship between albuminuria (measured as albumin/creatinine ratio (alb/Cr) in a random urine sample) and measures of glycaemic control (fructosamine, HbA1 and glucose) in 470 patients with non-insulin-dependent diabetes mellitus (NIDDM). Albumin excretion was in the microalbuminuric range (alb/Cr ratio > 5.4-40.3) in 112 (23.8%) and in the macroalbuminuric range (alb/Cr ratio > 40.3 mg/mmol) in 89 patients (18.9%). Fourteen percent (n = 67) of patients had a normal plasma HbA1 (< or = 8.5%) while 27% (n = 127) had a normal plasma fructosamine concentration (< or = 2.2 mmol/l). Using stepwise multiple regression analysis, plasma fructosamine concentration was found to be independently and negatively associated with urine albumin/creatinine ratio (B = 0.24, P < 0.006) in the macroalbuminuric group. Further analysis of the relationship between plasma albumin concentration and indices of glycaemic control showed that plasma albumin concentration correlated negatively with random plasma glucose concentration in the normoalbuminuric patients (r = -0.16, P = 0.008) but not in microalbuminuric or macroalbuminuric groups. HbA1 was not correlated with plasma albumin concentration. Our results indicate that albuminuria has an effect on the plasma fructosamine concentration which is independent of plasma albumin concentration.

Abstract 5643A: Pleurotus pulmonarius extract suppresses liver cancer development and progression through VEGF-mediated autocrine regulation of PI3K/AKT pathway

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths. However, the conventional chemotherapies are not only limited by late diagnosis, locally advanced and metastasis, but also by various unexpected side effects. Because of the diverse pharmacological characteristics including non-toxicity, potent biological activity and solubility, natural phytochemicals are receiving more and more attention in the implication of chemoprevention and chemotherapy recently. Our previous studies have reported the anticancer effects of several mushroom polysaccharides including the Poria cocos and Pleurotus tuber-regium. Interestingly, an active polysaccharide and protein complex isolated from mushroom Pleurotus pulmonarius, coded as PP, was screened out based on the antioxidant activity study of the mushroom species collection in our lab. However, whether PP has anti-cancer effects in liver cancer cells and the underlying molecular mechanisms remain to be elucidated. This study aims to explore the anticancer effect of PP, and to investigate the signaling pathways responsible for its suppressing effect. Our results indicated that the exposure of liver cancer cells to PP not only reduced the cancer cell proliferation and invasion but also enhanced the drug-sensitivity to conventional chemotherapeutic drugs cisplatin. More importantly, both oral administration and intraperitoneal injection of PP significantly inhibited the tumor growth of liver cancer cells in nude mice. Furthermore, treatment of PP triggered a marked suppression of the PI3K/AKT signaling pathway in liver cancer cells in vitro and in vivo, and overexpression of the constitutively active form of AKT, Myr-AKT, abrogated this effect and the inhibited proliferation and invasion by PP, suggesting the involvement of PI3K/AKT pathway in the function of PP in liver cancer cells. Interestingly, the data from western blot and ELISA (Enzyme-linked immunosorbent assay) demonstrated that treatment of liver cancer cells with PP reduced expression and secretion of vascular endothelial growth factor (VEGF), and addition of recombinant human VEGF attenuated the suppressive effects of PP on PI3K/AKT pathway and the cancer phenotypes. Taken together, our results indicated that PP, the active extract from Pleurotus pulmonarius, suppressed the proliferation, invasion, and drug-resistance of liver cancer cells in vitro and in vivo, and these effects are mediated by reduced expression and secretion of VEGF and the subsequent inhibited autocrine VEGF-induced activation of PI3K/AKT pathway. This study suggests potential therapeutic implication of PP in the treatment of liver cancer. The effects of PP on liver cancer stem cells and its chemopreventive effects in human liver cancer warrants further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5643A. doi:1538-7445.AM2012-5643A