Benny S. P. Fok

Testing the Reliability of a New Ultrasonic Cardiac Output Monitor, the USCOM, by Using Aortic Flowprobes in Anesthetized Dogs

We have used an animal model to test the reliability of a new portable continuous-wave Doppler ultrasonic cardiac output monitor, the USCOM. In six anesthetized dogs, cardiac output was measured with a high-precision transit time ultrasonic flowprobe placed on the ascending aorta. The dogs’ cardiac output was increased with a dopamine infusion (0–15 &mgr;g · kg−1 · min−1). Simultaneous flowprobe and USCOM cardiac output measurements were made. Up to 64 pairs of readings were collected from each dog. Data were compared by using the Bland and Altman plot method and Lin’s concordance correlation coefficient. A total of 319 sets of paired readings were collected. The mean (±sd) cardiac output was 2.62 ± 1.04 L/min, and readings ranged from 0.79 to 5.73 L/min. The mean bias between the 2 sets of readings was −0.0l L/min, with limits of agreement (95% confidence intervals) of −0.34 to 0.31 L/min. This represents a ±13% error. In five of six dogs, there was a high degree of concordance, or agreement, between the 2 methods, with coefficients >0.9. The USCOM provided reliable measurements of cardiac output over a wide range of values. Clinical trials are needed to validate the device in humans.

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,

The effect of peripheral resistance on impedance cardiography measurements in the anesthetized dog

In the vasodilated and septic patient, the impedance method of measuring cardiac output (CO) may underestimate the true value. In this study, we sought to determine whether impedance CO (COIC) measurements are influenced by total peripheral resistance (TPR). In eight anesthetized and ventilated dogs, a high-precision flowprobe was placed on the ascending aorta, and direct CO was measured (CO flowprobe (COFP)). Mean arterial blood pressure was measured from the femoral artery. Simultaneous COIC measurements were made. TPR (mean arterial blood pressure × 80/COFP) was varied over 1–2 h by using infusions of phenylephrine and adrenaline and inhaled halothane. The bias between methods of CO measurement (COIC − COFP) was calculated and compared with TPR by using correlation and regression analysis. A total of 547 pairs of CO measurements were collected from the 8 dogs as TPR was varied. COFP changed by a mean of 190% (range, 89%–425%), and TPR changed by a mean of 266% (range, 94%–580%) during the experiment. The impedance method underestimated CO when TPR was low and overestimated CO when TPR was high. There was a logarithmic relationship between the CO bias and TPR. Correlation coefficients (r) between the CO bias and TPR ranged from 0.46 to 0.89 (P < 0.0001). The bias changed by 0.62 ± 1.8 L/min, or by 34%, every time TPR halved or doubled. This finding explains the poor agreement between COIC and other methods of CO measurement found in validation studies involving critically ill patients.

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.

Evaluation of Impedance based indices of cardiac contractility in dogs

Objective.Cardiac function can be monitored simply and safely by the impedance method. A number of parameters that reflect cardiac contractility can be derived from the impedance waveform. These include the systolic time ratio (STR), the index of contracticity (IC), the acceleration index (ACI) and the Heather index. This study evaluates their reliability. Methods.In sixteen anaesthetized dogs an ultrasonic flow probe was placed on the ascending aorta using a left thoracotomy approach and catheter placed in the femoral artery to measure blood pressure. This allowed the reference measurement of cardiac contractility from blood flow (dF/dt(max)) and pressure (dP/dt(max)). Comparative 1-minute impedance based measurements were made by a RheoCardioMonitor (ACMA, Singapore), whilst contractility was increased 2 to 6 fold, over 113 (52 to 212) minutes, using dopamine and adrenaline infusions. The association between the reference and impedance measurements was determined by correlation. The correlation coefficients (r) were compared using paired t-tests. Results are presented as mean ± SD. Results.The ACI (r= 0.76 ± 0.13) and Heather index (r= 0.74 ± 0.14) were more closely associated with the reference measurement (dF/dt(max)) than IC (r= 0.65 ± 0.23) (p < 0.05) and STR (r= 0.33 ± 24) (p < 0.01). Results for ACI and the Heather index were similar. STR was unrelated to the reference method in 10 out of 16 experiments. Correlation was better when using flow probe data (dF/dt(max)) than arterial pressure data (dP/dt(max)) (p < 0.05). Conclusions.ACI and the Heather index were the most reliable impedance derived indices of cardiac contractility.

Pre‐operative hepatitis in a woman treated with Chinese medicines

A 37‐year‐old Hong Kong Chinese female with cervical cancer was scheduled for radical hysterectomy and lymphadenectomy. Her past health was good. Pre‐operatively, she was found to have a fatty liver, prolonged prothrombin time and abnormal liver function tests. Surgery was not postponed and she was anaesthetised uneventfully, using a general anaesthetic technique. The procedure lasted 4 h. Postoperatively, she developed a large pelvic haematoma and a wound infection. Her coagulation and liver function tests gradually returned to normal. No obvious medical cause for her liver dysfunction could be found. However, it emerged that she had received a 6‐week course of traditional Chinese medicines prior to admission. The prescriptions contained over 60 different ingredients, some of which were known to be hepatotoxic, cytotoxic or to cause bleeding. This was the most likely explanation for her liver dysfunction.

Affordable measurement of human total energy expenditure and body composition using one-tenth dose doubly labelled water

Background:The doubly labelled water (DLW) method is the technique of choice for measurement of free-living total energy expenditure (TEE) in humans. A major constraint on the clinical applicability of the method has been the expense of the 18O isotope.Method:We have used a reduced-dose (one-tenth of the currently recommended standard dose) of DLW for the measurement of TEE and body composition in nine healthy adult male volunteers.Results:TEE measured by reduced-dose DLW was positively correlated with resting energy expenditure measured by metabolic cart (r=0.87, P<0.01). Isotope-derived fat mass and body mass index were strongly correlated (r=0.86, P<0.01). In four subjects in whom we performed a complementary evaluation using standard-dose isotope enrichment, the TEE measurements were satisfactorily comparable (mean±s.d.: reduced dose 2586±155 kcal/day vs standard dose 2843±321 kcal/day; mean difference 257±265 kcal/day).Conclusion:These data indicate that DLW measurements of human energy expenditure and body composition can be performed at a substantially reduced dose (and cost) of isotope enrichment than is currently employed.

Bench to Bed Evidences for Pharmacokinetic and Pharmacodynamic Interactions Involving Oseltamivir and Chinese Medicine

Oseltamivir (OA), an ethyl ester prodrug of oseltamivir carboxylate (OC), is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1), commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although C max, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA), were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P < 0.01), such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P < 0.01). In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe.

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.