Factors Associated with Aspirin Resistance in Hong Kong Chinese Patients with Stable Coronary Heart Disease Using the Multiplate® Analyzer and Serum Thromboxane B2.

Introduction: Aspirin resistance may be associated with various conditions. We measured serum thromboxane B2 (TXB2) and platelet function using the Multiplate® Analyzer with arachidonic acid (ASPI) in patients on long term aspirin therapy to identify aspirin resistance and associated factors. Materials and Methods: Chinese patients with stable coronary heart disease had samples for serum TXB2 and ASPI measurement taken before and 1 h after taking a morning dose of 80 mg aspirin. Results: In 266 patients with mean age 66.6 ± 10.7 years, 17% were female and 55% were current or previous smokers. TXB2 and ASPI measurements were significantly higher before the dose than at 1 h post dose, with 46% of subjects having high ASPI values (AUC > 300 AU*min) pre dose compared with 27% at 1 h post dose. TXB2 and ASPI measures of platelet aggregation showed weak correlations, which were only significant before the dose (r = 0.219, p = 0.001). Increased ASPI measurements were associated with white blood cell (WBC) count, haematocrit, platelet count and heart rate at 24 h post dose but only with WBC count, smoking history and heart rate at 1 h post dose. Diabetes was not associated with reduced platelet response to aspirin. The WBC count associated with aspirin resistance was over 6.55 × 109/L by receiver operating characteristic analysis. Conclusions: The antiplatelet response to aspirin was reduced in a large proportion of patients. Patients with higher WBC count within the normal range appear to be at increased risk of aspirin resistance. Higher or more frequent doses of aspirin may be needed in many patients.

CYP2C19*2 Polymorphism Is Associated with Impaired Oral Clearance of Gliclazide in Healthy Chinese.

BACKGROUND: Previous studies suggest gliclazide is metabolised primarily by CYP2C19 rather than CYP2C9, unlike other sulphonylureas. CYP2C19 *2 and *3 polymorphisms are more common in Asians. METHODS: We investigated the effect of CYP2C19 polymorphisms on gliclazide pharmacokinetics in 15 healthy male Chinese subjects after a single 80mg oral dose. RESULTS: In CYP2C19 poor metabolisers (*2/*2, n=4), plasma area-under-the-curve was higher by nearly two-fold compared with intermediate metabolisers (*2 and *3 heterozygotes, n=7) and extensive metabolisers (*1/*1, n=4) (p<0.001). Apparent oral clearance was mean (SD) 0.70 (0.12), 1.22 (0.22) and 1.52 (0.47) mL/min/kg in poor, intermediate and extensive metabolisers, respectively (p = 0.005). CONCLUSION: CYP2C19*2 polymorphism is associated with increased total gliclazide concentration and reduced oral clearance. Pharmacogenetic studies are warranted on the impact of CYP2C19 polymorphisms on treatment response and hypoglycaemia.

Telmisartan increases systemic exposure to rosuvastatin after single and multiple doses, and in vitro studies show telmisartan inhibits ABCG2-mediated transport of rosuvastatin.

PURPOSE: The ATP-binding cassette transporter G2 (ABCG2) plays an important role in the disposition of rosuvastatin. Telmisartan, a selective angiotension-II type 1 (AT1) receptor blocker, inhibits the transport capacity of ABCG2, which may result in drug interactions. This study investigated the pharmacokinetic interaction between rosuvastatin and telmisartan and the potential mechanism. METHODS: In this two-phase fixed-order design study, healthy subjects received single doses of 10 mg rosuvastatin at baseline and after telmisartan 40 mg daily for 14 days. Patients with hyperlipidaemia who had been taking rosuvastatin 10 mg daily for at least 4 weeks were given telmisartan 40 mg daily for 14 days together with rosuvastatin. Plasma concentrations of rosuvastatin were measured over 24 h before and after telmisartan administration. In vitro experiments using a bidirectional transport assay were performed to investigate the involvement of ABCG2 in the interaction. RESULTS: Co-administration of telmisartan significantly increased the maximum plasma concentration (C max) and the area under the plasma concentration-time curve (AUC) of rosuvastatin by 71 and 26 %, respectively. The T max values were reduced after administration of telmisartan. There was no significant difference in the interaction of rosuvastatin with telmisartan between healthy volunteers and patients receiving long-term rosuvastatin therapy or among subjects with the different ABCG2 421 C>A genotypes. The in vitro experiment demonstrated that telmisartan inhibited ABCG2-mediated efflux of rosuvastatin. CONCLUSION: This study demonstrated that telmisartan significantly increased the systemic exposure to rosuvastatin after single and multiple doses.

Effect of common polymorphisms of the farnesoid X receptor and bile acid transporters on the pharmacokinetics of ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA), a natural, dihydroxy bile acid, promotes gallstone dissolution and has been attributed with several other beneficial effects. The farnesoid X receptor (FXR) may influence the pharmacokinetics of UDCA by modulating the expression of bile acid transporters. This exploratory study examined whether common functional polymorphisms in FXR and in bile acid transporter genes affect the pharmacokinetics of exogenous UDCA. Polymorphisms in genes for transporters involved in bile acid transport, solute carrier organic anion 1B1 (SLCO1B1) 388A>G and 521T>C, solute carrier 10A1 (SLC10A1) 800 C>T and ATP-binding cassette B11 (ABCB11) 1331T>C, and the FXR -1G>T polymorphism were genotyped in 26 male Chinese subjects who ingested single oral 500-mg doses of UDCA. Plasma concentrations of UDCA and its major conjugate metabolite glycoursodeoxycholic acid (GUDCA) were determined. The mean systemic exposure of UDCA was higher in the five subjects with one copy of the FXR -1G>T variant allele than in those homozygous for the wild-type allele (n = 21) (AUC0-24 h : 38.5 ± 28.2 vs. 20.9 ± 8.0 µg h/mL, P = 0.021), but this difference appeared mainly due to one outlier with the -1GT genotype and elevated baseline and post-treatment UDCA concentrations. After excluding the outlier, body weight was the only factor associated with plasma concentrations of UDCA and there were no significant associations with the other polymorphisms examined. None of the polymorphisms affected the pharmacokinetics of GUDCA. This study showed that the common polymorphisms in bile acid transporters had no significant effect on the pharmacokinetics of exogenous UDCA but an effect of the FXR polymorphism cannot be excluded.

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.

Prospective randomized trial of hybrid NOTES colectomy versus conventional laparoscopic colectomy for left-sided colonic tumors.

BACKGROUND: We conducted a randomized study of a laparoscopic technique for removing left-sided colon tumors that can reduce postoperative pain and other wound-related complications compared to the conventional technique. It is a novel technique of hybrid natural orifice translumenal endoscopic surgery (NOTES) colectomy (HNC) whereby laparoscopic colonic mobilization, transection, and anastomosis are performed intracorporeally. The specimen is then delivered through the anus using the transanal endoscopic operation (TEO) device, precluding the need for mini-laparotomy. We compared the short-term outcomes of patients who underwent HNC with those who underwent conventional laparoscopic colectomy (CL). METHODS: Patients suffering left-sided colonic tumor were recruited and were randomized into two groups: HNC and CL. Operative data and complications were prospectively recorded and analyzed. RESULTS: During a 3-year period, we recruited 70 patients (35 per group). No significant difference was observed between the two groups with respect to operating time (105 vs. 100 min, p = 0.851), blood loss (30 vs. 30 ml, p = 0.954), or length of hospital stay (5 vs. 5 days, p = 0.990). The maximum pain score during the first week was significantly lower in the HNC group (1 vs. 2, p = 0.017). No patients in the HNC group developed wound infection, whereas four patients in the CL group did so (p = 0.005). CONCLUSIONS: With this hybrid NOTES technique, selected patients with left-sided colonic tumors can enjoy the full benefits of minimally invasive surgery with significantly less wound pain and a lower wound infection rate than are observed with CL.

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.

CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects.

PURPOSE: The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol. METHODS: The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high-performance liquid chromatographic method. Subjects were genotyped for the CYP2C19 2 and 3, UGT1A1 6, 28 and 60, UGT2B7 2 and ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms. RESULTS: Subjects with the CYP2C19 2/ 2 genotype had a higher peak concentration (255.5 ± 80.1 vs. 156.0 ± 66.3 ng/mL; P < 0.05) and area under the concentration-time curve (AUC0-∞; 1,473.7 ± 493.6 vs. 502.8 ± 176.1 ng[Symbol: see text]h/mL; P < 0.001) than subjects with 60 or 28, and UGT2B7 2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0-∞ and lower total clearance than the wild-types (P < 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0-∞. CONCLUSION: Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects.

Laparoscopic reversal of Hartmann's procedure: safety and feasibility.

AIMS: The present study aimed to compare the surgical outcomes of patients receiving laparoscopic reversal of Hartmann's procedure (RHP) with those receiving open surgery. METHODS: Records of all patients with RHP performed in our unit (including laparoscopic and open surgery) between 2000 and 2012 were retrieved. Data were retrospectively reviewed and compared. RESULTS: Eighty-two RHPs were performed between 2000 and 2012. Thirty-five were performed with an open approach and 47 with a laparoscopic approach. Conversion rate was 28% in the laparoscopic group. There was no difference, between the two groups, in operation time or blood loss. The median length of stay was significantly shorter in the laparoscopic group (12 vs 14 days, P = 0.002) and fewer patients in the laparoscopic group had complications with post-operative paralytic ileus (2 vs 17%, P = 0.038). None of the patients in the laparoscopic group developed incisional hernia at the conclusion of follow-up, as opposed to five in the open group (0 vs 14%, P = 0.012). CONCLUSION: Laparoscopic RHP is safe and feasible, with more favorable surgical outcomes, when compared with open surgery. Conversion rate is acceptable. It should be the technique of choice for patients undergoing RHP.

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

BACKGROUND: Although flecainide is thought to be meta-bolized 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.

Impact of CYP2D6 polymorphisms on the pharmacokinetics of lovastatin in Chinese subjects.

PURPOSE: Although CYP3A4/5 enzymes play the predominant role in the metabolism of simvastatin and lovastatin, polymorphisms in CYP2D6 were reported to be associated with the cholesterol-lowering effect and/or tolerability of simvastatin. This study was performed to examine whether common CYP2D6 polymorphisms affect the pharmacokinetics of lovastatin, which is taken as the inactive prodrug lovastatin lactone and converted to active lovastatin acid. METHODS: A single-dose pharmacokinetic study was performed with lovastatin in 23 Chinese healthy male subjects. Plasma concentrations of lovastatin lactone and acid were determined by an LC-MS-MS method in samples collected over 24 h after single oral doses of 40-mg lovastatin. RESULTS: Compared with the CYP2D6 wt/wt group, the area under the plasma concentration-time curve (AUC(0-∞)) values for lovastatin lactone increased (P < 0.01) by average ratios (95% CI) of 1.57 (1.01-2.45), 2.11 (1.36-3.29), 2.52 (1.47-4.32), and 5.84 (3.16-10.78) in the wt/*10, *10/*10, *10/*5, and *5/*5 groups, and the values of lovastatin lactone plasma clearance (CL/F) were reduced on average (95% CI) by 40.4% (10.2-60.5%), 53.1% (29.3-68.9%), 63.8% (40.2-78.1%) and 84.2% (72.1-91.1%) in these genotype groups respectively. The pharmacokinetics of lovastatin acid did not differ among the genotype groups. CONCLUSION: This study demonstrates that CYP2D6 polymorphisms appeared to influence the disposition of lovastatin lactone in these subjects.

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.

The effects of increasing doses of noradrenaline on systemic and renal circulations in acute bacteraemic dogs.

OBJECTIVE: To determine the dose-response effects of noradrenaline on the systemic and renal circulations during septic shock. DESIGN AND SETTING: Prospective controlled experiment in a university animal laboratory. SUBJECTS: Eight anaesthetized dogs. INTERVENTIONS: Transonic flow probes were surgically placed on the aorta via a left lateral thoracotomy and on the left renal artery. Blood pressure was measured from the femoral artery. Acute bacteraemia shock was induced by injecting Escherichia coli bacteria intravenously. Increasing doses of noradrenaline (0.1, 0.2, 0.3, 0.4, 0.5 microg kg(-1) min(-1)) were infused intravenously for 30 min at 30-min intervals. The model was first validated in four dogs. MEASUREMENTS AND RESULTS: Mean arterial pressure, central venous pressure, cardiac output, and renal blood flow were measured. Systemic vascular resistance was derived. Induction of bacteraemia decreased mean arterial pressure, central venous pressure and systemic vascular resistance. Cardiac output slightly increased. Noradrenaline produced linear dose-dependent increases in both mean arterial pressure and systemic vascular resistance. The response was attenuated during bacteraemia. Under non-bacteraemic conditions the maximum dose of noradrenaline reduced the renal blood flow from 12+/-1 to 10+/-1 ml kg(-1) min(-1). Bacteraemia further reduced renal blood flow to 7+/-1 ml kg(-1) min(-1), which was partly restored by the maximum dose of noradrenaline to 11+/-3 ml kg(-1) min(-1). CONCLUSIONS: Noradrenaline can restore mean arterial pressure in bacteraemic shock and increases in mean arterial pressure are dose-dependent. The noradrenaline response is attenuated by bacteraemic shock. In bacteraemic shock noradrenaline also improves renal perfusion, as perfusion pressure increases. However, renal blood flow is not fully restored, suggesting that an element of impairment of renal blood flow exists due to the bacteraemia or noradrenaline.

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 x 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.

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 microg x kg(-1) x 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.

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.

The effects of candesartan and ramipril on adrenal catecholamine release in anaesthetized dogs.

We have investigated the effects of the angiotensin II type 1 receptor antagonist candesartan, and the angiotensin II converting enzyme inhibitor ramipril, on catecholamine release from the anaesthetized dog's adrenal gland. These drugs were given systemically in low and high doses. The gland was stimulated electrically (0.5-12 Hz) and by angiotensin II infusion (40 ng/kg/min). Electrical stimulation resulted in frequency-dependent increases in catecholamine release. Candesartan (0.8, 4.0 mg/kg) and ramipril (0.125, 0.625 mg/kg) increased basal catecholamine release along with decreases in blood pressure. Both drugs diminished direct nerve stimulation-induced catecholamine release. When both drugs were combined, their inhibitory effect was slightly enhanced. Candesartan blocked catecholamine release induced by angiotensin II. Ramipril was not tested in this respect. The percentage of noradrenaline released during electrical stimulation of the gland remained constant and ranged from 14% to 22%. Both drugs appear to act by blocking local modulation of catecholamine release by the chromaffin cells.