Marcel Gilbert

Effect of a low-glycaemic index -low-fat-high protein diet on the atherogenic metabolic risk profile of abdominally obese men

It has been suggested that the current dietary recommendations (low-fat-high-carbohydrate diet) may promote the intake of sugar and highly refined starches which could have adverse effects on the metabolic risk profile. We have investigated the short-term (6-d) nutritional and metabolic effects of an ad libitum low-glycaemic index-low-fat-high-protein diet (prepared according to the Montignac method) compared with the American Heart Association (AHA) phase I diet consumed ad libitum as well as with a pair-fed session consisting of the same daily energy intake as the former but with the same macronutrient composition as the AHA phase I diet. Twelve overweight men (BMI 33.0 (sd 3.5) kg/m2) without other diseases were involved in three experimental conditions with a minimal washout period of 2 weeks separating each intervention. By protocol design, the first two conditions were administered randomly whereas the pair-fed session had to be administered last. During the ad libitum version of the AHA diet, subjects consumed 11695.0 (sd 1163.0) kJ/d and this diet induced a 28 % increase in plasma triacylglycerol levels (1.77 (sd 0.79) v. 2.27 (sd 0.92) mmol/l, P<0.05) and a 10 % reduction in plasma HDL-cholesterol concentrations (0.92 (sd 0.16) v. 0.83 (sd 0.09) mmol/l, P<0.01) which contributed to a significant increase in cholesterol:HDL-cholesterol ratio (P<0.05), this lipid index being commonly used to assess the risk of coronary heart disease. In contrast, the low-glycaemic index-low-fat-high-protein diet consumed ad libitum resulted in a spontaneous 25 % decrease (P<0.001) in total energy intake which averaged 8815.0 (sd 738.0) kJ/d. As opposed to the AHA diet, the low-glycaemic index-low-fat-high-protein diet produced a substantial decrease (-35 %) in plasma triacylglycerol levels (2.00 (sd 0.83) v. 1.31 (sd 0.38) mmol/l, P<0.0005), a significant increase (+1.6 %) in LDL peak particle diameter (251 (sd 5) v. 255 (sd 5) A, P<0.02) and marked decreases in plasma insulin levels measured either in the fasting state, over daytime and following a 75 g oral glucose load. During the pair-fed session, in which subjects were exposed to a diet with the same macronutrient composition as the AHA diet but restricted to the same energy intake as during the low-glycaemic index-low-fat-high-protein diet, there was a trend for a decrease in plasma HDL-cholesterol levels which contributed to the significant increase in cholesterol:HDL-cholesterol ratio noted with this condition. Furthermore, a marked increase in hunger (P<0.0002) and a significant decrease in satiety (P<0.007) were also noted with this energy-restricted diet. Finally, favourable changes in the metabolic risk profile noted with the ad libitum consumption of the low-glycaemic index-low-fat-high-protein diet (decreases in triacyglycerols, lack of increase in cholesterol:HDL-cholesterol ratio, increase in LDL particle size) were significantly different from the response of these variables to the AHA phase I diet. Thus, a low-glycaemic index-low-fat-high-protein content diet may have unique beneficial effects compared with the conventional AHA diet for the treatment of the atherogenic metabolic risk profile of abdominally obese patients. However, the present study was a short-term intervention and additional trials are clearly needed to document the long-term efficacy of this dietary approach with regard to compliance and effects on the metabolic risk profile.

Effect of cigarette smoking on mexiletine kinetics.

The effect of cigarette smoking on the kinetics of a single, 200 mg, oral dose of the antiarrhythmic drug mexiletine was investigated in healthy subjects. Cigarette smoking had no effect on absorption or distribution of the drug, but it significantly reduced the elimination t½ from 11.1 ± 3.4 to 7.2 ±1.8 hours; the effect on clearance was less significant. Determination of the urinary concentrations of the three major metabolites of mexiletine (mexiletine glucuronide conjugate, hydroxymethylmexiletine, and p‐hydroxymexiletine) indicated that cigarette smoking selectively induced conjugation of mexiletine with glucuronic acid as well as aliphatic hydroxylation to yield hydroxymethylmexiletine, but that it had no effect on the formation of p‐hydroxymexiletine.

Improved high-performance liquid chromatographic assay for the stereoselective determination of mexiletine in plasma

A simple and sensitive high-performance liquid chromatographic procedure for resolution of mexiletine enantiomers has been developed. Proteins from plasma samples containing RS-mexiletine were precipitated with a mixture of barium hydroxide and zinc sulphate before extraction under alkaline conditions with diethyl ether. Organic extracts were evaporated to dryness, and the residues reconstituted with 0.03 M hydrochloric acid (20 microliters). Derivatization with o-phthalaldehyde N-acetyl-L-cysteine reagent was performed after alkalinization with 0.1 M sodium borate. An aliquot of the resulting solution was injected onto a reversed-phase C18 column and resolution of mexiletine diastereoisomeric derivatives was achieved with a mobile phase consisting of methanol-50 mM sodium acetate (65:35), at a flow-rate of 1 ml/min. The retention times of S-(+)- and R-(-)-mexiletine diastereoisomeric peaks were 14 and 15 min, respectively. Product elution was monitored by fluorescence detection using excitation and emission wavelengths fixed at 350 and 445 nm, respectively. Calibration curves were linear over the concentration range 2.5-500 ng/ml for each enantiomer (r greater than 0.99). The assay is shown to be suitable for pharmacokinetic studies after administration of a single oral dose of 200 mg of RS-mexiletine hydrochloride to healthy volunteers.

Stereoselective high-performance liquid chromatographic assay for the determination of sotalol enantiomers in biological fluids

A high-performance liquid chromatographic (HPLC) assay for determination of sotalol enantiomers in biological fluids was developed to assess the stereoselective disposition of the drug in man. Following extraction at pH 9.0 with a mixture of chloroform-isopropanol (3:1, v/v), the organic phase was evaporated to dryness and the residue derivatized with (-)-methyl chloroformate. Diastereoisomeric derivatives were resolved by HPLC (C8 column) with fluorescence detection (lambda ex = 235 nm and lambda em = 300 nm). Retention times of l- and d-sotalol derivatives were 13 and 15 min while that of the internal standard, S-(-)-atenolol, was 12.3 min. The detection limit of each enantiomer was 12.5 ng/ml using 1 ml of plasma or urine. Intra-day and inter-day coefficients of variation were less than 10% for each enantiomer in the range 0.125-2.5 micrograms/ml in plasma and 0.25-2.5 micrograms/ml in urine.

Stereoselective disposition of the antiarrhythmic agent mexiletine during the concomitant administration of caffeine.

Caffeine consumption is extensive in industrialized countries and its role in drug-drug interactions is often overlooked. CYP1A2, the major cytochrome P450 isoform involved in the metabolism of caffeine, has also been implicated in the formation of N-hydroxymexiletine, the major metabolite of mexiletine. Therefore, the objective of this study was to assess the effects of a clinically relevant dosage of caffeine on the stereoselective disposition of mexiletine. Fourteen healthy volunteers--10 extensive metabolizers (EMs) and 4 poor metabolizers (PMs) of CYP2D6--received a single 200 mg oral dose of racemic mexiletine hydrochloride on two occasions (1 week apart): once by itself and once during administration of caffeine (100 mg four times daily). Serial blood and urine samples were collected and pharmacokinetic parameters were estimated. Although the total clearance of mexiletine was not significantly altered by the coadministration of caffeine in EMs and PMs, a stereoselective decrease (16% in EMs and 14% in PMs) in the urinary recovery of N-hydroxymexiletine from the R-(-)-enantiomer was observed. Also, the partial metabolic clearance of R-(-)-mexiletine to N-hydroxymexiletine glucuronide was reduced from 126 +/- 48 mL/min to 106 +/- 32 mL/min and 152.6 (73.4-196.2) mL/min to 109 (77-127) mL/min by the coadministration of caffeine in EMs and PMs, respectively. Consequently, the R/S ratio for urinary recovery and the partial metabolic clearance of mexiletine to N-hydroxymexiletine were 28% lower during the coadministration of caffeine. In conclusion, data obtained in this study indicate that coadministration of caffeine does not lead to clinically significant changes in mexiletine plasma concentrations. However, results obtained suggest that CYP1A2 is involved in the formation of N-hydroxymexiletine.

The Brugada syndrome in Canada: A unique French-Canadian experience

UNLABELLED The Brugada syndrome (BS) is a clinical entity involving cardiac sodium channelopathy, typical electrocardiogram (ECG) changes and predisposition to ventricular arrhythmia. This syndrome is mainly recognized by specialized cardiologists and electrophysiologists. Data regarding BS largely come from multicentre registries or Asian countries. The present report describes the Quebec Heart Institute experience, including the clinical characteristics and prognosis of native French-Canadian subjects with the Brugada-type ECG pattern. METHODS AND RESULTS BS has been diagnosed in 35 patients (mean age 51 +/- 12 years) at the Quebec Heart Institute since 2001. Patients were referred from primary care physicians for ECG abnormalities, syncope or ventricular arrhythmia, or were diagnosed incidentally on an ECG obtained for other purposes. The abnormal ECG was recognized after a syncopal spell in four patients and during family screening in four patients. All of the others were incidental findings following a routine ECG. No patient had a family history of sudden cardiac death at younger than 45 years of age. In this population, right bundle branch block pattern with more than 2 mm ST segment elevation in leads V1 to V3 was recorded spontaneously in 25 patients and was induced by sodium blockers in 10 patients. The sodium channel blocker test was performed in 21 patients and was positive in 18 patients (86%). An electrophysiological study was performed in 20 of 35 patients, during which ventricular fibrillation was induced in five patients; three of the five patients were previously asymptomatic. An implantable cardioverter-defibrillator was implanted in six of 35 patients (17%), including three of four patients with a history of syncope. A loop recorder was implanted in three patients. After a mean follow-up of 36 +/- 18 months, one patient died from a noncardiac cause and one patient (with a history of syncope) received an appropriate shock from his implantable cardioverter-defibrillator. No event occurred in the asymptomatic population. CONCLUSIONS BS is present in the French-Canadian population and is probably under-recognized. Long-term prognosis of individuals with BS, especially in sporadic, asymptomatic cases, needs to be clarified.

Usefulness of Transesophageal Echocardiography in the Isolation of Pulmonary Veins in the Treatment of Atrial Fibrillation

Background: New imaging strategies for atrial fibrillation (AF) ablation should enhance the safety of this technique. The role of transesophageal echocardiography (TEE) in this setting has not been prospectively evaluated.

Effects of ciprofloxacin on the stereoselective disposition of mexiletine in man.

Mexiletine is extensively metabolized in man, with less than 10% of the dose being excreted unchanged in urine. Clinical drug-drug interaction studies as well as in vitro drug metabolism studies suggest that CYP1A2, in addition to CYP2D6, is involved in the metabolism of mexiletine in man. Therefore, the objective of the study was to determine whether potential inhibition of CYP1A2 by the quinolone antibiotic agent ciprofloxacin would alter the stereoselective disposition of mexiletine. Nineteen healthy men (10 smokers and 9 nonsmokers) received a single 200-mg oral dose of racemic mexiletine hydrochloride on 2 occasions: once alone and once during concomitant administration of ciprofloxacin 750 mg BID (starting 3 days before and up to 2 days after the administration of mexiletine). Serial blood and urine samples were collected for 48 hours, and pharmacokinetic parameters were derived. Total clearances of R-(−)- and S-(+)-mexiletine were 42% and 63% higher in smokers compared with nonsmokers (P < 0.05). This observation is in agreement with increased clearance of mexiletine under conditions of increased CYP1A2 activity. On the other hand, ciprofloxacin administration only marginally decreased R-(−)- and S-(+)-mexiletine clearances (2 to 5 L/h; P < 0.05) secondary to a decrease in mexiletine nonrenal clearance. In conclusion, the increase in mexiletine nonrenal clearance in smokers and its decrease during the combined administration of ciprofloxacin confirm the role of CYP1A2 in the overall clearance of the drug. Nevertheless, results obtained in this study suggest that no major drug interaction is to be expected during the concomitant administration of ciprofloxacin and mexiletine in patients.

Inhibitory effects of propafenone on the pharmacokinetics of caffeine in humans.

CYP1A2 is involved in the metabolism of both caffeine and propafenone, a class Ic antiarrhythmic agent. Despite the widespread consumption of caffeine, drug-drug interactions with this agent are often overlooked. This study investigated effects of propafenone on the pharmacokinetics of caffeine. Eight healthy volunteers were included in our study. A total of 300 mg of caffeine was given on 2 occasions, once alone and once during the coadministration of 300 mg propafenone. Serial blood samples were collected and pharmacokinetic parameters were estimated using a population pharmacokinetic approach. A one-compartment PK model with first-order absorption and elimination described plasma concentration profiles. Concomitant administration of propafenone decreased caffeine oral clearance from 8.3 ± 0.9 L/h to 5.4 ± 0.7 L/h (P < 0.05). Elimination half-life of caffeine was also increased 54% by propafenone. One of our volunteers was a poor metabolizer of CYP2D6. Concomitant administration of propafenone to this volunteer caused the greatest increase in caffeine plasma concentrations. These results support the concept of competitive inhibition between propafenone and caffeine. Our results suggest that propafenone causes significant inhibition of CYP1A2 activity leading to a decrease in the clearance of caffeine. Caffeine has intrinsic proarrhythmic effects; thus, its coadministration with an antiarrhythmic agent such as propafenone should be used with caution, especially in patients with poor CYP2D6 activity.

Combined Administration of Quinidine and Propafenone for Atrial Fibrillation: The CAQ‐PAF Study

Propafenone and its 5‐hydroxy metabolite exhibit different electrophysiological properties. Objectives of the CAQ‐PAF study were (1) to develop a strategy favoring propafenone instead of 5‐hydroxypropafenone in plasma following oral administration of propafenone and (2) to evaluate the potential of low‐dose quinidine to chronically inhibit CYP2D6. Patients (n = 102) with atrial fibrillation received propafenone 150 mg 3 times daily with either quinidine 100 mg twice daily or placebo. Throughout the study (follow‐up, 199 ± 155 days), quinidine successfully inhibited CYP2D6: propafenone concentrations were 3 times higher in patients receiving quinidine (1033 ± 611 ng/mL vs 328 ± 229 ng/mL; P < .001). Moreover, 80% (n = 10) of patients with propafenone levels greater than 1500 ng/mL were in sinus rhythm at 1 year. In contrast, recurrence of atrial fibrillation occurred in 22 of 23 patients with propafenone levels less than 1000 ng/mL (P < .0001). Thus, chronic inhibition of CYP2D6 is achievable with low‐dose quinidine in humans. Increased plasma levels of propafenone may be highly beneficial to prevent recurrence of atrial fibrillation.