The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes.

OBJECTIVE: To investigate the efficacy and safety of miglitol in combination with metformin in improving glycemic control in outpatients in whom type 2 diabetes is insufficiently controlled by diet alone. RESEARCH DESIGN AND METHODS: In this multicenter, double-blind, placebo-controlled study, 324 patients with type 2 diabetes were randomized, after an 8-week placebo run-in period, to treatment with either placebo, miglitol alone, metformin alone, or miglitol plus metformin for 36 weeks. The miglitol was titrated to 100 mg three times a day and metformin was administered at 500 mg three times a day. The primary efficacy criterion was change in HbA(1c) from baseline to the end of treatment. Secondary parameters included changes in fasting and postprandial plasma glucose and insulin levels, serum triglyceride levels, and responder rate. RESULTS: A total of 318 patients were valid for intent-to-treat analysis. A reduction in mean placebo-subtracted HbA(1c) of -1.78% was observed with miglitol plus metformin combination therapy, which was significantly different from treatment with metformin alone (-1.25; P = 0.002). Miglitol plus metformin also resulted in better metabolic control than metformin alone for fasting plasma glucose (-44.8 vs. -20.4 mg/dl; P = 0.0025), 2-h postprandial glucose area under the curve (-59.0 vs. -18.0 mg/dl; P = 0.0001), and responder rate (70.6 vs. 45.52%; P = 0.0014). All therapies were well tolerated. CONCLUSIONS: In type 2 diabetic patients, miglitol in combination with metformin gives greater glycemic improvement than metformin monotherapy.

Improved glycaemic control with miglitol in inadequately-controlled type 2 diabetics.

OBJECTIVE: The study compared the long-term efficacy and safety of miglitol to placebo in Type 2 diabetic outpatients inadequately controlled on combination therapy of diet, glibenclamide and metformin. METHODS: Type 2 diabetic patients (n = 154) receiving glibenclamide 7-20 mg/day and at least one 500-850 mg tablet metformin per day were randomized to receive additional miglitol or placebo for 24 weeks, titrated up stepwise from 25 to 100 mg trice daily. RESULTS: Addition of miglitol to sulphonylureas and metformin (per protocol analysis) produced a statistically, significantly greater reduction in HbA1c (-0.55%, P = 0.04) and postprandial glucose (-2.6 mmol/l, P = 0.0009) from baseline to endpoint than placebo (-0.2% and -0.6 mol/l, respectively). Reduction in fasting blood glucose was greater with miglitol than placebo, and there was a possible difference in favor of miglitol for fasting and postprandial triglyceride levels, but these did not reach statistical significance. Flatulence and diarrhea were reported by statistically, significantly more patients receiving miglitol than placebo, but adverse events overall were reported by only 10% more patients in the miglitol group. No cases of hypoglycaemia were reported. CONCLUSIONS: Miglitol can safely and effectively be added to long-term combination therapy in people with Type 2 diabetes inadequately controlled with glibenclamide plus metformin.

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects.

OBJECTIVE: The pharmacokinetics of a single i.v. dose of the new racemic beta-adrenoceptor-blocker nebivolol [0.073 mg base.kg-1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). METHODS: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4-5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. RESULTS: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss.kg-1) 11.2 l.kg-1; total clearance (CL) 51.6 h-1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l.h-1) were significantly higher in obese patients. But Vss.kg-1 (9.4 l.kg-1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15-18 l.h-1) and the t1/2 prolonged (32-34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. CONCLUSION: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.

[Combination of celiprolol and amiodarone in the treatment of recurrent ventricular tachycardia]. / L'association du céliprolol à l'amiodarone dans le traitement des tachycardies ventriculaires récidivantes.

The combination of beta-blockers and amiodarone has been shown to be affective in the treatment of refractory chronic ventricular tachycardia. However, the possible induction of excessive sinus bradycardia can constitute a limitation to the use of this treatment. Celiprolol is a cardioselective beta-blocker with a partial beta-2 agonist activity and an alpha-2 blocking activity, with a minimal depressant effect on heart rate. It therefore seemed useful to evaluate this drug in combination with amiodarone in patients with chronic ventricular tachycardia refractory to amiodarone alone. Twelve men with age of 57 +/- 16 years (9 with a history of myocardial infarction) received 200 mg of celiprolol per day associated with an average of 2 grams of amiodarone per week. Failure of oral amiodarone alone was confirmed by "reloading" (1,200 mg per day for 4 days) in 11 patients. The mean left ventricular ejection fraction was 36 +/- 19%, and was < or = 30% in 5 patients. Three patients were classified as stage 3-4 of the NYHA functional classification. Episodes of tachycardia were paroxysmal in 10 patients and diurnal in 10 cases. The effects of treatment were evaluated by clinical examination, continuous electrocardiographic monitoring, stress test and endocavitary electrophysiological investigation. No patient developed cardiac decompensation or collapse during beta-blocker treatment. In one case, the dose of celiprolol had to be decreased to 100 mg per day because of hypotension. No proarrhythmic effect was observed. The sinus rate remained unchanged after addition of celiprolol to amiodarone (57 +/- 3 bpm before versus 56 +/- 4 bpm after). On the stress test, the exercise capacity was maintained and no tachyarrhythmia was induced. Right ventricular refractory periods were not modified by celiprolol (mean effective period 289 +/- 20 ms before versus 294 +/- 20 ms after). Following a hospital stay of 17 +/- 7 days, the beta-blocker was discontinued in 5 patients because of persistence of permanent tachycardia in 1 case, and because of inducibility of a tachycardia with the same frequency as before treatment in the other 4 cases. No sudden death or haemodynamically unstable recurrence of ventricular tachycardia were observed during follow-up over a period of 38 +/- 24 months (range: 2-55) of the 7 patients in whom treatment was considered to be effective. Only one patient presented a temporary and reversible deterioration of heart failure. The absence of excessive bradycardia was also observed during follow-up. In one patient, celiprolol was replaced by another antiarrhythmic due to the recrudescence of inducibility to programmed stimulation. Three patients developed a spontaneous recurrence of sustained monomorphie ventricular tachycardia, which was well tolerated. In conclusion, these results suggest that celiprolol in combination with amiodarone in the treatment of refractory chronic ventricular tachycardia is a valuable therapeutic option because of its good inotropic and particularly chronotropic safety. However, the efficacy of treatment must be evaluated by a stress test and by endocavitary electrophysiological investigation including programmed ventricular stimulation in every case.

Evaluation of drug-induced QT interval modifications in dynamic electrocardiography: the case of bepridil.

Drug-induced modifications of QT interval are usually assessed through formulae defining the corrected QT interval "QTc". They are all based on the assumption that the correction is adequate, and that drug-induced heart rate variations and rate-dependent QT changes are proportional. Holter ECG allows to study the repolarization in selected RR cycles while controlling environmental rate-related and circadian influences. Repolarization duration was evaluated in 15 normal individuals and 13 patients with stable coronary artery disease and no heart failure who did not differ in terms of 24-hour heart rate, age and sex. The effects of a 3-month treatment with bepridil were assessed in the latter. Using the conventional evaluation through the corrected QT (Bazett formula), no difference was found between the two groups at baseline, and bepridil induced a non-significant 5% prolongation of QTc. At Holter recordings, the QTa (Q-T apex) duration was linearly correlated with the heart rate over 24 hours. To specifically study day-to-night variations and to exclude the rate-dependent and short-term autonomic influences. QTa was studied in populations of averaged QRS-T selected according to i) the last RR cycle length and ii) an identical mean RR interval during the preceding minute. Both RR values were fixed at 800 ms to obtain the "QTa-800" measured directly or extrapolated from linearly correlated, other RR values.(ABSTRACT TRUNCATED AT 250 WORDS)