Sirolimus-eluting stents, bare metal stents or coronary artery bypass grafting for patients with multivessel disease including involvement of the proximal left anterior descending artery: analysis of the Arterial Revascularization Therapies study part 2 (ARTS-II).

OBJECTIVE: The The Arterial Revascularization Therapies Study (ARTS)-II trial found no differences in survival or overall adverse events between sirolimus-eluting stents (SES) and the surgical arm of ARTS-I. Nevertheless, existing data suggest that patients with disease of the proximal left anterior descending artery (LAD) may derive particular benefit from coronary artery bypass grafting (CABG). We therefore analysed the clinical outcome of patients in ARTS-I and ARTS-II with proximal LAD involvement. DESIGN: Multicentre observational study. SETTING: Forty-five European academic hospitals. PATIENTS: Patients with multivessel coronary artery disease. INTERVENTIONS: Patients in ARTS-II with proximal LAD disease treated with SES (289/607, 48%) were compared with 187/600 (31%) bare metal stent patients (ARTS-I BMS) and 206/605 (34%) surgical patients (ARTS-I CABG) with proximal LAD involvement from ARTS-I. MAIN OUTCOME MEASURES: Major adverse cardiac and cerebrovascular events after 3 years. RESULTS: The Arterial Revascularization Therapies study part 2 (ARTS-II) subgroup had better survival than both ARTS-I groups (ARTS-II 98.6% vs ARTS-I BMS 95.7%, p = 0.05 and vs ARTS-I CABG 94.7%, p = 0.01) and lower rates of the hard clinical composite endpoint of death or non-fatal myocardial infarction (ARTS-II 3.1% vs ARTS-I BMS 9.6%, p = 0.002 and vs ARTS-I CABG 9.7%, p = 0.002). Although the ARTS-I CABG patients had a lower need for repeat revascularisation than ARTS-II (5.3% vs 13.1%, p = 0.002), the overall composite adverse event rates (death, myocardial infarction, stroke or any repeat revascularisation) were not significantly different between the ARTS-I CABG and ARTS-II patients (15.0% vs 18.0%, p = 0.4). CONCLUSIONS: SES are not inferior to CABG or bare metal stents for the treatment of patients with multivessel coronary disease including involvement of the proximal LAD.

Beneficial effects of fluvastatin following percutaneous coronary intervention in patients with unstable and stable angina: results from the Lescol intervention prevention study (LIPS).

AIMS: To investigate the effect on risk of major adverse cardiac events (MACE) of lipid lowering treatment with fluvastatin 80 mg/day after a first percutaneous coronary intervention in patients with stable and unstable angina. METHOD AND RESULTS: This prespecified subgroup analysis of the LIPS (Lescol intervention prevention study) analysed 1658 patients with documented diagnosis; 824 had unstable angina (417 randomly assigned to fluvastatin, 407 to placebo) and 834 had stable angina (including silent ischaemia; fluvastatin, 418; placebo, 416). Median follow up was 3.9 years. There was no significant effect of anginal status on long term risk of MACE. Fluvastatin treatment reduced the risk of MACE by 28% compared with placebo (p = 0.03) among patients with unstable angina, with no difference between patients with stable and patients with unstable angina (relative risk 1.07, 95% confidence interval 0.87 to 1.30, p = 0.53). Fluvastatin reduced coronary atherosclerotic events (MACE excluding restenosis) by 36% (p = 0.006) among patients with unstable angina and 31% (p = 0.02) among patients with stable angina. Fluvastatin caused similar reductions in total cholesterol and low density lipoprotein cholesterol concentrations in both patient groups. CONCLUSION: Treatment with fluvastatin 80 mg/day produced significant reductions in MACE and coronary atherosclerotic events after percutaneous coronary intervention in patients with average cholesterol concentrations. The beneficial effects of fluvastatin are observed in patients with unstable or stable angina alike.

Clinical efficacy and safety of beclomethasone dipropionate inhalation capsules inhaled by Cyclohaler compared with Becotide Rotacaps inhaled by Rotahaler.

The study was undertaken to compare the efficacy and safety of beclomethasone dipropionate inhalation powder inhaled by Rotahaler (Becotide Rotacaps, Glaxo Wellcome) and by Cyclohaler (Beclomethasone Cyclocaps, Pharmachemie). Both the Cyclohaler and the Rotahaler are single-dose dry powder inhalation devices for inhalation capsules. 182 asthma patients stabilized on inhaled beclomethasone dipropionate 800 micrograms daily, were randomly assigned to treatment with 800 micrograms beclomethasone dipropionate inhaled by Rotahaler (91 patients) or Cyclohaler (91 patients) in a double-blind manner, using the double-dummy method. It was shown that the asthma remained stable during the 16-week study period with both preparations. There were no statistically significant differences in the pulmonary parameters (morning PEF, evening PEF, FEV1). The test/reference ratio of the morning PEF (99.5%, CI 93.0% - 106.5%) was well within the equivalence interval, which had been set a priori from 85% to 117.6%. There were no marked differences between the Cyclocaps and Rotacaps group in symptom scores and adverse events. A total of 12 patients had an asthma exacerbation: 8 exacerbations occurred in the Rotahaler group and 4 in the Cyclohaler group. The difference was not statistically significant. The use of rescue medication was somewhat higher in the Rotahaler group, but the difference did not reach statistical significance. Significantly more patients (17 patients) withdrew from the study in the Rotahaler group than in the Cyclohaler group (5 patients). In conclusion, there was no difference in asthma control of patients treated with Beclomethasone Cyclocaps inhaled by Cyclohaler and Becotide Rotacaps inhaled by Rotahaler. Both preparations are therapeutically equivalent.

Formoterol as dry powder inhalation. A dose finding study in comparison with formoterol metered dose inhaler and placebo.

We compared the bronchodilator effects and systemic tolerability of 12, 24 and 48 micrograms formoterol DP capsules with 12 micrograms formoterol MDI and placebo in 30 patients with reversible obstructive airway disease. Pulmonary function tests were done and pulse rate and blood pressure were recorded. We observed significant differences between all active substances vs placebo regarding peak effect, duration of effect and AUC value. No significant difference was observed between either 12 or 24 micrograms formoterol DP and 12 micrograms from MDI in all mentioned parameters. With 48 micrograms DP, increased peak effect, AUC and duration of effect were noted. Heart rate Holter monitoring showed a slightly more pronounced effect with 48 micrograms. We conclude that 12 to 24 micrograms formoterol DP capsules are equivalent to 12 micrograms of formoterol MDI regarding efficacy and tolerability, while 48 micrograms formoterol DP capsules cause more profound effects in bronchodilation and on the heart rate.

Relationship between dose and serum concentrations of carbamazepine, phenytoin, phenobarbital, and primidone in a Sri Lankan population compared with a European population.

Concentrations of carbamazepine, phenytoin, phenobarbital, and primidone have been measured by high pressure liquid chromatography (HPLC) in serums of 177 Sri Lankan epileptic patients. Relationships between concentrations and dose per kg body weight of these drugs have been compared with those of patients in the Netherlands, using a matching procedure. Although variabilities in dose-concentration ratios were somewhat larger in Sri Lanka than in the Netherlands, no evidence was found of a systematic difference in pharmacokinetics between both populations.

Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine?

A double-blind randomized crossover design trial of carbamazepine (CBZ) and oxcarbazepine (OCBZ) was performed with 48 in-patients with epilepsy. All were stabilized on polytherapy including CBZ and had at least two seizures per week. CBZ was replaced by the trial medication. Each trial period started with a titration, followed by a 12-week steady state. Concomitant medications were kept constant during the trial. The criteria for assessment were seizure fit frequency and severity; tolerability; hematology and blood chemistry; plasma levels of antiepileptic drugs; EEG; cardiovascular parameters; and treatment preference. The following differences regarding OCBZ were detected: 9% reduction of the total number of seizures, with a significant reduction of tonic-clonic (20%) and tonic (31%) seizures; increased alertness and concentration ability in five patients; an allergic skin reaction with CBZ that completely disappeared in two patients while receiving OCBZ; an increase of valproate and phenytoin plasma levels in a number of patients, probably caused by reduced enzyme induction; a slight but significant reduction of serum Na, not causing clinical symptoms; less seizures than in the CBZ period in 25 patients (52%); and a preference for OCBZ in 23 patients (48%). We consider OCBZ at least as effective as CBZ with a slightly better tolerability. In severe cases, the wider therapeutic window might improve seizure control.

Carbamazepine and serum sodium levels.

Serum sodium levels of 674 epileptic patients were tabulated according to the following categories: less than 135 mmol/L, hyponatremia (28 patients); 135-145 mmol/L, normonatremia (530 patients); greater than 145 mmol/L, hypernatremia (116 patients). One hundred one patients were treated with antiepileptics without carbamazepine (CBZ), 113 with CBZ monotherapy, and 460 with CBZ plus other antiepileptic drugs. Twenty-three patients could be followed up after the first detection of a serum sodium level of less than 135 mg/L. Ten patients were consistently hyponatremic (greater than 50% of the follow-up measurements were less than 135 mg/L), whereas the remaining 13 were occasionally hyponatremic. The following facts could be derived from the study: (1) The hyponatremic group was significantly older compared with the other groups. (2) In patients not treated with CBZ, no hyponatremia was seen. Only two patients on CBZ monotherapy showed hyponatremia. (3) The combination of CBZ, valproic acid, especially in high dosages, and barbiturates seemed to lead to hyponatremia. (4) The excretion of antidiuretic hormone, measured in 12 patients, was subnormal (less than 25 ng/24 h) in seven hyponatremic patients and in three normonatremic patients and normal (25-250 ng/24 h) in two other normonatremic patients. (5) Cyclic AMP, measured in five hyponatremic patients, was normal. (6) In all patients the hyponatremia was slight and did not cause any clinical symptoms. Special treatment was not required.

Sodium valproate: serial monitoring of EEG and serum levels.

The clinical and electroencephalographic (EEG) effects of sodium valproate were studied in four patients by means of serial 24-hour EEG recordings and simultaneous hourly determinations of serum drug concentrations. The patients all had frequent clinical seizures and generalized spike-wave discharges. Valproate appeared to reduce diurnal paroxysmal discharges (PD) and clinical seizures, but the effect on nocturnal PD was less marked. The extent and duration of the depression of PD and seizures varied. Altering the distribution of the total daily dose may change the pattern of clinical seizures and PD. Valproate concentrations fluctuated widely over 24 hours, and the significance of single estimations often cited in the literature appears dubious. Peak serum concentrations above 100 micrograms per milliliter may be necessary in some patients to achieve clinical and EEG improvement.

The extraction of antiepileptic drugs. Model study on partition coefficients.

To compare the extraction behaviour of hexane, toluene, chloroform, 1,2-dichloroethane, diethylether, ethyl acetate and acetone towards phenobarbital, phenytoin, primidone and carbamazepine, partition coefficients of these drugs between the above solvents and water (saturated with ammonium sulphate when working with acetone) were measured at different pH-conditions. Acetone rendered the highest partition coefficients for all drugs. Ethyl acetate was second in the range, except for carbamazepine, which showed a specific affinity for the chlorinated hydrocarbons.