Evidence-based medicine: facts and controversies.

Evidence-based medicine is a paradigm shift in the biomedical field toward scientific-based clinical practice. It is recognized as the process of acquiring and applying into practice the best available research findings in a defined filed. Although the roots of evidenced-based medicine date back more than 150 years, the modern evidenced-based medicine concept has been rapidly and constantly developing in the past two decades.

Bioequivalence of a novel high-dose oral formulation of alpha-dihydroergocryptine.

The plasma pharmacokinetics of alpha-dihydroergocryptine (DHEC, CAS 14271-05-7) were investigated in 24 patients with Parkinson disease after the administration of repeated oral doses of 40 mg DHEC twice daily by means of a novel 40 mg DHEC tablet (Almirid 40 mg test T) and an established 20 mg DHEC tablet (Almirid 20 mg - reference R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design; steady-state was established by means of a stepwise up-titration from 5 to 40 mg b.i.

Bioequivalence studies with metformin: comparability of reference tablets from different origins.

Background: The choice of an appropriate reference product is still a problem within the European Union. When no direct comparisons between originator products in different countries are available, registration authorities are sometimes only prepared to grant registration for a generic product on the basis of a comparison with the originator product in the respective country. The aim of the investigation was therefore to evaluate the bioequivalence of reference products from different origins in two different bioequivalence trials with the same test drug.

Evaluation of the efficacy of a combined formulation (Grippostad-C) in the therapy of symptoms of common cold: a randomized, double-blind, multicenter trial.

Background: The aim of the present trial was to evaluate the efficacy of a combined product in the treatment of common cold and to examine the contribution of the separate components. In the published literature there is conflicting data on the efficacy of agents used in the treatment of common cold, especially when given in drug combinations.

Methods: A prospective, randomized, double-blind, multicenter, 4-arm, controlled trial was carried out in 1,167 patients with common cold treated with one of the following medications: Grippostad-C, a combination of acetaminophen, caffeine, chlorpheniramine and ascorbic acid (verum), ascorbic acid (control), chlorpheniramine and ascorbic acid (reference 1), as well as acetaminophen, caffeine, and ascorbic acid (reference 2).

Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol.

Aim: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians.

Methods: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared.

Effect of cimetidine on the pharmacokinetics of the metabolites of metamizol.

Metamizol (dipyrone) is hydrolyzed in the gastrointestinal tract to the pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA), which is transformed by both, oxidation to 4-formyl-amino-antipyrine (4-FAA) and demethylation to 4-amino-antipyrine (4-AA). 4-AA is acetylated to 4-acetyl-amino-antipyrine (4-AcAA). The aim of the present study was to investigate whether cimetidine will alter the pharmacokinetics of the metabolites of metamizol due to cimetidine-induced inhibition of the metabolic transformation of 4-MAA.

Double-blind randomized multicenter study on the efficacy of trapidil versus isosorbide dinitrate in stable angina pectoris.

Background: Trapidil is an inhibitor of phosphodiesterase I-IV with resulting positive lusitropic, vasodilating, and antiplatelet effects.

Hypothesis: This study was undertaken to compare the antianginal efficacy of trapidil with that of isosorbide dinitrate (ISDN) in patients with stable angina pectoris.

Methods: We studied 95 patients with stable angina pectoris who were randomized into a double-blind parallel group study with either oral trapidil or ISDN.

Genetic factors and risk of agranulocytosis from metamizol.

The role of genetic factors in the pathogenesis of agranulocytosis was investigated in agranulocytosis patients by phenotyping for N-acetyltransferase and glucose-6-phosphate polymorphism; by typing for gene products of the major histocompatability complex, ABO- and RH-blood groups, and haemoglobins; and by performing cytogenetic analysis of chromosome aberrations. Nine persons were identified as agranulocytosis cases in the period from 1982 to 1987 among the population of Sofia. They were contacted again 10 years after recovery from the disease.

Comparative bioavailability of two oral metamizole formulations. Influence of the acetylation phenotype.

The bioavailability of the four metabolites of metamizole (CAS 68-89-3), 4-methyl-amino-antipyrine (4-MAA), 4-formyl-amino-antipyrine (4-FAA), 4-amino-antipyrine (4-AA) and 4-acetyl-amino-antipyrine (4-AcAA) was compared after oral administration of a test (Analgin) and a reference formulation, both containing 1 g of metamizole. The study was conducted in 12 healthy volunteers according to an open, randomized, cross-over design. The geometric mean of the area under the serum concentration-time curves (AUC) of 4-MAA for the test formulation was 87.

Effect of verapamil and diltiazem on the rCBF and the rCBF autoregulation in cortex and thalamus of cats.

The effects of Verapamil and Diltiazem, administered at a dose of 0.3 mg/kg i.v.

Effects of nimodipine and flunarizine on the regional autoregulation of the CBF in cats.

The effects of nimodipine (3 micrograms/kg/min) and flunarizine (60 micrograms/kg/min) on the autoregulation of the regional cerebral blood flow (rCBF) in the cortex and thalamus of 28 cats were studied. The animals were anaesthetized with ether and alfa-chloralose. The rCBF was registered by the hydrogen clearance method with locally generated hydrogen.

The distribution of ciprofloxacin and its metabolites in human plasma, pulmonary and bronchial tissues.

The disposition of ciprofloxacin and its pharmacologically active metabolites (sulfociprofloxacin, oxociprofloxacin, and desethylenciprofloxacin) in plasma, lung and bronchial tissues was studied in 24 patients undergoing a partial or total resection of the lung. The patients were divided into four groups, a control group and groups in which ciprofloxacin (200 mg) was given i.v.

Pharmacokinetics and biliary concentrations of fleroxacin in cholecystectomized patients.

Patients with biliary tract infections received 800 mg of fleroxacin orally once daily on five consecutive days; cholecystectomy was on day 3. Starting on the day when dose 5 was administered, serial blood and T-drain bile samples were taken for 72 h and urine was collected for 96 h. The mean (+/- the standard deviation) peak concentration in plasma was 8.

Cisapride and cimetidine in the treatment of erosive esophagitis.

The efficacy of cisapride, as compared with cimetidine, in the treatment of erosive esophagitis was studied in a double-blind trial. One hundred and twenty-nine patients were assigned to one of four dosage schedules: cisapride 10 mg b.i.

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium.

The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC.

Protective effect of rioprostil on indomethacin-induced lesions of gastric and duodenal mucosa in healthy volunteers.

The protective effect of rioprostil against gastroduodenal mucosal lesions induced by indomethacin is investigated in a double-blind controlled trial on 36 healthy adult volunteers, divided into three groups. All the volunteers are treated with indomethacin, 50 mg t.d.

Effects of beta-adrenergic agents on the regional cerebral blood flow in cortex and thalamus of the cat.

The effects of the beta-adrenergic agents isoprenaline, terbutaline, l,d-propranolol, acebutolol, as well as d-propranolol, on the regional cerebral blood flow (rCBF) in cortex and thalamus and arterial blood pressure (ABP) were investigated following i.v. administration.

Comparison of the antihypertensive effects of celiprolol and acebutolol.

The antihypertensive effects of the new cardioselective beta-blocker celiprolol and acebutolol have been compared. Thirty patients with arterial hypertension WHO Grade I-II were treated in a double-blind fashion with celiprolol or acebutolol. Before starting the treatment and on Days 15 and 29, before the morning dose, blood samples were taken for measurement of the plasma level of celiprolol.

Autoregulation of the regional cortical and thalamic cerebral blood flow in cats.

The autoregulation of regional cerebral blood flow (rCBF) in cortex and thalamus upon an increase in systemic arterial blood pressure (ABP) was investigated in 27 cats before and after pretreatment with phentolamine (1 mg/kg, i.v.), propranolol (1 mg/kg, i.

Nabumetone (BRL 14777) presystemic elimination and disposition in patients with liver impairments.

The effect of presystemic elimination of nabumetone disposition was evaluated in 6 cirrhotic patients after oral administration of a single dose of 1000 mg of the drug. The data revealed the major role of hepatic metabolism in the removal of the drug from the body. The relatively high values of hepatic plasma excretion ratio (= 0.

Liver insufficiency as a factor modifying the pharmacokinetic characteristic of the preparation nabumetone.

The effectiveness of the nonsteroidal anti-inflammatory agent nabumetone is related to the formation of an active metabolite: 6-methoxy-2-naphthylacetic acid. The plasma concentrations of nabumetone and its active metabolite, after administration of 1,000 mg single dose p.o.

Pharmacokinetics and quantitative characterization of cefotiam excretion after intravenous administration to patients after cholecystectomy.

Six patients, aged 52 to 71 years, with T-tube drainage of the common bile duct and a urinary catheter after cholecystectomy, were studied in order to evaluate the urinary and biliary excretion and pharmacokinetics of cefotiam in the early postoperative period. Each patient received cefotiam 1 g i.v.