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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. At the same times physical examinations, and clinical and urine chemistry analyses were performed. At the 99% probability level both drugs had significantly lowered the systolic and diastolic blood pressures to normal values at the end of the second and fourth weeks. There was no significant difference between their antihypertensive efficacy. The decrease in diastolic blood pressure at the end of the second week was significantly correlated with the reciprocal of the plasma celiprolol concentration at steady-state at the end of the dosage interval. [ABSTRACT FROM AUTHOR]

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.d. from day D01 to D19; investigational treatments (40 mg DHEC b.i.d. by means of formulation R and T) were administered on day D20 and D21 according to a randomised, period-balanced within-subject cross-over; treatment with DHEC was down-titrated in stepwise fashion from day D22 to D34. Morning doses of 2 x 20 mg DHEC (reference) yielded a fast and relatively short lasting peak with a geometric mean Cmax of 2157 pg/mL (CV: 0.978) after a median tmax of 1.00 h. Cmin throughout the first 12 h was on average 189 pg/mL (CV: 0.908). There was a quite distinct diurnal effect: evening doses of 2 x 20 mg DHEC (treatment R), yielded a relatively lower exposure with geometric mean Cmax, Cav- and Cmin-values of 800 pg/mL (CV: 0.870), 389 pg/mL (0.813) and 177 pg/mL (CV: 0.942). In contrast, there was relatively little within-subject distinction between the two formulations: for the day profile after the morning dose, the estimated ratios of the true means (Pr:R) for Cmax Cmin and Cav were 1.18 (90% CI: 0.96 to 1.43 - CVm: 0.394), 0.96 (90% CI: 0.86 to 1.09 - CVm: 0.230) and 1.06 (90% CI: 0.93 to 1.21 - CVm: 0.254); for the night profile after the evening dose, the estimated ratio of the true means (muT:muR) for Cmax, Cmin and Cav were 1.11 (90% CI: 0.91 to 1.35 - CVm: 0.395), 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.232) and 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.220). In view of important medical-ethical constraints not to expose an unreasonably high number of subjects, these findings could be accepted as a sufficient demonstration of bioequivalence.

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. The study was carried out in 12 patients with duodenal ulcer treated with cimetidine 1,000 mg daily over 20 days. A single oral dose of metamizol 1,500 mg was administered 2 days prior to commencement of cimetidine therapy to all patients. Two further doses of 750 and 1,500 mg of metamizol were given in a randomized order on days 8 and 13 during cimetidine treatment. Blood samples for determination of metamizol metabolites were drown over 48 hours post dose. Drug assays for metamizol metabolites and cimetidine were performed using HPLC methods. The patients were phenotyped for CYP2D6 and acetylation polymorphism. The results revealed that cimetidine interacted with 4-MAA by increasing the systemic availability, prolonging the elimination half-life and decreasing the systemic clearance of 4-MAA, whereas the renal clearances of 4-MAA remained unchanged. Consistent with cimetidine-induced changes in the oxidation of 4-MAA to 4-FAA, as well as in the demethylation of 4-MAA to 4-AA, were the decreased rates of production and the lower maximum concentrations of 4-FAA and 4-AA when metamizol was administered during cimetidine treatment (p < 0.05). No correlation was found between the decrease in the production rates of 4-FAA induced by cimetidine and the hydroxylation abilities of the patients, this suggesting that CYP2D6 is not involved in the metabolism of 4-MAA to 4-FAA. The acetylation of 4-AA to 4-AcAA was not affected by cimetidine. Cimetidine produced an increase not proportional to the dose in the systemic availability only of 4-MAA, whereas the kinetics of the other metabolites changed proportionally to the increasing dose of metamizol.

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 87.61 (57.58-133.30) micrograms.h/ml and was similar to that for the reference formulation (86.83; 53.86-139.92 micrograms.h/ml). No statistically significant differences between test and reference formulation were found with respect to the rate of absorption (Cmax, tmax, 100 Cmax/AUC) of 4-MAA. For 4-FAA, 4-AA and 4-AcAA, the 90% confidence intervals of the bioavailability parameters lay also within the bioequivalence ranges. Four of the subjects were rapid and eight were slow acetylators. No differences were found between slow and rapid acetylators in the bioavailability of 4-MAA, the pharmacologically active metabolite of metamizole.

The effects of Verapamil and Diltiazem, administered at a dose of 0.3 mg/kg i.v., on the autoregulation of the regional cerebral blood flow (rCBF) in the cortex and the thalamus were studied on 28 cats. The animals were anesthetized with ether and alfa-chloralose. The rCBF was registered by the hydrogen clearance method with locally generated hydrogen. The mean arterial blood pressure (MABP) elevation was performed by an i.v. infusion of angiotensin (0.2 microgram/min). The mean initial values of the cortical rCBF were 71.15 ml/100g/min and of the thalamic rCBF -46.85 ml/100 g/min. The mean limits of the cortical rCBF autoregulation were: 137.5 mm Hg for the absolute limit (La) and 31.25 mm Hg for the relative limit (Lr). The mean limits of the thalamic rCBF autoregulation were: 157.75 mm Hg for the (La) and 46.5 mm Hg for the (Lr). Verapamil increased the cortical rCBF by 40% and the thalamic rCBF by 24%. The absolute limits of rCBF autoregulation were decreased by 22% in the cortex, and by 15% in the thalamus. The relative limits were decreased by 31% in the cortex and by 35% in the thalamus. Diltiazem increased the cortical rCBF by 42% and the thalamic rCBF by 6%. The absolute limits of rCBF autoregulation were decreased by 21% in the cortex and the thalamus. The relative limits were decreased by 52% in the cortex, and by 38% in the thalamus.

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. MABP elevation was performed by i.v. angiotensin infusion (0.2 +/- g/min). The initial values of the rCBF in the cortex were 71.1 ml/100g/min, and in the thalamus - 49.1 ml/100g/min. The limits of rCBF autoregulation in the cortex were: the absolute limit of autoregulation (La) 139 +/- 11 mm Hg, and the relative limit of autoregulation (Lr), 28 +/- 6 mm Hg. In the thalamus these values were: La 160 +/- 11 mm Hg, and Lr 47 +/- 7 mm Hg. Nimodipine increased the rCBF in the cortex by 58 per cent, and in the thalamus, by 38 per cent as compared to the initial values (p < 0.01). The limits of rCBF autoregulation in the cortex changed to 88 +/- 8 mm Hg for the La, and to 10 +/- 4 mm Hg for the Lr (p < 0.01); and in the thalamus, to 92 +/- 8 mm Hg for the La, and to 19 +/- 5 mm Hg for the Lr (p < 0.01). Flunarizine increased the rCBF in the cortex by 28 per cent, and in the thalamus by 24 per cent, as compared to the initial values (p < 0.01). The rCBF autoregulation in both cerebral structures was not influenced by flunarizine.

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. 1, 2 and 3 h before surgery. The concentrations of ciprofloxacin and its metabolites were determined by high performance liquid chromatography (HPLC). Ciprofloxacin concentrations in lung tissue were four times and in bronchial tissue twice those in plasma (p less than 0.01). The individual tissue concentrations of ciprofloxacin correlated with the individual plasma concentrations (r = 0.95 for lung; r = 0.94 for bronchi; p less than 0.001). Metabolite concentrations in both tissues and plasma were 10- to 100-fold lower than the concentrations of ciprofloxacin. These data suggest that the concentrations of the parent compound are essential for the therapeutic efficacy of ciprofloxacin.

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.d. (20 mg group) or q.i.d. (40 mg group), or cimetidine 400 mg b.i.d. (800 mg group) or q.i.d. (1600 mg group). Treatment lasted 8 to 12 weeks. The degree of esophagitis and the severity of diurnal and nocturnal heartburn and regurgitation were significantly (p less than 0.01) reduced in the four treatment groups. Endoscopy did not show any significant differences among the four groups, although cisapride tended to be more effective in moderate to severe esophagitis, in which cases mucosal healing (i.e. absence of erosions and ulcers) was observed in 69%, 64%, 55% and 55% of the patients treated with cisapride 40 mg, cisapride 20 mg, cimetidine 1600 mg and cimetidine 800 mg. Improvement in reflux symptoms in the two cisapride groups was not significantly different from that in the cimetidine 1600 mg group, but was better (p less than 0.05) than that in the cimetidine 800 mg patients. The severity score for all reflux symptoms had decreased by 79%, 74% (cisapride 40 mg and 20 mg), 69% and 57% (cimetidine 1600 mg and 800 mg) by the end of treatment. These results show that cisapride is at least as effective as acid-suppressing therapy in patients with reflux esophagitis, and is therefore a valuable alternative to it.

In acute experiments on cats under urethan anaesthesia and on dogs under chloralose-urethan narcosis the effect of the cinnarizine analogue Aligeron on local cortical cerebral blood flow (local CBF) and internal carotid blood flow was studied. The local CBF was recorded by means of a thermoclearance method using thermistor transducers. In addition the cortical pH and the arterial blood pressure were registered. For determination of internal carotid flow the flowmetric method was used accompanied by a simultaneous registering of heart rate and arterial blood pressure. Cinnarizine and papaverine were used as reference compounds. The results obtained show that Aligeron increases both the internal carotid flow (with 64% in a dose of 5 mg/kg) and the local CBF (with 30% in a dose of 1 mg/kg and 40% at 5 mg/kg). This effect is higher and longer-lasting than those of cinnarizine and papaverine.

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 (= 0.60 +/- 0.04) and of the total intrinsic clearance (= 90.74 +/- 15.87 l/h) places nabumetone between drugs with intermediate properties; clearance being partly dependent on plasma (blood) flow rate and on the hepatic metabolism whose systemic availability was 32% of the dose. Very good coincidence was obtained when ranging patients according to morphological evaluation of liver impairments was compared to the values of nabumetone disposition parameters. There was a statistically significant positive correlation (r = 0.831, p less than 0.05) between the fraction of the dose reaching the systemic circulation, f, and the gamma-GT "normalization index" (i.e., ratio between the observed decrease of serum gamma-glutamyl transpeptidase activity and the pretreatment difference from the upper normal value). A definite interpretation of the data cannot be provided until more knowledge about the effect of 6-mO-2-naphthylacetic acid on nabumetone metabolism is available.

The effect of N-[3-(1-benzyl-cycloheptyl-oxy)-propyl]-N,N-dimethyl-amine (bencyclan-hydrogenfumarate, Fludilat¿ on the cerebral vascular system was studied by means of the following methods: 1. In pigs regional cerebral cortical blood flow was continuously recorded with a heat conduction device, cortical pH with a glass electode in which the flat measuring surface and the reference were close together. Cortical pO2 was recorded with a multiwire platinum electrode. Systemic arterial blood pressure was monitored by means of a Statham transducer. 2. In a second series in cats the perivascular space of small pial arteries or arterioles was perfused with cerebro-spinal fluid (CSF) to which bencyclan had been added. The perfusion was performed by means of micropipettes. Local cortical blood flow increased slightly for some minutes after slow infusion of 1--3 mg/kg bencyclan. Rapid injection caused initially a significant decrease in arterial blood pressure, which was accompanied by a transient decrease in CBF and in cortical pH. After the return of the arterial blood pressure to its initial value, CBF increased. Cortical pO2 and cortical pH returned to initial values. After slow infusion of the substance the pH variation was usually very slight or it was missed completely. Perivascular microperfusion wtih CSF containing bencyclan caused dilatation of those pial sections which were in contact with the drug. High concentration of the drug caused stronger dilatations than did low concentrations. It is concluded that the substance causes dilatations of the cerebral vessels and that this dilatation occurs also during constant perivascular pH.

The influence of piracetam (2-oxo-1-pyrrolidine-acetamide, Pyramem) on the cerebral circulation and brain bioelectrical activity of cortex and mesencephalic reticular formation (RF) was studied in acute experiments on cats which were encéphale isolé preparations. The methods of local cerebral rheoencephalography (REG) and electroencephalography (EEG) were used. The following REG parameters were assayed: anacrotic section of the curve and its relative part, amplitude and duration of the wave. The arterial blood pressure was followed continuously. The results show that upon piracetam administration (150 mg/kg i.v.) an improvement of the REG parameters of the cortex and RF is observed-an increase of the amplitude and decrease of the values of the anacrotic section of the curve and its relative part. The changes observed indicate a cerebro-vascular resistance decrease and give indirect evidence of cerebral blood volume increase. EEG data are characterized mainly by an increase of alpha-waves, both of cortex and RF. Suggestions for possible mechanism of action of piracetam are made.

The experiments were carried out on cats anesthetized with chloralose, curarized and artificially ventilated. The local cortical CBF was recorded by the thermoclearance technique. The cAMP level in the grey matter of the cerebral cortex and the arterial blood pressure, as well as the arterial blood gas content were measured. Increased concentration of CO2 in the inspired mixture (paCO2 = 79.8 +/- 8.5 mm Hg) caused an enhancement of CBF, without inducing changes in the cAMP level (1.71 +/- 0.07 nmoles/g wet weight). Increasing the PaCO2 up to 184.42 +/- 12.3 mm Hg produced neither a further increase of CBF, nor a rise of cAMP level. Adrenaline injected into the cerebral ventricles led to an increase of cAMP up to 4.42 +/- 0.7 nmoles/g without changing CBF. Saline in the same volume increased cAMP level to a smaller degree (2.71 +/- 0.26 nmoles/g). No changes in CBF were registered. Dibutyryl cAMP, cAMP and adenosine injected into a. lingualis did not significantly change the CBF.

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. The experiments were performed in 64 cats anaesthetized with ether and chloralose. The rCBF was measured using the thermistor thermoclearance technique. Isoprenaline, as well as terbutaline (1, 3, 5 micrograms/kg) decreased the cortical rCBF and the ABP (p less than .05). Both adrenergic agonists increased the thalamic rCBF despite the decrease in ABP (p less than .05). L,d-propranolol (1 mg/kg) abolished the effects of isoprenaline and terbutaline on thalamic rCBF. Acebutolol (0.6 mg/kg) or d-propranolol (0.5 mg/kg) did not alter isoprenaline- and terbutaline-induced effects on rCBF in thalamus. L,d-propranolol decreased the thalamic rCBF, whereas d-propranolol increased the rCBF in thalamus (p less than .05). Acebutolol did not change the thalamic rCBF significantly. The results obtained indicate that beta-adrenergic agents have heterogeneous effects on rCBF in cortex and thalamus. Their effects on thalamic rCBF seem to be accomplished by beta 2-adrenoceptor stimulation.

The effect of the cinnarizine analogue Aligeron on the resistance of cerebral and peripheral blood vessels was studied in acute experiments on cats and dogs. The resistance of the cerebral vessels was determined directly and indirectly. For direct determination the method of autoperfusion was used. The resistance was calculated indirectly as a quotient of mean arterial blood pressure and internal carotid blood flow. For evaluation of Aligeron effect on the resistance of the peripheral blood vessels and method of autoperfusion of the femoral artery was used. Aligeron was administered i. v. and i. a. In some of the experiments the compound was applied on the background of previously injected dihydroergotamine. Cinnarizine and papaverine were used as reference compounds. The results show that Aligeron decreases considerably the cerebral and peripheral resistance vessels tone, and its effect is higher than those of cinnarizine. For the realization of this effect most probably its direct myotropic action plays the main role. The reduction of its effect after alpha-adrenergic blockade suggests an involvement of some adrenergic blocking properties in its mechanism of vascular action.

The effect of piracetam (2-oxo-1-pyrrolidine-acetamide, Pyramem) on the local cortical cerebral blood flow (CBF) and oxygen balance in the brain was studied on cats anesthetized with ether-chloralose. The changes in local CBF were registered by means of the thermistor thermoclearance technique. pO2 and pCO2 were determined in blood samples from the femoral artery and superior sagittal sinus and arterio-venous differences of O2 and CO2 partial pressures (AVD-O2 and AVD-CO2) were calculated. The experiments were made on normoxic animals and on animals with slight hypoxia. Piracetam administration (100 mg/kg i.v.) leads to an increase in local cortical CBF corresponding to a change in the specific thermoconductivity of the brain of 0.6 . 10(-4) cal . cm-1 . sec-1 . degrees C-1. This effect is observed in 84% of the experiments with normoxia (arterial pO2 96.0 +/- 21.0 mm Hg) and in 40% of the experiments with slight hypoxia (arterial pO2 59.9 +/- 6.0 mm Hg). Changes in AVD-O2 and AVD-CO2 are not observed. Most probably the increase in CBF does not participate in the mechanism of the protective action of piracetam in hypoxia.

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., are followed at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, 30 and 48 h in 6 patients with laboratory evidence for functional liver insufficiency caused by liver cirrhosis, confirmed by biopsy. In the patients with liver insufficiency the mean values of Cmax and AUC0-24 h for 6-methoxy-2-naphthylacetic acid were 26.75 +/- 8.45 mg/l and 623.64 +/- 161.8 mg X h/l respectively. They did not differ significantly from the values observed in healthy volunteers [v. Schrader et al. 1983]. The Tmax-value was prolonged to 8 h, compared to 4 h Tmax-value of the volunteers. There is a tendency towards a reduced bioavailability of 6-methoxy-2-naphthylacetic acid after nabumetone administration in patients with a more severely expressed pathologic impairment, compared to patients with slight morphologic changes of the liver parenchyma.

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.v.) or acebutolol (1.2 mg/kg, i.v.). The animals were anaesthetized with ether and chloralose. rCBF was measured by thermistor thermoclearance technique. ABP elevation was produced by angiotensin i.v. infusion. rCBF autoregulation was evaluated using different criteria--limits and indices of autoregulation. The data obtained indicate that thalamic rCBF is more resistant to ABP elevation than cortical rCBF. Phentolamine did not change rCBF autoregulation in cortex and thalamus. Propranolol did not change the cortical but increased the thalamic rCBF resistance to ABP elevation. Acebutolol did not influence rCBF autoregulation in thalamus. The results suggest that different mechanisms are involved in rCBF autoregulation in cortex and thalamus. They can be selectively influenced by pharmacological agents.