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The aim of this study was to assess the influence of renal function on the pharmacokinetics, pharmacodynamics, safety, and tolerability of the acetylcholinesterase inhibitor metrifonate. Four groups of six age- and gender-matched subjects with varying degrees of renal function (creatinine clearances more than 90, 60-90, 30-60, and less than 30 mL/min/ 1.73 m2, respectively) were administered a single 50-mg oral dose of metrifonate. Blood and urine samples were collected for 24 hours and concentrations of metrifonate and its metabolites dichlorvos, dichloroacetic acid, and M3 were determined. Inhibition of acetylcholinesterase activity in erythrocytes and butyrylcholinesterase in plasma were also measured. Metrifonate was well tolerated in all treatment groups. The urinary excretion of metrifonate and dichlorvos decreased with decreasing renal function but accounted for less than 2% of the elimination. There were no statistically significant differences in primary pharmacokinetic parameters--Cmax, t(max), area under the concentration-time curve (AUC), and t1/2--of metrifonate and dichlorvos among the different groups. The excretion of dichloroacetic acid and M3 was not influenced by renal impairment. Acetylcholinesterase was not inhibited, whereas butyrylcholinesterase was inhibited markedly but independently of renal function. No metrifonate dose adjustments are needed when treating subjects with renal impairment.

Background: Unfractionated heparin is used widely; however, control of the level of anticoagulation remains its greatest problem, with fewer than 35% of patients having activated partial thromboplastin times (aPTTs) within a range of 55 to 85 seconds in recent trials., Methods and Results: We developed and tested a prototype of an automated heparin control system (AutoHep) in which a computer-based titration algorithm adjusted the heparin infusion to reach a target aPTT. In 1 study, 12 healthy male subjects received an intravenous infusion of heparin with the rate determined by AutoHep and were randomized to receive an initial bolus or no bolus of heparin preceding the infusion. A second study evaluated the automated blood sampling system in 12 subjects. Of the 344 end-point aPTT measurements, 78% were within +/-10 seconds of the target (prespecified primary end point), and 89% were within a +/-15-second range. The time to achieve a target aPTT was 93 minutes without and 150 minutes with an initial heparin bolus. The total percentage of time within the target range +/-15 seconds was 46 of 48 hours (96%). The automatic blood sampling system successfully obtained 96% of all scheduled samples., Conclusions: These results suggest that the AutoHep system has the potential to significantly improve aPTT control of intravenous heparin compared with current clinical practice.

The objectives of the two studies reported here were the investigation of the influence of tablet breaking and food on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new levodopa/benserazide formulation with a biphasic drug delivery profile (Madopar DR). Both studies had an open-label, randomised, two-way crossover design and were conducted in 12 healthy young subjects. The pharmacokinetics of levodopa and 3-OMD after one intact or two halved tablets were very similar with average Cmax and tmax 1.9 mg x l(-1) and 1.2 h, respectively. Administration of the formulation after a standard breakfast did not influence the extent of levodopa absorption but increased the absorption rate. Cmax and tmax were on average 2.1 mg x l(-1) and 1.3 h, respectively, in the fed condition and 1.5 mg x l(-1) and 2.5 h in the fasted condition. The presence of food did not markedly affect the plateau in levodopa levels between about 1 and 3 h after intake. In conclusion, the release characteristics in healthy subjects of the new levodopa/benserazide formulation are influenced only to a minor extent by concomitant intake of food or by tablet breaking.

Aims: The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple-dose regimens., Methods: Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3-O-methyldopa (3-OMD) and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa., Results: Endogenous concentrations of levodopa and 3-OMD increased dose-dependently (from 8 up to 52 microg l(-1) and from 0.02 up to 0.50 mg l(-1) , respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration-time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l(-1) h at benserazide doses of 100-200 mg three times daily. Benserazide caused a dose-dependent increase in the AUC of 3-OMD from 7.4 to 106 mg l(-1) h at doses of 200 mg. Formation of DOPAC was dose-dependently suppressed, with benserazide 5 mg three times daily already halving its AUC., Conclusions: The benserazide-dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.

The bioequivalence and relative bioavailability of a new sustained release formulation of diltiazem (120 mg, Diltiazem-Mepha 120 retard, CAS 33286-22-5) in comparison with a 120 mg reference formulation was investigated in a randomised 2-way cross-over study in 18 healthy volunteers following multiple, twice daily dosing for 5 days. Blood samples were taken prior to the morning dose on days 1 to 4 and before and periodically during 32 h after the last administration in the morning of day 5. The diltiazem concentration was determined using a HPLC method. The following primary and secondary pharmacokinetic parameters were derived from the individual plasma concentration time courses on day 5:Cmax and AUC tau (primary parameters) and PTF,PTS, t1/2, tmax and F(rel) (secondary parameters). For the new test formulation mean (SD) Cmax was 168.9 (49.1) ng/ml and AUC tau was 1343 (313) ng . h/ml, whereas these values were 194.7 (44.2) ng/ml and 1460 (444) ng . h/ml for Cmax and AUC tau of the reference formulation, respectively. Smaller inter-subject variations of the diltiazem plasma concentrations following administration of the test formulation were found, which could be due to an improved retardation principle. However, the point-estimate and 90% confidence interval around the point-estimate fall inside the bioequivalence acceptance range of 0.70-1.43 for Cmax and 0.80-1.25 for AUC tau. Therefore, from the results of this study it can be concluded that the test formulation is bioequivalent with the reference formulation following multiple dose, twice daily administration.

Objectives: Mazapertine is a structurally novel antipsychotic compound with high affinity for D2, D3, 5-HT1a, and alpha 1 receptors. The objectives were to determine whether tolerance to orthostatic hypotension caused by this compound could be induced by slowly increasing the dose administered and to investigate its effect on cognitive and motor functions., Methods: Thirteen healthy male subjects received incremental oral doses of mazapertine (from 5 to 50 mg over 7 days; n = 10) or placebo (n = 3) in part I and single doses in parts II (20 or 30 mg or placebo) and III (40 mg or placebo) in a double-blind fashion. Blood pressure, heart rate, cardiac hemodynamics, cognitive functions, and occurrence of acute extrapyramidal symptoms were investigated., Results: Mazapertine appears to be safe and well tolerated when administered orally for 7 days to normal healthy men. No accumulation of serum prolactin occurred after multiple dosing, suggesting limited potential for inducing galactorrhea. The drug was rapidly absorbed, and kinetics appeared to be dose dependent, without accumulation. The elimination half-life was about 5 to 10 hours. No evidence of any positive or negative cognitive effects could be detected. Mild motor symptoms were observed only at high doses (not statistically significant). Mazapertine had a minimal effect on cardiac output and stroke volume. Tolerance to hypotension could be induced by slowly increasing the dose administered., Conclusions: Mazapertine is well tolerated when administered orally for seven days, and tolerance to hypotension can be induced by slowly increasing the dose administered. Therefore, nothing precludes further clinical testing on patients with schizophrenia.

The absorption, pharmacokinetics and bioavailability of ibuprofen (CAS 15687-27-1) were investigated for an ibuprofen gel preparation (ibugel) for percutaneous application, and compared to a standard oral ibuprofen tablet preparation. The monocentric, randomised, 2-way cross-over study with 7-day wash-out period was performed on 18 healthy female volunteers with an average age of 26.3 +/- 4.8 years (range: 20-38 years), average weight 60.4 +/- 7.6 kg, and average height 164.7 +/- 5.9 cm. Blood samples were taken from the volunteers before administration of the tablet or gel, and periodically during 24 h after administration. The ibuprofen content in these samples was determined using a validated HPLC method. Main pharmacokinetic parameters derived from individual plasma concentration-time courses included: Cmax, tmax, AUCO-->24, AUCO-->infinity, MRTO-->infinity, t1/2 and Frel. For percutaneous application of 500 mg ibuprofen (10 g 5% gel on the back, area of 20 x 20 cm) with occlusion for 2 h, a Cmax of 7.1 +/- 4.4 micrograms/ml (95% confidence interval (CI): 5.0-9.1) was obtained at 2.4 +/- 0.8 h (95% CI: 2.0-2.8). For oral administration of 400 mg, Cmax was 36.7 +/- 7.5 micrograms/ml (95% CI: 33.2-40.1) at 1.1 +/- 0.8 h (95% CI: 0.7-1.5). The (dose-corrected) relative bioavailability of the topical ibuprofen was found to be 22 +/- 12% (95% CI: 14-30%) of that after oral administration. The plasma elimination half-life was 2.5 +/- 1.4 h (95% CI: 1.9-3.2) for topical administration, and 1.8 +/- 0.5 h (95% CI: 1.6-2.1) after oral administration (not significant, p > 0.05). The surprisingly high levels of ibuprofen found in the plasma after percutaneous application are still below the threshold where systemic side effects might be expected (10 micrograms/ml). The high peak plasma concentration and relative bioavailability of percutaneous ibuprofen are likely due to the galenical formation of the gel preparation, which contains isopropyl alcohol and propylene glycol as co-solvents and is adjusted to pH 5, and to the use of occlusion.

An investigation on the bioavailability of a new tablet with 160 mg sotalol hydrochloride (CAS 959-24-0, Rentibloc 160), was performed in a two-way cross-over study with 16 volunteers. The relative bioavailability with respect to a reference preparation for AUC0-infinity was 98.1% and for Cmax 100.8%. A positive decision for bioequivalence derived from the usual confidence intervals for both parameters. The difference in tmax showed no clinical relevance. The new formulation is bioequivalent to the reference.

Hemolysis-inducing properties of the new calcium antagonist Ro 40-5967 administered intravenously to 39 healthy male subjects were investigated in a placebo-controlled study. The volunteers were randomized into five parallel groups of 9 subjects each: three groups, receiving infusions of 40 mg Ro 40-5967 in 60, 30, and 15 min, respectively; one group receiving 80 mg Ro 40-5967 in 30 min as two simultaneous doses of 40 mg in the cubital veins of both arms; and one group receiving 80 mg Ro 40-5967 in 30 min in one arm. Within each group, 3 subjects received placebo under randomized double-blind conditions. Plasma haptoglobin decreased by 67% after 3.5 h in 2 subjects who received 80 mg Ro 40-5967 in one arm (treatment schedule thereupon discontinued). Serum bilirubin levels also increased in a dose-dependent manner in all groups as compared with placebo. Other parameters of hemolysis remained unchanged; no hemoglobinuria was observed. The intravascular hemolysis observed on infusion limits the therapeutic application of Ro 40-5967 to oral use only.

Bioequivalence of a New Sotalol Hydrochloride Tablet Formulation Compared with a Standard Preparation An investigation on the bioavailability of a new tablet with 80 mg sotalol hydrochloride (Rentibloc mite, CAS 959-24-0) was performed in a two-way cross-over study with 16 persons. The relative bioavailability with respect to a reference preparation for AUC0-infinity was 101.9% and for Cmax 104.5%. A positive decision for bioequivalence derived from the usual confidence intervals for both parameters. The difference in tmax showed no clinical relevance. The new formulation is bioequivalent to the reference.

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.

The efficacy of multiple oral administration of the renin inhibitor Ro 42-5892 [(S)-alpha-](t-butylsulfonyl)-methyl]hydrocinnamamido]-N-[1S , 2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imi dazole-4- propionamide] was studied. Forty-nine patients with moderate essential hypertension were randomly assigned to three groups that entered an 8-day double-blind oral treatment period: daily administration of placebo (group A), 300 mg Ro 42-5892 (group B), or 600 mg Ro 42-5892 (group C). Four hours after the last oral drug intake, placebo was administered intravenously to subjects in group A and 100 mg Ro 42-5892 was administered intravenously to subjects in groups B and C. Sitting systolic and diastolic blood pressures were measured on days 1 and 8 with a blood pressure device. On day 1, systolic blood pressure maximally decreased by 13.3 +/- 9.3, 20.2 +/- 11.2, and 24.1 +/- 11.3 mm Hg in groups A, B, and C, respectively (mean +/- SD; p < 0.01 for group A versus group C). Diastolic blood pressure maximally decreased 9.4 +/- 5.7, 13.9 +/- 8.7, and 11.8 +/- 5.7 mm Hg (difference not significant). On day 8, systolic blood pressure maximally decreased 19.5 +/- 16.5, 26.5 +/- 17.4, and 30.5 +/- 18.4 mm Hg and diastolic blood pressure maximally decreased 14.8 +/- 5.0, 16.2 +/- 9.0, and 17.9 +/- 12.7 mm Hg (difference not significant) compared with pretreatment values. Intravenous drug administration did not further reduce blood pressure, suggesting that the mode of action and not the low bioavailability was the limiting factor for the low efficacy.

Introduction: Remikiren (Ro 42-5892) is a potent and specific inhibitor of human renin in vitro. Its in vivo action on plasma renin activity (PRA), immunoreactive renin, and blood pressure has been shown in pilot studies in humans., Objective: To investigate tolerability, hemodynamic effects, and biochemical effects of remikiren in relation to its pharmacokinetics after single ascending intravenous and oral doses in healthy humans., Methods: In this double-blind, placebo-controlled, two-way crossover (intravenous and oral) study, single ascending doses of 10, 20, 40, 80, 160, and 320 mg (intravenous) and 100, 200, 400, 800, and 1600 mg (oral) were given; six subjects received active drug and three received placebo at each dose level. At regular intervals, blood pressure, heart rate, cardiac output, PRA, immunoreactive renin, and drug plasma levels were determined., Results: The compound was well tolerated except at the 1600 mg oral dose level at which diarrhea occurred in two subjects. At neither dose were there effects on blood pressure, heart rate, or cardiac output relative to placebo. PRA and angiotensin I production rate decreased and immunoreactive renin increased dose dependently after both intravenous and oral administration. The duration of these effects was also dose dependent and was longer than 12 hours with higher doses. Systemic plasma clearance, volume of distribution, and absolute bioavailability of remikiren were in the magnitude of 900 ml/min, 70 L, and below 1%, respectively. The angiotensin I production rate correlated in a sigmoidal way with plasma drug concentrations independent of the route of administration., Conclusion: Remikiren is a potent inhibitor of renin in humans with long-lasting effects after both intravenous and oral administration.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40-5967 were investigated in 64 patients with hypertension. In a double-blind, placebo-controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose-dependently reduced over the full 24-hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, -34/-25 mm Hg, p less than 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose-dependently increased and concentration-effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40-5967 has a long-lasting antihypertensive effect after once-daily administration.

The effect of the new renin inhibitor Ro 42-5892 was evaluated in healthy volunteers after both intravenous and oral administration. In a preliminary study, 14 subjects received a 10-min infusion of Ro 42-5892 at doses ranging from 0.001 to 1 mg/kg. Plasma renin activity (PRA) and angiotensin (Ang) II levels were maximally suppressed in a dose-dependent manner at the end of the infusion. Plasma active renin concentration increased up to threefold. In a second study, 24 volunteers received placebo or 100, 600, or 1,200 mg of Ro 42-5892 p.o. in a single-blind, randomized fashion. Within 30 min after drug intake, PRA and plasma Ang I and Ang II levels fell to their nadir. Both Ang I and Ang II were measured specifically after extraction on phenylsilylsilica and separation by isocratic HPLC. The degree as well as the duration of inhibition were dose related. The decrease in plasma Ang lasted maximally for 2 h. Active renin increased dose dependently and remained elevated for more than 8 h after the 1,200 mg dose. A theoretical generation rate of Ang I was calculated for individual plasma samples assuming Michaelis-Menten kinetics for competitive inhibition and steady-state conditions. This calculated Ang I generation rate, based on plasma active renin concentrations and drug levels, closely correlated with actually measured Ang I and Ang II levels (r = 0.90, n = 88) over the whole 8 h time period. Thus, a sustained renin inhibition by Ro 42-5892, as indicated by increased plasma active renin levels, induces a much shorter fall in plasma Ang I and II apparently because of a rise in renin secretion.

In clinical pharmacology studies, cilazapril, after its bioactivation to cilazaprilat, was characterised as a potent, reversible angiotensin converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours, which is consistent with saturable binding to ACE. Despite the arterial vasodilatation, only slight increases in heart rate occurred during cilazapril administration. Cilazapril had no acute effect on cardiovascular reflexes, and increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close positive correlation was found between the cilazaprilat plasma concentration and degree of ACE inhibition. The potency of cilazaprit, defined as the concentration of cilazaprilat causing 50% inhibition of ACE, was approximately 1 microgram/L plasma. In short term studies in patients with hypertension, it appeared that more than 90% inhibition of plasma ACE was needed to obtain blood pressure reduction. Results of various dose-response studies established the indirect relationship between dose, the plasma concentration of the drug, and the blood pressure response, and identified the dose producing the maximal effect to be 5mg. Cilazapril inhibited ACE for a relatively long period which was extended in patients with severe chronic renal impairment or hepatic failure. In these patients a reduction of the dose and/or less frequent administration is recommended. There was no clinically relevant interaction of cilazapril with food, furosemide (frusemide), digoxin or coumarins. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril, and an additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with indomethacin and cilazapril might occur, potentially reducing the blood pressure-lowering effect of cilazapril. In general, cilazapril was well tolerated.

Magnetic resonance spectroscopy of fluorine (19F) has been used to noninvasively study the in vivo pharmacokinetics of a model drug, fleroxacin (a fluoroquinolone antibiotic agent), in healthy human subjects. After oral administration, fleroxacin was detected in 19F magnetic resonance spectra from both liver and calf muscle and four magnetic resonance examinations were undertaken during a 24-hour period. By combining plasma analysis by high performance liquid chromatography with the magnetic resonance data, the following pharmacokinetic parameters (mean values) were obtained: tmax, 1.4, 4.6, and 5.6 hours in liver, plasma, and muscle, respectively; Cmax, 53, about 250, and about 60 mumol/L in plasma, liver, and muscle, respectively; t1/2, 4.4 hours (fast phase) and 10.8 hours (slow phase) in liver and 14.2 hours in plasma. The study documents for the first time the potential use of 19F magnetic resonance spectroscopy to noninvasively observe the time-related changes of a fluorine-containing drug in human tissues after oral administration.

The efficacy of three antihypertensive treatments given for 3 weeks each, 2.5 mg cilazapril, a new potent long-acting angiotensin-converting enzyme (ACE) inhibitor, 120 mg propranolol, and the combination of both, were compared in 17 patients suffering from essential hypertension. Blood pressure control (i.e. sitting diastolic blood pressure at rest less than or equal to 90 mm Hg) was achieved in about 40% of the patients by the monocomponents, the combination therapy increased the rate to 80%. An additional blood pressure-lowering effect of the combination was also observed during isometric exercise (handgrip) but not during isotonic exercise (bicycle). At rest and during isometric exercise on cilazapril alone cardiac output rose, total peripheral resistance fell, on propranolol the inverse reactions occurred. On the combination cardiac output and total peripheral resistance decreased. During isotonic exercise propranolol slightly decreased (VO2max fell, lactate concentration went up), cilazapril slightly increased aerobic capacity (VO2max went up and lactate concentration fell) and exercise tolerance. These effects were partially attenuated by the combination. The additional blood pressure-lowering effect of the combination was assumed to be due to the suppression of the renin-angiotensin-aldosterone system (the ACE inhibitor and the betablocker act in a synergistic way), a peripheral vasodilation, and the reduction of sympathetic tone expressed as heart rate reduction and hence a decrease in cardiac output. It is concluded that the combination of an ACE inhibitor and a betablocker seems to exert a good antihypertensive activity not only at rest but also during exercise.