Effects of tedisamil, atenolol and their combination on heart and rate-dependent QT interval in healthy volunteers.

AIMS: Tedisamil is a new blocker of K+ currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a beta-adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests. METHODS: The effects of tedisamil (100 mg twice daily) and atenolol (50 mg twice daily) on heart rate and QT interval duration were analysed in a three-period crossover study in healthy male volunteers. RESULTS: This study showed that tedisamil exerted a significant (P<0.05) bradycardic action at rest (-10 beats min(-1); 95% CI: -6 to -15 beats min(-1)) similar to atenolol (-14 beats min(-1); -11 to -17) and drug combination (-9 beats min(-1); -6 to -12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (-42 beats min(-1); -37 to -47) and combination (-47 beats min(-1); -41 to 52). Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000 ms, but not at RR<700 ms (combination). Tedisamil alone and in combination induced a reverse rate-dependent QT interval prolongation. CONCLUSIONS: These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.

Moxonidine and cognitive function: interactions with moclobemide and lorazepam.

OBJECTIVE: Moxonidine represents a new generation of centrally acting antihypertensive drugs. It binds to I1-imidazoline receptors and exerts its antihypertensive activity through a reduction in systemic vascular resistance, while cardiac output remains unchanged or even increases slightly. Moxonidine is prescribed for the treatment of mild to moderate hypertension. Typical doses are 0.4 to 2.0 mg given as one dose in the morning or as divided doses in the morning and evening. METHODS: The effects of moxonidine 0.4 mg once daily in combination with moclobemide or lorazepam were investigated in two, double-blind, randomised, placebo-controlled, two-way crossover studies in a total of 48 healthy volunteers. Safety assessments were made in each study and included pre- and post-study measurement of blood pressure, heart rate, ECG, haematology, blood biochemistry, and urinalysis, and recording of adverse events. RESULTS: In the first study, moxonidine alone was found to produce small but statistically significant impairments of vigilance detection speed at 4 h and 6 h. Lowering of subjective alertness was also observed. Repeat dosing with moxonidine produced an impairment of memory scanning performance. These findings were not reproduced in the second study, in which moxonidine alone produced an improvement in immediate word recall at 4 h and 6 h. No interactions were observed when moxonidine was co-administered with moclobemide. Moxonidine, when co-administered with lorazepam, produced interactions with three tasks requiring high levels of attention: choice, simple reaction time and digit vigilance performance; memory tasks; immediate word recall, delayed word recall accuracy; and visual tracking. A total of 47 adverse events were reported in study 1. Moxonidine produced a slight decrease of systolic and diastolic blood pressure. In study 2, a total of 55 adverse events were reported. In both trials, the most frequently reported events were tiredness and dryness of mouth, the latter occurring only under the moxonidine treatment. There were no clinically relevant changes observed in blood pressure, pulse rate, and laboratory tests in either study, nor was there any evidence of any interaction between moxonidine and either moclobemide or lorazepam. CONCLUSION: Moxonidine was found to be safe and well tolerated in healthy volunteers. However, the impairments on attentional tasks were greater when moxonidine was co-administered with lorazepam 1 mg. These effects should be considered when moxonidine is codosed with lorazepam, although they were smaller than would have been produced by a single dose of lorazepam 2 mg.

[Absolute bioavailability of folic acid after oral administration of a folic acid tablet formulation in healthy volunteers]. / Absolute Bioverfügbarkeit von Folsäure nach einmaliger oraler Gabe einer Folsäure-Tablettenzubereitung an gesunde Versuchspersonen.

5 mg folic acid were administered in two sessions to 9 female and 8 male healthy subjects within a balanced 2-way crossover trial either as one Folsan tablet (CAS 59-30-3, test preparation A) or as 2.5 ml of an injection solution (Folsan 2, reference preparation B). Folic acid was determined in serum and urine collected in fractions over 12 h after administration by means of a radioassay. Before each session a saturation period of 9 days duration was performed by administering 1 tablet per day containing 5 mg folic acid followed by a 4-day wash-out period. The mean predose serum level of folic acid amounted to 17.9 +/- 5.62 ng/ml before the oral and 18.2 +/- 5.73 ng/ml before the intravenous administration. The post dose serum levels were corrected with the individual predose levels. After oral administration of test preparation. A a mean peak serum concentration of 243 +/- 33.0 ng/ml (Cmax) was obtained after 2.24 +/- 0.85 h (tmax). The mean area under the corrected serum level time curve was determined with 1160 +/- 177 ng x h/ml (AUC(0-12)). 6 min after intravenous administration serum levels ranged from 559 to 1490 ng/ml. Following correction with the individual predose levels the mean area under the curve amounted to 1550 +/- 249 ng x h/ml. The individual bioavailability ratios of AUC(0-12) (A versus B) varied between 49.3% and 96.7%. The mean absolute bioavailability of folic acid was 76.2% +/- 13.8% (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetics and relative bioavailability of iron and folic acid in healthy volunteers]. / Pharmakokinetik und relative Bioverfügbarkeit von Eisen und Folsäure bei gesunden Versuchspersonen.

The pharmacokinetics and the relative bioavailability of iron and of folic acid was investigated in a randomized, balanced 2-way cross-over study with 14 healthy male participants. The drugs were given in a combined preparation dragée (Ferro-Folsan) containing 100 mg of ferrous-II-sulfate x 1.5 H2O (CAS 13463-43-9) and 0.85 mg of folic acid (CAS 59-30-3). Other established preparations were used as reference drugs. All subjects had a normal iron body level and were brought to a saturated folic acid level prior to the investigation. After administration of 2 dragées of the test medication and determination of serum iron level until 9 h p.a., a relative bioavailability of 64%, compared to an equal dose of a ferrous-II-sulfate-ascorbic acid reference solution, was calculated. From the serum folate AUC (0-9 h) the relative bioavailability was evaluated with 97% for the oral formulation compared to the i.m. administration. The ratio of the cumulative renal folate excretion in the 0-9 h interval amounted to 76% for the oral compared to the i.m. administration. However, in order to understand this differing result it should be kept in mind that during the first hours following parenteral administration a greater amount of the unchanged compound is renally excreted than after oral dosing. This is presumably based upon the different rate of absorption following both administrations with a steeper absorption phase following the parenteral dose.

Steady state investigation of possible pharmacokinetic interactions of moxonidine and glibenclamide.

The aim of the study presented here was to determine possible pharmacokinetic interactions of moxonidine and glibenclamide at steady state in 18 healthy male volunteers. Multiple oral doses of 0.2 mg of moxonidine b.i.d. (q. 12 h) and of 2.5 mg of glibenclamide o.i.d. (q. 24 h) were administered alone and in combination in an open, non-randomized, three-treatment design. The preparations were given for 5 days in each of the 3 periods. The results of this multiple dose study did not indicate substantial pharmacokinetic interactions of the drugs. Regarding the influence of glibenclamide on the pharmacokinetics of moxonidine, no significant changes were seen at all. In the presence of moxonidine, a minor decrease of bioavailability of glibenclamide was detectable, as could be derived from the AUC and clearance data. The actual differences were small and not considered to be of clinical significance.

[Bioavailability of folic acid following intramuscular and intravenous administration to healthy volunteers]. / Bioverfügbarkeit von Folsäure nach intramuskulärer und intervenöser Gabe an gesunde Versuchspersonen.

Bioavailability of Folic Acid Following Intramuscular and Intravenous Administration to Healthy Volunteers 2 mg folic acid (Folsan 2, CAS 59-30-3) were either i.m. or i.v. administered as injection solution to 15 male healthy subjects within an open balanced two-way crossover study. The concentration-time profile of folic acid was determined up to 12 h p.a. in serum and urine using a radioassay. Each change-over phase included a 9 days lasting saturation phase with once-per-day oral administration of a tablet containing 5 mg folic acid. Saturation was performed in order to guarantee filled-up endogenous folate storage compartments in the body of the subjects. After a four-day wash-out phase the subjects were confined and the basic serum level and basic renal 0-12 h folate excretion determined. On the following morning the respective dose of 2 mg folic acid was either i.m. or i.v. applied to the subjects (treatment day 14). 11 (i.m.) and 15 (i.v.) venous blood specimens were drawn up to 12 h p.a. and urine collected following the same schedule as the day before in 4 different fractions. The mean predose level of folic acid in serum was 13.2 +/- 4.85 ng/ml before the i.m. administration and 13.3 +/- 5.59 ng/ml before i.v. administration. The serum concentration data following the respective single administrations were corrected by subtraction of the individual predose values. After 0.50 +/- 0.19 h (mean tmax) the folate serum level increased by 101 +/- 27.2 ng/ml after the i.m. dose. Serum concentration decreased in the following 6-8 h approximately to the predose values.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of pharmacokinetic interactions between moxonidine and digoxin.

The potential for pharmacokinetic interactions between moxonidine and digoxin at steady-state was investigated in 15 healthy male volunteers. Multiple oral doses of 0.2mg moxonidine twice daily and 0.2mg digoxin once daily were administered alone and in combination in a randomised 3-period crossover design. The drugs were administered for at least 5 days. The results indicate that neither moxonidine nor digoxin influences the pharmacokinetics of the other drug under steady-state conditions.

Influence of food on the oral bioavailability of moxonidine.

Moxonidine is a new centrally acting anti-hypertensive with a very low adverse drug reaction profile. Among others, the aim of the study presented here was to determine the influence of food on the pharmacokinetics of moxonidine. Single oral moxonidine doses of 0.2 mg fasting and 0.2 mg non-fasting were administered in a randomized cross-over study. Eighteen subjects participated in the study, all of whom completed the study according to the protocol. Three sets of analytical plasma data could not be evaluated pharmacokinetically giving a total number of 15 evaluable cases. Renal excretion was evaluated for all 18 subjects. Food intake had no influence on the pharmacokinetics of moxonidine. The relative bioavailability of moxonidine administered under non-fasting conditions reached 94% of the bioavailability after fasted administration. Food intake resulted in a slight decrease of Cmax and a minimal increase of tmax as compared to the fasted treatment. The absorption half-life t1/2a showed a minor prolongation. These differences were not statistically significant in any of the parameters. For t1/2 lambda 2, CLtot and Ae(24h) no statistically significant differences were found between the fasting and non-fasting treatment. The amount of moxonidine excreted unchanged in urine accounted for about 46% of the dose administered after both treatments.

Pharmacokinetics and relative bioavailability of prajmalium bitartrate after single oral dosing.

Pharmacokinetics and relative bioavailability of the marketed prajmalium bitartrate tablet (Neo-Gilurytmal, CAS 2589-47-1) compared to an oral solution were investigated in an open, randomized, single-dose two-fold crossover study in 20 healthy male volunteers. One subject was identified to be a poor metabolizer. In the study population with normal metabolic status the two oral formulations proved to be bioequivalent with regard to the pharmacokinetic parameters Cmax, AUC(0-Tlast), AUC(0-infinity) and Ae(24h). tmax was prolonged after administration of the tablets. The relative bioavailability of prajmalium bitartrate from the tablet amounted to 112%. The poor metabolizer demonstrated in both oral formulations high plasma concentrations, increased AUCs and prolonged terminal half-lives as well as increased renal excretion of prajmalium bitartrate.

Absolute bioavailability of moxonidine.

In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean +/- standard deviation] 3438 +/- 962 pg.h/ml (AUC(0----Tlast)) and 3674 +/- 1009 pg.h/ml (AUC(0----infinity)) for treatment A; 3855 +/- 1157 pg.h/ml (AUC(0----Tlast)) and 4198 +/- 1205 pg.h/ml (AUC(0----infinity)) for treatment B. Mean peak plasma concentrations of 1495 +/- 646 pg/ml were attained at 0.56 +/- 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 +/- 1342 pg/ml at 0.17 +/- 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h)) in absolute figures and as percentage of the dose administered were 102 +/- 26 micrograms or 51 +/- 13% for the tablet and 122 +/- 33 micrograms or 61 +/- 16% for the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)