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  • Springer  (85)
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 28 (1985), S. 659-664 
    ISSN: 1432-1041
    Keywords: BTS 49465 ; hypertension ; pharmacokinetics ; blood pressure effect ; heart rate effect ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60° head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.
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  • 2
    ISSN: 1432-1041
    Keywords: renin ; aldosterone ; dopamine ; natriuretic hormone ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute natriuretic effect of human atrial natriuretic peptide (ANP) has been well described in man. We have now studied possible hormonal mediators of this effect. We studied six healthy volunteers on two occasions when they received either an infusion of ANP of 1.5 pmol·kg−1·min−1 for 30 min followed by 15 pmol·kg−1·min−1 for a further 30 min, or matching vehicle infusions in a randomized single-blind fashion. On the placebo day, plasma renin activity (PRA) rose from 1.26±0.08 to 1.57±0.14 ng A1·ml−1·h−1, while on the ANP study day PRA fell from 1.45±0.15 to 1.28±0.05 ng A1·ml−1·h−1 (p〈0.01). No significant changes were found in plasma aldosterone concentrations or in urinary dopamine excretion. These results provide evidence that ANP suppresses renin release in man.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 46 (1994), S. 23-28 
    ISSN: 1432-1041
    Keywords: Atenolol ; Captopril ; Central effects ; short term administration ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The central effects of atenolol (50 mg tds) and captopril (50 mg tds) ingested for a period of seven days were studied in ten healthy volunteers. A placebo and two active control drugs, methyldopa (250 mg tds) and oxazepam (10 mg), were included in the design. Oxazepam was ingested on the seventh day only, with a placebo being taken on the preceding six days. On the seventh day, central effects of the drugs were tested at 10.00–11.00 h (session 1), immediately before the subjects' last dose of each drug and at 2.5–3.5 h after the final dose of each drug (1330–1430 h, session 2). Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. Recordings of the EEG and body sway were carried out. Neither atenolol nor captopril altered performance at any of the skills tested. There were no effects on subjectively assessed alertness or mood with captopril, while atenolol significantly increased wakefulness in session 2 and when the two sessions were meaned. Similarly, captopril did not modify body sway, while with atenolol there was a significant decrease in activity in the frequency range 1.0–2.75 Hz from session 1 to session 2. Both captopril and atenolol modified the electrical activity of the brain, with captopril increasing delta and theta activity and atenolol reducing delta, alpha and beta activity. Methyldopa significantly increased the number of involuntary rest pauses in the finger tapping task, and the choice reaction time from session 1 to session 2. There was a decrease in passivity during the first session and an increase in wakefulness in session 2 with methyldopa. This drug also decreased body sway in the frequency range 1.0–2.75 Hz activity in session 2, while oxazepam decreased bodys was at 1.0 to 2.75 Hz and increased activity at 2.5–3.0 Hz in session 2. Oxazepam reduced delta, theta and alpha content of the EEG. The present study has been unable to demonstrate any development of adverse central effects with captopril over a period of 7 days of drug ingestion. With atenolol adverse effects were present following short term dosing but were not more pronounced than with acute ingestion seen in previous studies. However effects on the electrical activity of the brain with atenolol remained after 7 days suggesting that the changes reported previously with single ingestions do not disappear.
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  • 4
    ISSN: 1432-1041
    Keywords: Felodipine ; Nitrendipine ; Nifedipine ; enantiomers ; blood pressure ; heart rate ; concentration-effect relationship ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all 20 mg solution p.o.) on non-invasively measured blood pressure and heart rate were investigated in a randomised, double-blind, cross-over study in 12 normotensive, young, healthy males. Compared to baseline values, heart rate increased more after rac-felodipine treatment (+47% at maximum) than rac-nitrendipine (+40%) and nifedipine (+38%); only small and variable changes in blood pressure were observed with any of the drugs. The baseline-corrected area under the heart rate-time curve up to 4 h after the administration of rac-felodipine was 197% and 180% larger than after nifedipine and rac-nitrendipine treatment, respectively. The effects on heart rate could be fitted individually to a sigmoidal Emax-model without hysteresis for all drugs under investigation. The relative potencies of the unbound drugs for their indirect effects on heart rate were 1:7:43 for nifedipine, rac-nitrendipine and rac-felodipine, respectively. The active (S)-enantiomers of felodipine and nitrendipine appeared to be 9-and 60-times as potent as nifedipine in this respect, assuming no (inter)activity of the (R)-enantiomers. Individual and mean changes in blood pressure were small, they were not related to plasma concentrations, and did not differ between treatments.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 21 (1982), S. 433-441 
    ISSN: 1432-1041
    Keywords: antipyrine ; antipyrine metabolites ; drug metabolism ; route of administration ; healthy volunteers ; urinary excretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8±1.9% of the dose was excreted in urine as unchanged antipyrine in 48h, 24.9±6.3% as 4-hydroxyantipyrine, 16.5±3.2% as norantipyrine, 13.0±2.2% as 3-hydroxymethyl-antipyrine and 5.8±1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 27 (1984), S. 447-452 
    ISSN: 1432-1041
    Keywords: alaproclate ; antipyrine clearance ; serotonin reuptake inhibitor ; healthy volunteers ; antipyrine metabolism ; metabolite clearance ; alaproclate kinetics ; inhibition of drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Alaproclate, a selective serotonin reuptake inhibitor, presently undergoing clinical trial for the treatment of major depressive disorders, has been shown to inhibit hexobarbital metabolism in mice. In the present study the influence of oral alaproclate on the total plasma clearance of antipyrine and on the formation of its metabolites was investigated in 10 healthy volunteers. The peak level of alaproclate was reached after about 1.5 h, and after a distribution phase, its plasma elimination half-life was between 3.0 and 3.5 h. Antipyrine tests were performed before treatment, during the first four doses and after the seventh dose of alaproclate 200 mg/day. During treatment, total plasma antipyrine clearance and the clearance for production of all antipyrine metabolites were reduced by 30%, indicating non-selective inhibition of oxidative drug-metabolizing enzyme activity in man by alaproclate. After the last dose of alaproclate, antipyrine plasma clearance and the clearance to its metabolites returned to control values. In order to allow more detailed evaluation of the results, the time course of the clearances for production of metabolites was investigated. This revealed that the extent of inhibition of metabolite formation by alaproclate was dependent on the plasma alaproclate level, indicating a rapidly reversible inhibition.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 3 (1975), S. 1-11 
    ISSN: 1573-8744
    Keywords: hexobarbital pharmacokinetics ; intravenous infusion ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The plasma levels of hexobarbital in humans were determined during and after a 30-min or 60-min zero-order intravenous infusion. Hexobarbital kinetics could be described by conceiving the body to exhibit two compartments. The plasma concentrations were fitted to the postinfusion equation and the parameters intrinsic to the two- compartment open model were estimated. The elimination half-life varied considerably among the 14 individuals (160–441 min), which could mainly be explained by the greatly varying metabolic clearance of the compound (123–360 ml /min). The apparent volume of distribution per kilogram of body weight was relatively constant (1.10±0.12 liters/kg).
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 28 (1985), S. 113-117 
    ISSN: 1432-1041
    Keywords: nadolol ; nifedipine ; tachycardia ; cardiovascular response ; healthy volunteers ; pharmacokinetics ; exercise heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a placebo controlled exercise protocol using healthy volunteers the effects of nadolol 80 mg and 160 mg orally and of nadolol 80 mg during treatment with nifedipine 20 mg 8 hourly were compared. Resting systolic and diastolic blood pressures were reduced by both nifedipine (p〈0.05) and nadolol (p〈0.01) acting alone. An unexpected finding was that nifedipine alone significantly inhibited exercise tachycardia (p〈0.01) (8 to 12 h post dose). Predictably both doses of nadolol produced significant reduction in exercise tachycardia which was still apparent at 24 h. There was a linear relationship between log10 plasma nadolol concentration and reduction in exercise heart rate. The combined inhibitory effects of nifedipine and nadolol 80 mg on exercise heart rate showed partial additivity but did not summate. There was no pharmacokinetic interaction between the 2 drugs. The inhibition of exercise tachycardia by nifedipine, not previously documented, is consistent with an effect of the drug on the sinus node, as has been reported in in-vitro studies, and may contribute to the drugs efficacy in angina.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 19 (1981), S. 53-55 
    ISSN: 1432-1041
    Keywords: digoxin ; bioavailability ; dose-dependency ; urinary excretion ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine healthy volunteers received single 0.25, 0.5, 1.0, 1.5, and 2.0 mg doses of oral digoxin tablets in random sequence on five occasions separated by at least 4 weeks. Urinary excretion of immunoassayable digoxin was determined from 8 consecutive 24 h urine samples collected after each dose. Mean values of cumulative urinary excretion of digoxin at the 5 doses were: 40.9, 35.6, 36.4, 34.1, and 33.5% of the dose (F=0.64; d. f.=4.32; N. S.). Mean values of urinary excretion half-life were: 2.48, 2.03, 2.20, 2.07, and 1.87 days (F=2.87; d. f.=4.32;p=0.05). Thus, the bioavailability of orally administered digoxin tablets in healthy volunteers is dose-independent over an 8-fold range of doses.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 24 (1983), S. 509-515 
    ISSN: 1432-1041
    Keywords: cibenzoline ; pharmacokinetics ; bioavailability ; urinary excretion ; antiarrhythmic drug ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of cibenzoline (UP 339.01), a new antiarrhythmic drug, was studied after i.v. and oral administration to 5 healthy subjects. Cibenzoline levels in plasma and urine cibenzoline were measured by a GLC method. After i.v. administration, the total clearance was 826 ml · min−1. The fraction of cibenzoline excreted unchanged in the urine was 0.602 and it was correlated with the creatinine clearance. After i.v. and oral administration, the renal clearances were 499 ml · min−1 and 439 ml · min−1, and the half-lives were 4 h 01 min and 3 h 24 min, respectively. The differences were not significant. Availability by the oral route was 0.92, the maximum plasma concentration being observed at 1 h 36 min. The results were compared with those for other antiarrhythmic drugs.
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