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  • Articles  (32)
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  • Springer  (32)
  • American Institute of Physics
  • Cell Press
  • International Union of Crystallography (IUCr)
  • Oxford University Press
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 31 (1986), S. 285-290 
    ISSN: 1432-1041
    Keywords: imipramine ; ranitidine ; cimetidine ; pharmacokinetics ; metabolism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml−1) or ranitidine (1.14 µg·h·ml−1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 31 (1986), S. 299-302 
    ISSN: 1432-1041
    Keywords: femoxetine ; cimetidine ; pharmacokinetics ; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between femoxetine and cimetidine has been evaluated in 8 healthy volunteers. Two volunteers received single doses of femoxetine, and 6 were given multiple doses of femoxetine for 7 days with and without concurrent cimetidine. No influence of cimetidine was observed on the kinetics of single doses of femoxetine, but after multiple doses the plasma concentration of femoxetine was significantly increased. Similarly, the AUC at steady state tended to be increased, but not to a significant extent. Concurrent cimetidine did not cause a reduction in the AUC of the active desmethyl metabolite. It is recommended that femoxetine is given in reduced doses (e.g. 400 mg) when administered with cimetidine.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 14 (1978), S. 15-19 
    ISSN: 1432-1041
    Keywords: Tocainide ; electrocardiography ; hemodynamics ; healthy volunteers ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tocainide is a new antiarrhythmic drug with a chemical structure related to that of lidocaine. In the present study, healthy volunteers were investigated after infusion of tocainide 450 mg over 45 min. In nine subjects His bundle electrograms, sinus recovery time and ventricular effective refractory periods were recorded. No major changes were seen. In eight cases the hemodynamic effects at rest and during exercise were studied. No significant circulatory effects were observed. No clinically important side-effects were noted.
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  • 4
    Electronic Resource
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    Springer
    European journal of clinical pharmacology 30 (1986), S. 171-175 
    ISSN: 1432-1041
    Keywords: caffeine ; verapamil ; coffee ; blood pressure ; slow calcium-channel blockade ; drug interaction ; healthy volunteers ; plasma catecholamines ; plasma renin activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An increase in blood pressure after coffee and caffeine has recently been reported. A possible pharmacological mechanism for this pressor response is a rise in the intracellular calcium concentration, caused by an increase in calcium influx due to a direct effect of caffeine. Accordingly, the cardiovascular effects of drinking coffee after placebo and verapamil 3 × 80 mg in 1 day in 10 normotensive volunteers have been examined in a single-blind study. After placebo, coffee led to an increase in blood pressure (7/14 mm Hg), and a fall in heart rate (−7 beats/min); forearm blood flow did not change. Plasma epinephrine rose (257%), plasma norepinephrine did not change and the plasma renin activity fell significantly. The haemodynamic and humoral changes after coffee were not altered by pretreatment with verapamil. It is concluded that increased transmembrane calcium influx after caffeine does not appear to be an important pharmacological mechanism for the circulatory effects of coffee.
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  • 5
    Electronic Resource
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    Springer
    European journal of clinical pharmacology 31 (1986), S. 177-182 
    ISSN: 1432-1041
    Keywords: glibenclamide ; bioavailability ; pharmacokinetics ; dissolution ; hypoglycaemia ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A study has been carried out investigating four different marketed oral preparations of glibenclamide, correlating the effectiveness of the drug in these preparations in lowering plasma glucose concentrations with (i) the in vitro dissolution of the drug, measured by the British Pharmacopoeal and Desaga methods, and (ii) the in vivo bioavailability, assessed in 12 healthy human volunteers. The two dissolution methods yielded different rank orders of ease of dissolution of the drug from the various preparations; the findings of neither dissolution method correlated adequately with the results of the in vivo bioavailability studies, which correctly predicted the abilities of the preparations to reduce plasma glucose concentrations. Relative to an oral glibenclamide solution the bioavailabilities of the drug from three tablet preparations were 0.69, 0.49 and 0.24. The mean elimination half-life of the drug was 1.5 h and assuming complete bioavailability of the drug from oral solution the mean systemic clearance was 0.095 l kg−1h−1, and the mean apparent volume of distribution was 0.20 l kg−1. It is concluded that it may be unsafe to use in vitro dissolution data as a basis for assessing the bioequivalences of different glibenclamide preparations intended for oral use.
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  • 6
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    European journal of clinical pharmacology 30 (1986), S. 177-182 
    ISSN: 1432-1041
    Keywords: perindopril ; blood pressure ; heart rate ; parasympathetic ; sympathetic ; converting enzyme inhibitor ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of the angiotensin converting enzyme inhibitor, perindopril, on autonomic function was assessed in a double blind, placebo controlled, crossover study in 10 normotensive males. Eight milligram of perindopril given orally lowered blood pressure without a change in heart rate. Perindopril enhanced the vagally mediated heart rate variation with deep breathing. There was no impairment of the responses to either bicycle exercise at 175 W for 5 min or isometric handgrip. The pressor response to cold was not changed and the response to the Valsalva manoeuvre was unaltered. These results suggest that the absence of tachycardia after perindopril may be in part related, as has been reported with other converting enzyme inhibitors, to enhanced cardiac parasympathetic tone. Vagomimetic action may be a property of converting enzyme inhibitors in general.
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  • 7
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    European journal of clinical pharmacology 30 (1986), S. 269-271 
    ISSN: 1432-1041
    Keywords: gastric antisecretory agent ; 40 749 RP ; long acting drug ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 40 749 RP, a pyridyl-2-tetrahydrothiophene derivative is known to be a potent gastric antisecretory agent in animals and man. In 27 healthy volunteers in four double-blind cross-over studies, this activity has been examined against basal and pentagastrin stimulated gastric acid secretion. The effect of a single oral dose of 2 mg/kg was still present after 12, 24 and 48 h. The effect of 1 mg/kg was definitely increased after treatment for 7 days as compared to a single dose of 1 mg/kg.
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  • 8
    Electronic Resource
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    European journal of clinical pharmacology 30 (1986), S. 323-329 
    ISSN: 1432-1041
    Keywords: methylprednisolone ; prednisolone ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition and plasma binding of methylprednisolone were examined in seven normal volunteers following the administration of 5, 20 and 40 mg of intravenous methylprednisolone sodium succinate. Methylprednisolone exhibits linear plasma protein binding averaging 77%. The mean plasma methylprednisolone clearance of 337 ml·h−1. kg−1 was independent of dose. The steroid appears to moderately distribute into tissue spaces with a mean volume of distribution of 1.41·kg−1. Methylprednisolone disposition parameters were compared with the non-transcortin bound parameters for prednisolone. The prednisolone plasma clearance based on the transcortin free-drug is similar to methylprednisolone total plasma clearance. However, the corrected volume of distribution of prednisolone is only one-half that of methylprednisolone. The disposition rate of these two steroids is thus similar, in spite of their metabolic control by different enzymatic pathways and major influence of saturable transcortin binding on prednisolone elimination.
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  • 9
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    European journal of clinical pharmacology 30 (1986), S. 355-357 
    ISSN: 1432-1041
    Keywords: substance P ; mucociliary activity ; inflamatory reactions ; nose ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Substance P (SP), a potent inflammatory agent, has been found in sensory nerve fibres in the nasal mucosa in several experimental animals as well as in man. It may participate in the inflammatory response as part of the mucosal defence against foreign materials. In experimental animals SP has been found to increase mucociliary in airway mucosa. The present study was performed in order to find out the relationship between topically applied SP and nasal mucociliary function in humans. Thirteen healthy volunteers were challenged with 65 µg SP or placebo in a randomized cross over fashion and mucociliary transport time was determined each time using the saccharine dye test. The dose of SP was chosen after an open dose-response study. No statistically significant change in the mucociliary transport time was found after challenge with SP as compared to placebo. The possible reasons for this are discussed.
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  • 10
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    European journal of clinical pharmacology 30 (1986), S. 581-584 
    ISSN: 1432-1041
    Keywords: dihydroergotamine ; venoconstriction ; nasal spray ; healthy volunteers ; i.m. administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A parenteral formulation of dihydroergotamine (DHE) is the only galenical form now available for the treatment of acute attacks of migraine in which a rapid onset of action is required. A recently developed nasal spray of DHE has been compared with intramuscular DHE for its venoconstrictor activity. In a randomised double-blind, cross-over trial, 9 healthy male volunteers received a single dose of DHE 1 mg intranasally, DHE 0.5 mg i.m. or placebo (intranasally and i.m.) on three different occasions, with an interval of at least 1 week between doses. Both active treatments, but not placebo, produced marked venoconstriction as shown by reduced compliance of superficial hand veins. The effect persisted for more than 8 h. The maximum venoconstrictor effect of 1 mg DHE intransally was 40±12% (mean ± SEM) and after 0.5 mg i.m. it was 52±15%. The time course of the venoconstrictor effect was similar after both routes of administration. Blood pressure and heart rate changes in these normotensive subjects were almost identical after dihydroergotamine and placebo. The results suggest that the nasal spray could be used as an alternative to parenteral DHE, permitting self-administration of the drug for the treatment of acute attacks of migraine.
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  • 11
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    European journal of clinical pharmacology 30 (1986), S. 741-744 
    ISSN: 1432-1041
    Keywords: cimetidine ; subchronic administration ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26–29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t1/2β and Vβ were similarly unchanged. However mean renal clearance (CLR) and fe were significantly increased following 2 weeks of drug dosing (CLR 5.41 ml·min−1 kg−1; fe 0.61) compared to control (CLR 4.00 ml·min−1·kg−1; fe 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml·min−1·kg−1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.
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  • 12
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    European journal of clinical pharmacology 31 (1986), S. 419-422 
    ISSN: 1432-1041
    Keywords: bupranolol ; transdermal delivery system ; beta1- and beta2-adrenoceptor binding ; steady-state concentration ; healthy volunteers ; plasma concentrations ; beta-adrenoceptor antagonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6–15 nmol/l (equivalent to 1.5–4 ng/ml in plasma) at beta1- (rat salivary gland) and beta2-adrenoceptors (rat reticulocytes) in receptor binding studies with3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t1/2=2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.
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  • 13
    ISSN: 1432-1041
    Keywords: metronidazole ; metabolism ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p〈0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.
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  • 14
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    European journal of clinical pharmacology 31 (1986), S. 239-242 
    ISSN: 1432-1041
    Keywords: piroximone ; cardiotonic drug ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy, male subjects received single intravenous and oral doses of piroximone. Plasma piroximone concentrations were assayed up to 8 h after each dose by HPLC. Urinary excretion of the parent compound was also determined. Following the oral dose, piroximone reached peak plasma concentrations within 30 to 90 min. The t1/2 of the terminal decay phase was 2.8 h, the mean apparent volume of distribution was 2.5 l/kg, and the mean total body clearance was 755 ml/min. Mean urinary recovery of parent drug within 24 h was 50% after the intravenous dose and 41% after the oral dose. Renal clearance accounted for approximately 50% of total body clearance. Oral bioavailability, estimated from AUC or urinary recovery, was 80%.
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  • 15
    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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  • 16
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    European journal of clinical pharmacology 31 (1986), S. 371-374 
    ISSN: 1432-1041
    Keywords: oxaprozin ; drug interaction ; acetaminophen ; cimetidine ; ranitidine ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve healthy male volunteers participated in a single-dose four-way crossover study to evaluate potential drug interactions with oxaprozin, a nonsteroidal antiinflammatory agent of the propionic class. The four modes of administration were:a. oxaprozin, 1200 mg alone;b. oxaprozin during concurrent acetaminophen, 500 mg 4 times daily;c. oxaprozin with cimetidine, 300 mg 4 times daily;d. oxaprozin with ranitidine, 150 mg every 12 hours. Acetaminophen, cimetidine, or ranitidine were begun 24 hours prior to oxaprozin dosage and continued for the 10-day duration of each trial. No significant differences existed among the four treatment conditions in peak plasma oxaprozin concentration (86 µg/ml), volume of distribution (0.23 l/kg), time of peak concentration (3.7 h after dosage), or elimination half-life (54 h). Oxaprozin oral clearance was significantly lower (by 20%) during both the cimetidine and ranitidine trials versus control (0.047 vs 0.047 vs 0.059 ml/min/kg), but clearance during acetaminophen was not significantly different from control. Thus acetaminophen, cimetidine or ranitidine has only a small influence on the pharmacokinetics of a single oral dose of oxaprozin. The reduction in oxaprozin clearance due to cimetidine or ranitidine is statistically significant but small in magnitude.
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  • 17
    ISSN: 1432-1041
    Keywords: thromboxane A2-receptor blocker ; BM 13.177 ; single dose pharmacokinetics ; platelet aggregation ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamic effect on platelet activation of a single 800 mg oral dose of BM 13.177 have been investigated in 8 male volunteers. BM 13.177 disappeared from plasma with a terminal elimination half-life of 0.85 h. 52% of the dose was excreted unchanged in urine. Assuming complete absorption, total clearance was calculated to be 741.3 ml/min and renal celearance to range from 310.4 to 396.9 ml/min. The pharmacodynamic studies were performed ex vivo/in vitro in platelets stimulated either with methyl mercury chloride or with U 46619. Methyl mercury chloride is a platelet activator that requires TXA2 formation from endogenous arachidonic acid, whereas U 46619 is a stable PGH2 analogue and thromboxane mimetic at the platelet TXA2/PGH2 receptor. A close correlation between the plasma concentration-time profile of BM 13.177 and inhibition of platelet shape change or aggregation was demonstrated.
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  • 18
    ISSN: 1432-1041
    Keywords: bufuralol ; hepatic oxidation ; debrisoquine/sparteine phenotype ; stereo- and regioselectivity ; metabolites ; healthy volunteers ; drug metabolism ; polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of the debrisoquine/sparteine-type of oxidation polymorphism on plasma bufuralol concentration and the pattern of urine metabolites was studied in extensive and poor metabolizer subjects. (+)- and (−)-bufuralol, and (+)- and (−)-OH-bufuralol in plasma were determined by enantioselective HPLC, and urinary bufuralol and its metabolites were assayed by gas chromatography-mass spectrometry. Three hours after administration of racemic bufuralol the plasma (−)/(+) isomeric ratio for unchanged bufuralol was 1.84 in extensive metabolizers, indicating preferential clearance of the (+)-isomer through aliphatic 1′-hydroxylation and glucuroconjugation, while the (−)-isomer was mainly eliminated by aromatic 4-hydroxylation. Poor metabolizers were characterized by impaired 1′- and 4-hydroxylation, with almost total abolition of the stereoselectivity of these reactions. The data strongly suggest that both 1′- and 4-hydroxylation are catalyzed by the same enzyme. These in vivo observations are in agreement with recent in vitro data obtained in human liver microsomes from phenotyped patients and support the concept of deficiency of a highly stereoselective cytochrome P-450 isozyme as the cause of this polymorphism.
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  • 19
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    European journal of clinical pharmacology 31 (1986), S. 339-342 
    ISSN: 1432-1041
    Keywords: ketanserin ; ketanserin-ol ; pharmacokinetics ; reduction-oxidation equilibrium ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic reduction-oxidation equilibrium between ketanserin and ketanserin-ol was studied after oral dosing of both substances to two healthy volunteers. Comparison of plasma Cmax and AUCs indicated that the equilibrium was shifted towards ketanserin-ol. There is evidence that ketanserin-ol elimination is the slowest step dictating the terminal half-life of ketanserin.
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  • 20
    ISSN: 1432-1041
    Keywords: citalopram ; antidepressant drug ; pharmacodynamics ; adverse effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Citalopram, a selective 5-HT uptake inhibitor with antidepressant properties, was assessed in three studies in 12 healthy subjects using a battery of EEG, psychological, subjective and symptomatic measures. Study A involved the administration of citalopram, 20 mg and 40 mg, amitriptyline 50 mg and placebo in single dose using a balanced cross-over design. The test battery was applied before, and 1 and 3 h after each drug. Citalopram decreased slow-wave EEG activity whereas amitriptyline increased power in most EEG wavebands. Citalopram increased tapping rate and symbol copying whereas amitriptyline impaired these and other psychomotor tasks. Subjectively, amitriptyline was much more sedative than citalopram and produced more complaints of dry mouth. Study B comprised the administration of citalopram in the usual clinical dose of 40 mg, amitriptyline in the low clinical dose of 75 mg and placebo, each given for 9 nights using a balanced cross-over design. The test battery was applied on the first morning (pre-drug) and on the morning after the last nightly dose. None of the physiological tests showed any drug effects. Subjectively, citalopram was associated with feelings of shaking, nausea, loss of appetite and physical tiredness; amitriptyline produced feelings of shaking, nausea, loss of appetite, dryness of mouth, irritability, dizziness and indigestion; in general, amitriptyline effects were more marked than those of citalopram. Plasma samples were taken on the last day and plasma concentrations of both drugs and their metabolites were found to be in the expected range for the regimens used. In the third study (C), 12 healthy subjects took similar courses of citalopram, amitriptyline and placebo. On the morning of the 8th day, a test dose of ethanol was given. The battery of tests was given predrug, on Days 4/5 and on Day 8, before and 1 and 3 h after the ethanol. Amitriptyline increased the 7.5–13.5 Hz waveband. Amitriptyline impaired critical flicker fusion frequency, tapping, DSST and reaction time; citalopram affected DSST and immediate memory recall. The subjective and symptomatic effects of the drugs were similar to those in Study B. Plasma concentrations of citalopram, amitriptyline and their desmethylated metabolites were in the expected range for the regimens used. Ethanol had the expected effects, impairing performance and producing sedation. No evidence for potentiation of ethanol and drug effects were found, most interactions being additive, or even with some symptoms subtractive. It is concluded that in clinical use citalopram should have little or no effect on cognitive and psychomotor performance, produce minimal sedation but some nausea, loss of appetite and insomnia. Interactions with ethanol should be unremarkable.
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  • 21
    ISSN: 1432-1041
    Keywords: diclofenac sodium ; triamcinolone acetate ; pharmacokinetics ; drug interactions ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seventy-five mg diclofenac sodium were given intramuscularly to 15 subjects alone and in combination with 40 mg triamicinolone acetate. Plasma levels of diclofenac were measured and pharmacokinetic parameters were calculated. The results indicate no statistically significant differences for most of the parameters. The maximum plasma concentrations (Cpmax) was increased by about 20% in combination with the glucocorticoid, whereas terminal elimination rate did not change significantly.
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  • 22
    ISSN: 1432-1041
    Keywords: tiapamil ; desmethyltiapamil ; pharmacokinetics ; cardiovascular effects ; cirrhotic patients ; plasma protein binding ; impaired hepatic elimination ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tiapamil 70 mg was administered i.v. to 8 healthy male volunteers and 8 patients (7 males, 1 female) with biopsy proven hepatic cirrhosis. Two of the patients also received 600 mg p.o. Serial plasma and urine samples were collected and the parent drug in plasma and urine and desmethyl-tiapamil in urine were assayed by a specific HPLC method. The plasma and urine data for the parent drug after i.v. and p.o. dosing were simultaneously fitted to linear p.o. and i.v. two compartment models with exit from and input into the central compartment. Absorption was assumed to be a first order process. In the volunteers the mean pharmacokinetic parameters were: 101 l for the steady-state volume of distribution, 750 ml·min−1 for nonrenal clearance, 195 ml·min−1 for renal clearance and 1.7 h for the half-life of the terminal disposition phase. The urinary recoveries of the parent drug and desmethyltiapamil averaged 21.4 and 0.8% of the dose, respectively. In the patients the steady-state volume of distribution, the amount of unchanged drug in urine and the half-life of the terminal disposition phase were significantly increased (171 l, 29.0% of the dose, 3.5 h, respectively). Decreased plasma protein binding in the patients accounted for the larger steady-state volume of distribution. The nonrenal clearance of 519 ml·min−1, tended to be smaller in the patients than in the volunteers. Together with the increased urinary recovery of tiapamil in the patients this indicates a moderately impaired elimination capacity in the cirrhotics. The renal clearance was similar in the patients (213 ml·min−1) and the volunteers. The absolute oral bioavailability of tiapamil was 55 and 49% in 2 patients. No effects of tiapamil on heart rate or supine blood pressure were detected, either in volunteers or in patients. Negative dromotropic effects were found in 2 volunteers and 2 patients after i.v. dosing.
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  • 23
    ISSN: 1432-1041
    Keywords: enprofylline ; theophylline ; bronchial reactivity ; histamine inhalation test ; healthy volunteers ; pharmacokinetics ; bronchodilatation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double blind, placebo controlled, crossover study the pharmacokinetics and acute effects of enprofylline and theophylline on airway reactivity during histamine challenge were investigated in 10 healthy volunteers. The pharmacokinetic parameters of enprofylline were (mean): elimination half-life 1.9 h, total body clearance 191.1 ml · kg−1 · h−1, volume of distribution 0.48 l · kg−1, and protein binding 49%. Bronchial reactivity in the histamine inhalation test was expressed as the concentration causing a 20% fall in FEV1.0 (PC20). Mean PC20 values were lowest after placebo and highest after theophylline with the enprofylline values in between. Only the difference in PC20 Safter placebo and theophylline was statistically significant (p〈0.05). At the time of determination of the PC20, the serum concentration of enprofylline was between 16.5 and 11.8 µmol/l, and that of theophylline was between 78.3 and 61.1 µmol/l. Adverse actions of enprofylline were nausea (3/10) and cardiovascular reactions (2/10), whereas theophylline mainly caused restlessness (3/10) and tremor (2/10). Thus enprofylline, in one-fifth of the serum concentration of theophylline cannot be regarded as equipotent in terms of bronchoprotection.
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  • 24
    ISSN: 1432-1041
    Keywords: nitrendipine ; digoxin ; plasma levels ; interaction ; systolic time intervals ; adverse effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of two different doses of nitrendipine on plasma digoxin levels, urinary recovery and systolic time intervals was investigated in 8 healthy volunteers. Following a loading dose, digoxin 0.25 mg b.d. p.o. was given alone for 2 weeks. Then 0.25 mg digoxin b.d. was administered for two 1-week periods combined with nitrendipine 10 mg or 20 mg once daily. The study was completed with another digoxin monotherapy phase lasting 7 days. Nitrendipine 20 mg daily led to a significant increase in plasma digoxin levels and in its area under the plasma concentration-time curve AUC (0–12) compared to digoxin monotherapy. The AUC (0–12) was 9.7 ng ml−1h when digoxin alone was given and 11.2 ng ml−1h on co-administration of the calcium antagonist. Urinary recovery and renal clearance of digoxin were slightly but not significantly increased by nitrendipine. Nitrendipine 10 mg once daily caused a small, insignificant tendency to elevate the plasma digoxin level. Nitrendipine co-administration (10 and 20 mg once daily) did not significantly alter systolic time intervals, as non-invasively measured haemodynamic parameters, compared to digoxin treatment alone. Thus, nitrendipine 20 mg daily caused a significant increase in plasma digoxin concentrations and in its AUC, which would rarely be of clinical relevance.
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  • 25
    ISSN: 1432-1041
    Keywords: Diltiazem ; slow-release tablet ; pharmacokinetics ; atrioventricular conduction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effect of a slow-release and a conventional diltiazem tablet on atrioventricular conduction were compared in a randomized cross-over study after a single dose and at steady state in 12 healthy volunteers. The time to peak concentration was significantly delayed after the slow-release as compared to the conventional tablet, both after a single dose (2.7 vs. 0.9 h) and at steady-state (1.9 vs. 0.9 h). The peak concentration was also significantly reduced. There was no marked loss in bioavailability with the slow-release formulation. The maximal fluctuations in serum diltiazem at steady-state for the slow-release tablet were markedly less than after the conventional tablet (62 vs 87%). The PQ-interval was longer after the conventional tablet as compared to the slow-release tablet (both in doses of 120 mg) after a single dose (187 vs 163 ms) and at steady-state (197 vs 174 ms). The maximal prolongation was seen 1 h after intake of the drug. Heart rate was decreased only by 6–9 beats/min, irrespective of the dose. Slow-release diltiazem appears to have many advantages over a conventional tablet.
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  • 26
    Electronic Resource
    Electronic Resource
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    European journal of clinical pharmacology 29 (1986), S. 679-683 
    ISSN: 1432-1041
    Keywords: cardioselectivity ; beta-adrenoceptor blockers ; diacetolol ; acebutolol ; metoprolol ; propranolol ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 1. The beta-adrenergic selectivity of diacetolol, the major metabolite of acebutolol, has been compared with that of acebutolol, metoprolol and propranolol in 11 normal subjects. 2. Bronchial and cardiac beta-adrenoceptor blockade were assessed on separate occasions after diacetolol 600 mg, acebutolol 400 mg, metoprolol 200 mg, propranolol 80 mg and placebo. 3. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose response curve to inhaled isoprenaline after each beta blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the 5th minute of exercise at 70% of the subject's maximum work rate. 4. There was a significant reduction in exercise heart rate with all 4 beta-blocking drugs when compared with placebo, 22% for diacetolol, 24% for acebutolol, 25% for propranolol and 28% for metoprolol. The reduction with metoprolol was significantly greater than the reduction with the other three beta-adrenoceptor antagonists. 5. Mean dose ratios for the airway isoprenaline dose response curves after each of the 4 beta-blocking drugs were 2.4 for diacetolol, 2.7 for metoprolol, 8 for acebutolol and 72 for propranolol. The difference between diacetolol and metoprolol was not significant. 6. Thus diacetolol appears to be more cardioselective than acebutolol and both are more cardioselective than propranolol in man. Metoprolol is probably more cardioselective than diacetolol though interpretation of the differences in exercise heart rate is complicated by the fact that diacetolol has some intrinsic sympathomimetic activity.
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  • 27
    ISSN: 1432-1041
    Keywords: phenobarbital ; propylhexedrine salt ; barbexaclone ; bioavailability ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of phenobarbital (PB) was compared after oral administration of equivalent doses of the drug as the acid or the propylhexedrine salt (barbexaclone) to 7 normal volunteers. The absorption and elimination parameters were very similar. It was concluded that propylhexedrine did not affect the serum kinetics of PB given as barbexaclone.
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  • 28
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 30 (1986), S. 57-60 
    ISSN: 1432-1041
    Keywords: nifedipine ; pharmacokinetics ; oral contraceptives ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of Nifedipine were measured following single oral doses of Nifedipine Slow Release (Adalat Retard) on three separate occasions to young, healthy volunteers of both sexes. Intra- and inter-subject variability were assessed by comparing the pharmacokinetic parameters, AUC, Cmax and T50%AUC. Interindividual variability was less than that observed in other studies with the betablockers, metoprolol and propranolol and there was no evidence of differences between the sexes.
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  • 29
    Electronic Resource
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    European journal of clinical pharmacology 30 (1986), S. 121-123 
    ISSN: 1432-1041
    Keywords: dezocine ; opioid analgesics ; pharmacokinetics ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous (IV) dezocine, and bioavailability of intramuscular (IM) and subcutaneous (SQ) dezocine, were evaluated in healthy male volunteers. Elimination half-life following 5, 10, and 20 mg IV doses averaged 2.6–2.8 h, and was independent of dose. Clearance decreased slightly, although significantly, with dose. After Deltoid IM injection, dezocine was rapidly absorbed (peak level: 0.6 h after dose), with bioavailability 97%. Thus dezocine has extensive distribution, high clearance and short half-life over a range of IV doses. It is rapidly and completely absorbed following IM or SQ administration.
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  • 30
    Electronic Resource
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    European journal of clinical pharmacology 31 (1986), S. 165-168 
    ISSN: 1432-1041
    Keywords: bromerguride ; dopamine antagonist ; pharmacokinetics ; pharmacodynamics ; prolactin level ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and urinary excretion of the dopamine antagonist, bromerguride, were measured by radioimmunoassay in healthy male volunteers given 50 µg i.v. and oral doses of 1 and 2 mg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of bromerguride declined biphasically, with half-lives of 7 min and 1.2h. The total clearance was 32 ml·min−1·kg−1 and the apparent volume of distribution was 3.6 l/kg. The bioavailability of oral bromerguride was 29% after 1 mg and 25% after 2 mg. The drug was almost totally metabolized and less than 0.05% of the dose was excreted in urine in 24 h after oral administration. Plasma prolactin levels were increased in a dose-dependent manner for about 8 h. Side-effects were minimal, mainly being tiredness and headache in some of the volunteers.
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  • 31
    Electronic Resource
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    Springer
    European journal of clinical pharmacology 29 (1986), S. 685-689 
    ISSN: 1432-1041
    Keywords: digoxin ; food ingestion ; ECG ; healthy volunteers ; haemodynamic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of the ingestion of food and digoxin on the cardiovascular system alone and in combination have been observed in eight healthy subjects. A positive inotropic response was seen following food (2.5 MJ) and intravenous digoxin (0.01 mg/kg) with significant decreases in QS2Index (QS2I) pre-ejection period (PEP) and PEP/LVET (LVET — left ventricular ejection time). These responses were potentiated when food and digoxin were combined. Opposing effects of food and digoxin on % diastole (%D) and diastolic time were observed, food decreasing %D and DT while digoxin increased these variables. Both food and digoxin decreased T-wave amplitude, and digoxin alone or in combination with food decreased QTc. The positive inotropic effect of a 2.5 MJ mixed meal and a loading dose of digoxin in healthy subjects are of similar degree, different mechanism, and are potentiated in combination.
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  • 32
    ISSN: 1432-1041
    Keywords: idazoxan ; pharmacokinetics ; alpha 2-adrenoceptor antagonist ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A high performance liquid chromatographic method was developed for the quantitative determination of idazoxan in plasma. The assay was used to study the disposition of the drug after intravenous infusion and oral administration to five normal subjects. After i.v. administration the kinetics could be described by a two compartment model with a mean elimination half life of 4.20 h. The mean calculated volume of distribution during the elimination phase was 3.20 l/kg−1 and the mean plasma clearance was 824 ml min−1. After oral administration a lag period before onset of absorption was observed in all five volunteers, the plasma levels declining monoexponentially from the peak concentration with a mean elimination half life of 5.58 h. The absolute availability varied between 26% and 41% with a mean value of 34%. Invitro measurements produced a blood/plasma ratio of 1.3 for idazoxan.
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