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  • healthy volunteers  (37)
  • Springer  (37)
  • American Chemical Society
  • American Institute of Physics (AIP)
  • Oxford University Press
  • 2005-2009
  • 1980-1984  (37)
  • 1984  (37)
Collection
Publisher
  • Springer  (37)
  • American Chemical Society
  • American Institute of Physics (AIP)
  • Oxford University Press
Years
  • 2005-2009
  • 1980-1984  (37)
Year
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 26 (1984), S. 627-630 
    ISSN: 1432-1041
    Keywords: bupropion ; ethanol ; pharmacokinetic interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A study was performed to determine whether there is a pharmacokinetic interaction between alcohol and the novel antidepressant bupropion. In the first part 8 healthy male volunteers received single doses of 100 mg bupropion hydrochloride orally on 2 occasions accompanied by either ethanol in orange or plain orange drink according to a balanced cross over design. Plasma bupropion concentrations were determined by radioimmunoassay and kinetics analysed with the aid of NONLIN. Blood alcohol levels were assessed by breathalyser. The disposition of bupropion was adequately described by a 2 compartment model and kinetic parameters were not significantly altered by the presence of alcohol. In the second part of the study the same subjects received 40 ml ethanol in orange drink 3.5 h after ingestion of 100 mg bupropion or dummy tablet in a double blind cross over fashion. Bupropion did not affect alcohol kinetics. In contrast to many other psychotropic drugs there is no evidence for a kinetic interaction between bupropion and alcohol.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 26 (1984), S. 635-637 
    ISSN: 1432-1041
    Keywords: theophylline ; inhalation ; saliva-serum distribution ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers received an iv infusion of 317 mg lysine theophylline (equivalent to 197 mg anhydrous theophylline) in order to calculate theophylline clearance by standard methods. They subsequently received a 20 minute inhalation of nebulised lysine theophylline. Serum and salivary theophylline concentrations were measured and all saliva was collected for the first hour. From these concentrations estimates were made of the distribution of theophylline into the blood and saliva with 40% to 94% identified in the blood. Very high salivary concentrations were reached during the inhalation phase with saliva: serum concentration ratios of between 60 and 1600.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 27 (1984), S. 115-117 
    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; Ro 15-1788 ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (〈0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.
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  • 4
    ISSN: 1432-1041
    Keywords: nitroglycerin ; plasma concentration ; transdermal administration ; bioavailability ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 healthy volunteers, intravenous infusions of nitroglycerin 4.8 and 10.6 µg/min yielded mean steady-state plasma concentrations of 0.5±0.02 and 0.82±0.04 ng/ml as determined by a gas chromatographic/mass spectrometric method. The plasma concentrations reached in the same subjects 17 h after application of Nitroderm TTS 5 and 10 with in vivo release rates of 3.7 and 5.7 µg/min were 0.28±0.01 and 0.37±0.01 ng/ml, respectively. Thus, 75% of the quantity of nitroglycerin released by the systems passed into the circulation. The inter-individual and intra-individual variations in plasma concentrations were similar for both modes of administration. The nitroglycerin-induced morphological changes in the fingerpulse wave were clearly dose-dependent, but it seems that this pharmacodynamic parameter is determined less by the plasma concentration than by the nitroglycerin content of the vascular wall.
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  • 5
    Electronic Resource
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    Springer
    European journal of clinical pharmacology 27 (1984), S. 371-373 
    ISSN: 1432-1041
    Keywords: disodium chromoglycate ; nasal airway resistance ; platelet activating factor ; healthy volunteers ; rhinomanometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirteen healthy subjects participated in a double blind, randomized, cross-over investigation of whether or not intranasal disodium chromoglycate could block the change in nasal airway resistance induced by platelet activating factor (PAF). Placebo or active drug was given for 3 days before intranasal challenge with PAF. Nasal airway resistance before and at intervals after callenge was determined with a rhinomanometer. Pretreatment with disodium chromoglycate blocked the decrease in nasal airway resistance induced by PAF. This indicates an alternative mode of action of disodium chromoglycate in the treatment of allergic airway diseases.
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  • 6
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; metabolites ; pharmacokinetics ; single/multiple oral doses ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of canrenone and ‘total metabolites’ after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and ‘total metabolites’ were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2α) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2β) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of ‘total metabolites’ after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of ‘total metabolites’ was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and ‘total metabolites’ were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.
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  • 7
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    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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  • 8
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    Springer
    European journal of clinical pharmacology 27 (1984), S. 471-475 
    ISSN: 1432-1041
    Keywords: acyclovir ; A515U ; 6-deoxyacyclovir ; pharmacokinetics ; prodrug ; antiviral chemotherapy ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A515U (6-deoxyacyclovir) is an analogue of acyclovir devoid of antiviral activity in vitro but which is well absorbed and undergoes conversion to acyclovir after oral administration to rats. The tolerance and pharmacokinetics of various doses of A515U have been studied in 8 healthy volunteers. Single oral doses of 25, 50, 100, 200 and 400 mg A515U and 400 mg acyclovir for comparison were administered to the volunteers at weekly intervals. Concentrations of the parent drug and acyclovir were determined in plasma and urine. The prodrug was well tolerated and did not cause adverse reactions or changes in haematological or biochemical variables. It was well absorbed and conversion to acyclovir was rapid and extensive at all doses. Plasma concentrations of acyclovir achieved with 50 mg A515U orally were comparable to and less variable than those produced by 400 mg acyclovir. A515U was rapidly cleared with a short plasma elimination half life of approximately 0.5 h. The attainment of high plasma concentrations of acyclovir by oral administration of a prodrug may represent an important advance in antiviral chemotherapy.
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  • 9
    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; visual function ; intrinsic effect ; Ro 15-1788 ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ro 15-1788 is a specific benzodiazepine antagonist, which has also been shown to have some agonist properties. Since benzodiazepine receptors are involved in the physiological mechanisms of vision, a possible intrinsic effect of Ro 15-1788 was sought in 6 healthy volunteers by study of psychophysical flicker thresholds, including critical fusion frequency and low frequency modulation threshold, and pattern reversal visual evoked response, using double blind cross-over methodology. In each session 2 tablets of Ro 15-1788 30 mg were administered. Using a two factorial univariate analysis of variancé, no change was detected in any of the parameters studied.
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  • 10
    Electronic Resource
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    Springer
    European journal of clinical pharmacology 27 (1984), S. 535-538 
    ISSN: 1432-1041
    Keywords: pindolol ; healthy volunteers ; heart rate ; intrinsic sympathomimetic activity ; diurnal heart rate ; nocturnal heart rate ; rebound effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect on heart rate of pindolol 5, 15 and 30 mg/day, a beta-adrenoreceptor blocker possessing intrinsic sympathomimetic activity, administered to 8 healthy volunteers for 14 days was studied. Heart rate was continuously recorded over 24 h during placebo treatment before each sequence, every 2 days during treatment, and then on the 15th, 17th and 18th days. Pindolol in the three doses used had no significant effect on mean heart rate over 24 h. It tended to lower mean diurnal heart rate non-significantly between noon and 6 p.m. Pindolol raised nocturnal heart rate between midnight and 6 a.m. to a comparable extent at all the doses used. Sympathetic tone is at its lowest during that period, which makes it possible to detect the intrinsic sympathomimetic activity of pindolol. After cessation of treatment, a rebound effect was observed, cardioacceleration being most marked after 30 mg/day.
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  • 11
    ISSN: 1432-1041
    Keywords: zetidoline ; prolactin ; aldosterone ; dopamine ; healthy volunteers ; pharmacodynamic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The neuroendocrinological effects of acute oral administration of 20 mg zetidoline, a new antipsychotic drug with antidopaminergic properties, were evaluated in 8 healthy volunteers, by a double-blind, crossover comparison with placebo. Zetidoline significantly increased serum prolactin (p〈0.01 at 1–3 h; p〈0.05 at 4–6 h). No significant change was observed in blood levels of aldosterone, renin, cortisol, growth hormone and electrolytes, or in blood pressure and heart rate. The data suggest that the drug increases prolactin through blockade of dopaminergic receptors. The lack of change in the aldosterone levels may be evidence against the hypothesis of dopaminergic control of aldosterone secretion.
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  • 12
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    European journal of clinical pharmacology 26 (1984), S. 463-470 
    ISSN: 1432-1041
    Keywords: dihydroergotamine ; 8′-hydroxy-dihydroergotamine ; plasma metabolites ; bioavailability ; receptor affinity ; healthy volunteers ; liver microsomal incubates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations and urinary excretion of dihydroergotamine and its metabolites have been measured after a single oral administration of 3 mg tritium-labelled drug to 6 male volunteers. The plasma level of non-volatile radioactivity declined biphasically with α- and β-phase half-lives of 2.1 h and 32.3 h, respectively. The peak plasma concentration was reached within 3.2h. Urinary excretion of total non-volatile radioactivity was low, amounting to 1.0% of the dose. The parent drug and four metabolites could be quantitated in urine and plasma samples. Metabolite 4 (8′-hydroxy-dihydroergotamine) was isolated from incubates of rat and monkey liver microsomal preparations. In human liver microsomal incubates, metabolite 4 was shown to be the primary metabolite of dihydroergotamine. In receptor binding studies performed with mammalian brain preparations, metabolite 4 had IC50-values at 6 monoaminergic binding sites similar to those of dihydroergotamine. Thus, it appears that the active principle consists at least of dihydroergotamine and its 8′-hydroxy derivative. As the concentration of metabolite 4 exceeded 5–7 times that of dihydroergotamine in urine and plasma, the bioavailability of dihydroergotamine should be reevaluated, taking into account the plasma concentrations of the parent drug and of its acitve metabolite, 8′-hydroxydihydroergotamine.
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  • 13
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    European journal of clinical pharmacology 27 (1984), S. 191-196 
    ISSN: 1432-1041
    Keywords: pizotifen 5-hydroxyindoleacetic acid ; homovanillic acid ; urinary excretion ; healthy volunteers ; migraine prevention
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of 0.5 mg pizotifen or a placebo was administered to 10 healthy male volunteers in a double blind cross-over trial. 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in hourly urine samples were determined by liquid chromatography with amperometric detection. The 5-HIAA levels were strongly correlated with the HVA levels in control samples (r=0.95, p〈0.001). Pizotifen produced a significant increase in the urinary 5-HIAA/HVA ratio over the 3 hours following absorption of the drug (+0.21, +0.18, +0.19, p〈0.05). The increase demonstrates an interaction between pizotifen and 5-HT metabolism, which may be involved in its antimigraine effect.
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  • 14
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    Springer
    European journal of clinical pharmacology 27 (1984), S. 483-489 
    ISSN: 1432-1041
    Keywords: radiosensitiser ; pharmacokinetics ; healthy volunteers ; tumour patients ; Ro 03-8799
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new hypoxic cell radiosensitiser, Ro 03-8799 has been administered intravenously to human volunteers and its kinetic parameters derived from plasma and urine data. Good penetration of drug into tumour tissue is found, consistent with its large volume of distribution. The plasma clearance of this compound is rapid due to high metabolic and renal clearances. These parameters combine to produce an elimination half-life of 5.6 h, approximately half that of misonidazole, a well studied radiosensitiser. It is hoped that this decrease in total body exposure will also reduce the cumulative toxicity seen when misonidazole is administered repeatedly.
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  • 15
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    European journal of clinical pharmacology 27 (1984), S. 501-503 
    ISSN: 1432-1041
    Keywords: valpromide ; valproic acid ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.
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  • 16
    ISSN: 1432-1041
    Keywords: trimethoprim ; concentration ; urinary excretion ; healthy volunteers ; steady state ; pharmacokinetics ; serum creatinine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady state pharmacokinetics of trimethoprim was determined after 300 mg orally once daily to 6 healty volunteers for 9 days. The microbiological assay of plasma level was unreliable at trimethoprim concentrations 〉4 µg/ml, so results from an HPLC-assay are given. Steady state was present after 3 days. The plasma concentration peaked 1 to 4 h (mean 2.0 h) after the dose at a mean of 6.0 µg/ml (range 3.1–9.5 µg/ml); the minimum value was 1.5 µg/ml (range 0.6–2.9 µg/ml). The mean AUCss was 77 µg/ml · h and the mean plasma clearancess was 67 and 74 ml/min on Days 8 and 9. Renal clearance was about 60% of the plasma clearance. The average plasma half life was 10.6 h (range 8.7–15.3 h). Thus, there was considerable interindividual variation in all pharmacokinetic parameters. 72 h after the last dose trimethoprim was detectable in plasma in only 1 of the 6 subjects. The minimum urinary concentration of trimethoprim during treatment was always well above (range 22 to 220 µg/ml) the MIC values for most urinary tract pathogens. Therefore, a daily dose of 300 mg trimethoprim results in a therapeutic concentration in urine at steady state that lasts throughout the dosing interval and in most subjects probably lasts also for a further 24 h. Trimethoprim administration raised mean serum creatinine from 67 to 97 µmol/l, probably due to competitive inhibition of the tubular secretion of creatinine.
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  • 17
    ISSN: 1432-1041
    Keywords: acetylsalicylic acid ; platelet function ; salicylate ; controlled release formulation ; single dosing ; continuous dosing ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The extent to which a controlled release acetylsalicylic acid (ASA) formulation inhibited platelet function has been evaluated in single and chronic dosing studies. In the single dose study, the platelet inhibitory effect of the controlled release formulation was compared with that of an equivalent dose of soluble ASA and an equimolar dose of sodium salicylate (SA). In the chronic dosing study, ASA dose-response curves for platelet function, including cyclooxygenase activity, were determined for various doses (20–1300 mg) of the controlled release (enteric coated pellets) ASA formulation taken by volunteers daily for one week. Platelet function was assessed by the degree of inhibition of aggregation for several aggregating agents, and the degree of inhibition of activity of platelet cyclooxygenase quantified by the estimation of malondialdehyde (MDA) production. Plasma ASA and SA concentrations were also determined in each study. The controlled release product inhibited platelet function to the same extent as an equimolar dose of soluble ASA, but did so with much lower and sometimes undetectable peak systemic plasma ASA concentrations. SA, the direct metabolite of aspirin, did not have any effect on platelet function. The ASA dose-platelet function response curves obtained from chronic dosing with the controlled release formulation appeared to be similar to those reported previously for the soluble product. The inhibition of platelet function appeared to be unrelated to plasma ASA concentrations.
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  • 18
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    European journal of clinical pharmacology 27 (1984), S. 23-27 
    ISSN: 1432-1041
    Keywords: hypertension ; alpha2-adrenoceptors ; blood pressure ; clonidine ; guanfacine ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time courses of the changes in plasma growth hormone and noradrenaline concentrations in response to 15 min infusions of clonidine 0.2 mgs and guanfacine 2 mgs, were studied in six normal volunteers, in a double-blind, randomised, crossover study. Plasma noradrenaline fell within 15 min of the commencement of drug administration, by 36±14% after clonidine (p〈0.05) and by 32±11% (p〈0.05) after guanfacine. Plasma growth hormone was not significantly elevated until the 30th minute to 12.0±4.7 lU/ml (p〈0.05) after clonidine and 14.7±11.5 lU/ml (p〈0.05) after guanfacine, having been undetectable prior to both drugs. The reduction in plasma noradrenaline by these α2-adrenergic agonists, prior to activation of central adrenoceptors as detected by changes in plasma growth hormone, is evidence for a peripheral component in their sympatholytic effect.
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  • 19
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    European journal of clinical pharmacology 27 (1984), S. 75-80 
    ISSN: 1432-1041
    Keywords: bupropion ; alcohol interaction ; healthy volunteers ; performance ; autonomic functions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of bupropion and ethanol were examined alone and in combination in a placebo controlled, double-blind, crossover study in 12 healthy volunteers. Results were subjected to analysis of variance and differences ofp〈0.05 taken as significant. In the main study using the Wilkinson auditory vigilance test, no active treatment or combination of treatments produced significant change compared with placebo. However, when compared with bupropion 100 mg, vigilance was significantly impaired by 32 ml alcohol alone though not when combined with bupropion. No significant changes in reaction time or short term memory occurred. Visual analogue scales indicated that the subjects were mentally slower after alcohol 32 ml than after placebo. Combination of bupropion 100 mg with alcohol 32 ml abolished this difference. A similar pattern occurred with group ratings indicating mental sedation. Subjects were clearly able to differentiate between the 16 ml and 32 ml doses of alcohol when assessing their degree of inebriation. Combination of bupropion with alcohol made no difference to the ratings of inebriation. The top dose of alcohol tended to increase energy in the low frequency EEG bands. Combination of the top alcohol dose with bupropion, however, produced a significant reversal with lowered energy in the 4–7.5 Hz band. Combination of bupropion with alcohol failed to change the blood alcohol concentration achieved.
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  • 20
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    European journal of clinical pharmacology 27 (1984), S. 119-121 
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
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  • 21
    ISSN: 1432-1041
    Keywords: nitroglycerin ; plasma concentration ; transdermal administration ; bioavailability ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 healthy volunteers, intravenous infusions of nitroglycerin 4.8 and 10.6 µg/min yielded mean steady-state plasma concentrations of 0.5±0.02 and 0.82±0.04 ng/ml as determined by a gas chromatographic/mass spectrometric method. The plasma concentrations reached in the same subjects 17 h after application of Nitroderm TTS 5 and 10 with in vivo release rates of 3.7 and 5.7 µg/min were 0.28±0.01 and 0.37±0.01 ng/ml, respectively. Thus, 75% of the quantity of nitroglycerin released by the systems passed into the circulation. The inter-individual and intra-individual variations in plasma concentrations were similar for both modes of administration. The nitroglycerin-induced morphological changes in the fingerpulse wave were clearly dose-dependent, but it seems that this pharmacodynamic parameter is determined less by the plasma concentration than by the nitroglycerin content of the vascular wall.
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  • 22
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    European journal of clinical pharmacology 27 (1984), S. 453-458 
    ISSN: 1432-1041
    Keywords: dipyrone ; metabolism ; metabolite pharmacokinetics ; acetylation polymorphism ; healthy volunteers ; dapsone phenotyping
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the dipyrone metabolites 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA) were evaluated following the administration of a single oral 1.0 g dose of dipyrone to 23 healthy volunteers. Twelve were slow and 11 were rapid acetylators as previously determined by dapsone phenotyping. For MAA and FAA the mean peak plasma concentrations were 10.5±2.8 µg/ml and 2.1±0.8 µg/ml and the half-lives were 3.3±1.0 and 10.1±1.8 h, respectively. No significant difference was found between rapid and slow acetylators in MAA and FAA kinetics. For AA, the mean peak plasma concentrations were 2.7±0.6 and 1.6±0.7 µg/ml (p〈0.01), the peak times 6.7±2.1 and 3.1±1.1 h (p〈0.01) and the half-lives were 5.5±1.0 and 3.8±1.2 h in slow and rapid acetylators, respectively. For AAA, the mean peak plasma concentrations were 1.6±0.4 and 4.4±1.1 µg/ml (p〈0.01) and the peak time 16.1±5.1 and 10.0±2.6 h (p〈0.01) in slow and rapid acetylators, respectively. There was no difference in the elimination half-life between the two groups (10.6±2.2 h). Thus, it has been demonstrated that the AAA/AA ratio is an indicator of the acetylation phenotype, as it is closely correlated with that determined by dapsone (r=0.895, p〈0.0005).
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  • 23
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    European journal of clinical pharmacology 27 (1984), S. 495-497 
    ISSN: 1432-1041
    Keywords: ranitidine ; aldosterone secretion ; sodium depletion ; drug interference ; plasma renin activity ; biochemical parameters ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of a 3-day oral course of ranitidine on plasma aldosterone level has been studied in 6 normotensive volunteers maintained in a state of sodium depletion. A significant fall in plasma aldosterone (p〈0.05–0.02), in both the overnight recumbency levels and in the levels obtained during a two hour period of ambulation was observed. The change took place in the absence of variation in plasma renin activity and potassium. Plasma cortisol and prolactin levels were lower after ranitidine at the beginning of the test but their values were not significantly different after ambulation during ranitidine therapy. Ranitidine appears to interfere with aldosterone secretion in vivo.
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  • 24
    ISSN: 1432-1041
    Keywords: cimotaxone ; MAO inhibitor ; plasma prolactin ; circadian rhythm ; healthy volunteers ; hypothalamic MAO ; prolactin secretion ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prolactin (PRL) secretion is stimulated by serotonin (5-HT) and inhibited by dopamine (DA). 5-HT is generally recognized as a substrate for type A monoamine oxidase (MAO), whereas DA is considered as a substrate for either A or B, or both forms of MAO, depending on the species and tissues used. The effect of cimoxatone, a reversible, selective MAO-A inhibitor, on diurnal variation in plasma PRL level was investigated in healthy adults after a single 40 mg oral dose, as an indirect approach to investigating whether DA is preferentially a substrate for Type A or B MAO in man. The circadian rhythm in PRL, stress conditions and diet were taken into account in the present study, which was placebo-controlled. There was a slight but significant reduction in circulating PRL in the six subjects, which persisted for at least 9 h after cimoxatone. However, the duration of the decrease in plasma PRL was shorter than the inhibition of MAO-A. The results are not inconsistent with the presence of both forms of MAO in the human hypothalamus and with DA as a substrate for both forms in this region, if it is assumed that the hypothalamic concentrations of the drug during the period 0–9 hours was sufficiently high to inhibit DA deamination by both forms of MAO.
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  • 25
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    European journal of clinical pharmacology 26 (1984), S. 129-131 
    ISSN: 1432-1041
    Keywords: aprindine ; antiarrhythmic agent ; healthy volunteers ; plasma level ; oral administration ; pharmacokinetics ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t1/2β) increased from 8.0±2.1 h (SD) after a 25 mg dose to 9.4±2.9 h after 50 mg and to 15.8±2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (Vdss/F) and during β-phase (Vdβ/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (Cmax) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t1/2β after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.
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  • 26
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    European journal of clinical pharmacology 26 (1984), S. 603-608 
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; pinacidil pyridine-N-oxide ; urinary excretion ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7±6.0 mmHg. Maximum rise in heart rate was 23.8±6.6 beats/min. Pinacidil serum distribution half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\alpha }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\alpha }$}}}$$ ) was 13.4±8.5 min and elimination half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\beta }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\beta }$}}}$$ ) was 2.13±0.49 h. The apparent volume of distribution (Vdβ) was 90.3±13.21 and total body clearance was 31.1±9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40–400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 ± 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6±9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.
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  • 27
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    European journal of clinical pharmacology 26 (1984), S. 761-767 
    ISSN: 1432-1041
    Keywords: drug absorption ; intoxication ; activated charcoal ; disopyramide ; indomethacin ; trimethoprim ; healthy volunteers ; adsorption capacity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of various charcoal-to-drug ratios for the absorption of drugs was studied in 6 healthy volunteers and in vitro at two pHs. Disopyramide 200 mg, indomethacin 50 mg and trimethoprim 200 mg were ingested on an empty stomach with 100 ml water. After 5 min the subjects ingested a charcoal suspension in 300 ml — 2.5 g, 10 g, 25 g or 50 g of Norit A, or 10 g of PX-21, or water 300 ml only. Increasing the dose of activated charcoal from 2.5 g to 50 g reduced the gastrointestinal absorption of disopyramide and indomethacin from 30–40% to 3–5%, and that of trimethoprim from 10% to 1% of the respective controls. Disopyramide and trimethoprim were best adsorbed by charcoal in vitro at neutral and indomethacin at acid pH, but saturation of the adsorption capacity was apparent at charcoal-to-drug ratios less than 7.5. Combining the in vitro and in vivo results it can be concluded that the dose of activated charcoal to be given in acute intoxication should be as large as possible, because the drug history is often unknown.
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  • 28
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    European journal of clinical pharmacology 27 (1984), S. 75-80 
    ISSN: 1432-1041
    Keywords: bupropion ; alcohol interaction ; healthy volunteers ; performance ; autonomic functions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of bupropion and ethanol were examined alone and in combination in a placebo controlled, double-blind, crossover study in 12 healthy volunteers. Results were subjected to analysis of variance and differences ofp〈0.05 taken as significant. In the main study using the Wilkinson auditory vigilance test, no active treatment or combination of treatments produced significant change compared with placebo. However, when compared with bupropion 100 mg, vigilance was significantly impaired by 32 ml alcohol alone though not when combined with bupropion. No significant changes in reaction time or short term memory occurred. Visual analogue scales indicated that the subjects were mentally slower after alcohol 32 ml than after placebo. Combination of bupropion 100 mg with alcohol 32 ml abolished this difference. A similar pattern occurred with group ratings indicating mental sedation. Subjects were clearly able to differentiate between the 16 ml and 32 ml doses of alcohol when assessing their degree of inebriation. Combination of bupropion with alcohol made no difference to the ratings of inebriation. The top dose of alcohol tended to increase energy in the low frequency EEG bands. Combination of the top alcohol dose with bupropion, however, produced a significant reversal with lowered energy in the 4–7.5 Hz band. Combination of bupropion with alcohol failed to change the blood alcohol concentration achieved.
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  • 29
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    European journal of clinical pharmacology 27 (1984), S. 23-27 
    ISSN: 1432-1041
    Keywords: hypertension ; alpha2-adrenoceptors ; blood pressure ; clonidine ; guanfacine ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time courses of the changes in plasma growth hormone and noradrenaline concentrations in response to 15 min infusions of clonidine 0.2 mgs and guanfacine 2 mgs, were studied in six normal volunteers, in a double-blind, randomised, crossover study. Plasma noradrenaline fell within 15 min of the commencement of drug administration, by 36±14% after clonidine (p〈0.05) and by 32±11% (p〈0.05) after guanfacine. Plasma growth hormone was not significantly elevated until the 30th minute to 12.0±4.7 lU/ml (p〈0.05) after clonidine and 14.7±11.5 lU/ml (p〈0.05) after guanfacine, having been undetectable prior to both drugs. The reduction in plasma noradrenaline by these α2-adrenergic agonists, prior to activation of central adrenoceptors as detected by changes in plasma growth hormone, is evidence for a peripheral component in their sympatholytic effect.
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  • 30
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    European journal of clinical pharmacology 27 (1984), S. 119-121 
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
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  • 31
    ISSN: 1432-1041
    Keywords: acetylsalicylic acid ; platelet function ; salicylate ; controlled release formulation ; single dosing ; continuous dosing ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The extent to which a controlled release acetylsalicylic acid (ASA) formulation inhibited platelet function has been evaluated in single and chronic dosing studies. In the single dose study, the platelet inhibitory effect of the controlled release formulation was compared with that of an equivalent dose of soluble ASA and an equimolar dose of sodium salicylate (SA). In the chronic dosing study, ASA dose-response curves for platelet function, including cyclooxygenase activity, were determined for various doses (20–1300 mg) of the controlled release (enteric coated pellets) ASA formulation taken by volunteers daily for one week. Platelet function was assessed by the degree of inhibition of aggregation for several aggregating agents, and the degree of inhibition of activity of platelet cyclooxygenase quantified by the estimation of malondialdehyde (MDA) production. Plasma ASA and SA concentrations were also determined in each study. The controlled release product inhibited platelet function to the same extent as an equimolar dose of soluble ASA, but did so with much lower and sometimes undetectable peak systemic plasma ASA concentrations. SA, the direct metabolite of aspirin, did not have any effect on platelet function. The ASA dose-platelet function response curves obtained from chronic dosing with the controlled release formulation appeared to be similar to those reported previously for the soluble product. The inhibition of platelet function appeared to be unrelated to plasma ASA concentrations.
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  • 32
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    European journal of clinical pharmacology 27 (1984), S. 115-117 
    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; Ro 15-1788 ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (〈0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.
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  • 33
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    European journal of clinical pharmacology 27 (1984), S. 335-339 
    ISSN: 1432-1041
    Keywords: transdihydrolisuride ; dopamine agonist ; pharmacokinetics ; pharmacodynamics ; prolactin levels ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and urinary excretion of the dopamine agonist, transdihydrolisuride (TDHL), were measured by radioimmunoassay in healthy male volunteers given TDHL 50 µg i.v. and oral doses of 200, 400 and 800 µg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of TDHL declined with a half-life of 37±19 min. The total clearance was 38±27 ml/min/kg and the apparent volume of distribution was 1.3±0.4 l/kg. The bioavailability of oral TDHL was proportional to the dose; after 200, 400 and 800 µg the bioavailability was 20±25%, 31±24% and 48±26%. TDHL was almost totally metabolized and less than 0.5% of the dose was excreted unchanged in urine in 24 h. Plasma prolactin levels were depressed by 66±15%, 75±11% and 80±7% after TDHL 200 µg, 400 µg and 800 µg. The effect lasted for more than 12 h after the lowest dose and for more than 24 h after 400 and 800 µg. Side effects, mainly nausea and headache, only occurred at the two highest dose levels.
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  • 34
    ISSN: 1432-1041
    Keywords: molsidomine ; vasodilators ; pharmacokinetics ; pharmacodynamics ; dose-response relationship ; haemodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 12 healthy male volunteers, molsidomine 1, 2 and 4 mg i.v. increased resting heart rate and decreased systolic blood pressure, the latter still being affected after 8 hours. After single oral doses of 1 and 2 mg, systolic pressure tended to be reduced for 90 minutes and exercise heart rate tended to be increased. After oral treatment with 2 mg molsidomine three times daily for 1 week, the pharmacokinetic parameters and the effects on heart rate and blood pressure after the final dose were not different from those after the first dose. The terminal half-life was independent of dose and route of administration. Clearance and distribution volume were not dose-dependent. The bioavailability of a 2 mg oral dose of molsidomine was 44%. Inter-individual variation in heart rate, blood pressure and pharmacokinetics was observed.
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  • 35
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    European journal of clinical pharmacology 27 (1984), S. 303-306 
    ISSN: 1432-1041
    Keywords: frusemide ; renal function ; ageing ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of IV frusemide was studied in six healthy young (mean age 26.5 years, range 21–33) and six healthy old (mean age 72.8 years, range 66–80) volunteers. A 24-h urine collection before frusemide showed no difference in volume and sodium excretion, although the old excreted less potassium. Creatinine clearance was significantly reduced in the older subjects. After frusemide, 20 mg IV, the pattern of sodium and water excretion over a 5-h period was different in the two groups. The peak effect was greater in the young and occurred within the first 30 min, but was delayed to between 30 and 60 min in the old. Thus in the young the time for 50% of the total sodium and water to be excreted was half that in the old. This delay in sodium and water excretion was related to baseline creatinine clearance. However, the total water, sodium and potassium excreted in the 5 h after frusemide did not differ in the two groups. These results suggest that the renal effects of frusemide are different in healthy elderly subjects as compared to the young. The delayed and reduced peak response is consistent with fewer nephrons in the elderly kidney.
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  • 36
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    European journal of clinical pharmacology 27 (1984), S. 319-324 
    ISSN: 1432-1041
    Keywords: theophylline ; enprofylline ; terbutaline ; haemodynamic response ; adenosine antagonism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic response to two xanthines, enprofylline and theophylline, was studied in 6 healthy male volunteers at rest, during exercise and in combination with the beta2-agonist, terbutaline. At rest the haemodynamic effects of both xanthines were small and were qualitatively different from each other. While theophylline exerted a “pressor” response, enprofylline seemed to have arterial dilating ability. During exercise both xanthines as compared to placebo were associated with a higher heart rate and in general with increased systolic blood pressure. In combination with terbutaline enprofylline and theophylline both increased systolic blood pressure more than placebo, i. e. they augmented the positive inotropic effect of terbutaline. The systolic blood pressure was higher after theophylline than enprofylline despite their equipotent bronchodilator activity. This may reflect different inotropic effects of the xanthines as well as a difference in their influence on the response to adenosine.
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  • 37
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    European journal of clinical pharmacology 27 (1984), S. 325-328 
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release ; pharmacokinetics ; chronic administration ; healthy volunteers ; plasma levels ; GCMS assay ; stable isotope technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new sustained-release preparation of theophylline (Dilatrane à Action Prolongée capsules filled with homogenous microgranules) has been after its studied administration to 7 healthy volunteers at 8 p.m. in order to achieve therapeutic levels at night and in the morning. In separate trials the test dose of 500 or 600 mg was administered for 7 days, once daily at 8 p.m. Plasma theophylline levels were measured by capillary gas chromatography with a mass specific detector after pentylation, using internal standards labelled with stable isotopes (15N-1,3 and 13C-2 theophylline). The new sustained-release preparation showed a monophasic regular absorption phase with very low interindividual variability. After administration, the plasma level stayed within 80% of the peak levels for 8.5±1.5 h. There was a good correlation between the dose and the steady state plasma level (r=0.9587; p〈0.05). This preparation can be chronically administered once daily day at 8 p.m. in order to achieve a therapeutic level during the night and the morning, and to provide sufficient protection during the nycterohemeral period, with a once dose a day schedule.
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