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  • Articles  (323)
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  • Chemistry and Pharmacology  (323)
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  • Articles  (323)
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  • Springer  (323)
  • American Institute of Physics (AIP)
  • Blackwell Publishing Ltd
  • Oxford University Press
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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 631-634 
    Details
    ISSN: 1432-1041
    Keywords: salbutamol ; albuterol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min−1·1.73 m−2. Peak plasma concentrations of 10–20 ng·ml−1 were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02456001
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  • 2
    Electronic Resource
    Electronic Resource
    A comparison of the effects of fluvoxamine and amitriptyline on autonomic functions in healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 529-533 
    Details
    ISSN: 1432-1041
    Keywords: Fluvoxamine ; Amitriptyline ; antidepressants ; cholinergic functions ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have compared the effects of single oral doses of fluvoxamine (50 mg and 100 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced, double-blind, crossover design. Amitriptyline significantly reduced salivation, the miosis evoked by locally applied pilocarpine, and the sweat secretion evoked by locally applied carbachol. Fluvoxamine also significantly attenuated carbachol-evoked sweat gland activity, although to a smaller degree than amitriptyline; fluvoxamine did not significantly alter salivation or pilocarpine-evoked miosis. Neither treatment significantly altered the miotic responses evoked by brief light stimuli. Heart rate and blood pressure were not greatly affected by either treatment, although the fall in heart rate (erect posture) with placebo was significantly reduced by amitriptyline (100 mg). The results suggest that fluvoxamine has some antimuscarinic activity in man, but is considerably less potent in this respect than amitriptyline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314863
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  • 3
    Electronic Resource
    Electronic Resource
    The effect of exercise on atropine pharmacokinetics (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 395-397 
    Details
    ISSN: 1432-1041
    Keywords: atropine ; exercise ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the mean volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t1/2, 4.2 vs 3.5 h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 ml·min−1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml−1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml−1). In T5, Ex significantly decreased the t1/2 (3.4 h), Vz (182 l) and CL (575 ml·min−1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min−1), elimination rate constant (ke, 0.0012 vs 0.0015 min−1), Cp (14 ng·ml−1) and AUC (53.3 ng·h·ml−1). These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315417
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  • 4
    Electronic Resource
    Electronic Resource
    Comparative antidotal efficacy of activated charcoal tablets, capsules and suspension in healthy volunteers (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 501-505 
    Details
    ISSN: 1432-1041
    Keywords: activated charcoal ; antidotal efficacy ; healthy volunteers ; formulation ; paracetamol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of several formulations of activated charcoal (AC) was compared by measuring the intestinal absorption of a solution of 1 g paracetamol administered 2 min before administration of 5 g AC as suspension (200 ml), tablets (40 of 125 mg) or capsules (25 of 200 mg). The suspension medium without AC was used as the control treatment. Based on the results of a pilot experiment, an 8 subject panel was used in a two 4×4 Latin square design. All treatments with AC resulted in a statistically significant decrease in paracetamol absorption compared to the control treatment. The suspension was considerably and significantly more effective than the tablets or capsules. Treatment with tablets was slightly but significantly more effective than capsules. The intake of large numbers of tablets and capsules was difficult. In the hospital AC suspensions are available. For first aid elsewhere, at home, at the working place or in the general practitioner's surgery a preservable and easily redispersible AC formulation would be preferable to the present solid forms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280944
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  • 5
    Electronic Resource
    Electronic Resource
    Endoscopic evaluation of the effect of ketoprofen, ibuprofen and aspirin on the gastroduodenal mucosa (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 685-687 
    Details
    ISSN: 1432-1041
    Keywords: NSAID ; Gastrotoxicity ; gastroscopy ; healthy volunteers ; ibuprofen ; ketoprofen ; aspirin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Endoscopic lesions of the gastric mucosa were evaluated in 12 healthy volunteers after administration of single doses of ketoprofen (25 mg), ibuprofen (200 mg) and aspirin (500 mg) in a randomized, double-blind, crossover study. The grades of the lesions (according to Lanza's scale) were lower after the administration of ketoprofen than aspirin and were comparable to ibuprofen. An endoscopic score 〉1 was observed in 3 cases after ibuprofen or ketoprofen, and in 8 cases after aspirin. At a time when low, single doses of NSAIDs are widely used as analgesics, gastroscopy makes it possible directly to assess the local agressivity of these molecules. In this way it was possible to demonstrate that the local toxicity of NSAIDs was lower than that of aspirin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265938
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  • 6
    Electronic Resource
    Electronic Resource
    Effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 675-679 
    Details
    ISSN: 1432-1041
    Keywords: Tolbutamide ; Magnesium hydroxide ; chlorpropamide ; gastrointestinal absorption ; drug interaction ; healthy volunteers ; plasma glucose ; plasma insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide was examined in a total of 32 healthy volunteers in two separate, randomized parallel-group studies, with 16 subjects in each study. After an overnight fast, the first group of 8 volunteers ingested 500 mg tolbutamide or 250 mg chlorpropamide with 150 ml water, and the second group the same doses of the active drugs with 150 ml water containing 850 mg magnesium hydroxide. Magnesium hydroxide increased the area under the plasma tolbutamide concentration-time curve (AUC) from 0 to 1 h and from 0 to 2 h by 5-fold and 2.5-fold, respectively. The peak plasma concentration, peak time and total AUC were not significantly altered. The incremental insulin area and the decremental glucose area from 0 to 1.5 h were significantly larger in the magnesium hydroxide group than in the controls. The maximum insulin response to tolbutamide was increased fourfold by coadministration of magnesium hydroxide, and it occurred about 1 h earlier than in the control group. In addition, the maximum fall in plasma glucose concentration was attained about 1 h earlier in the antacid group. A tendency to an increased rate of chlorpropamide absorption was observed after magnesium hydroxide, but it did not appear to affect the insulin and glucose responses to chlorpropamide. It is concluded that magnesium hydroxide increased the early bioavailability of tolbutamide, resulting in enhanced insulin and glucose responses. A tendency toward accelerated chlorpropamide absorption by magnesium hydroxide was also observed, but the efficacy of chlorpropamide was unaffected.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265936
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  • 7
    Electronic Resource
    Electronic Resource
    Absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in man (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 473-476 
    Details
    ISSN: 1432-1041
    Keywords: dDAVP ; bioavailability ; gastrointestinal tract ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i. v. administration the subjects received 4 μg dDAVP. For intestinal administration 400 μg dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA. Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i. v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml·min−1·kg−1, amount excreted in urine 2.0 μg and renal clearance was 0.8 ml·min−1·kg−1. The mean bioavailability (f) after gastric application was 0.19% (range 0.02–0.35%). f was 0.24% after duodenal application (range 0.04–0.62%), 0.19% after jejunal (range 0.01–0.41%), 0.03% after distal ileal (range 0.01–0.08%), 0.04% after proximal colonic (range 0.01–0.12%) and 0.04% after rectal (0.01–0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions. The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315546
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  • 8
    Electronic Resource
    Electronic Resource
    Differential cardiovascular effects of propranolol, atenolol, and pindolol measured by impedance cardiography (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 47-53 
    Details
    ISSN: 1432-1041
    Keywords: Atenolol ; Propranolol ; Pindolol ; transthoracic electrical bioimpedance ; cardiac output ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have evaluated Sramek's method of impedance cardiography as a non-invasive way of detecting the cardiovascular effects of drugs. We made cardiovascular measurements using the method during passive tilting and exercise 2 h after the oral administration of atenolol (50 and 100 mg), propranolol (40 and 80 mg), pindolol (5 and 10 mg), and placebo in seven separate studies involving eight healthy male volunteers. Equivalent doses of the pure antagonists atenolol (β1) and propranolol (β1, β2) produced similar reductions in heart rate, systolic blood pressure, and cardiac index, and increases in stroke volume and total peripheral resistance, particularly during exercise. In contrast the partial agonist pindolol produced increases in heart rate and cardiac index, and reductions in peripheral resistance at rest. During passive tilting and exercise pindolol reduced heart rate, but cardiac output and total peripheral resistance were unchanged except at the highest levels of exercise. The similar cardiovascular effects of atenolol and propranolol, but differing effects of pindolol, are consistent with reports using other methods of measurement. This suggests that impedance cardiography may have a place in the non-invasive assessment of the cardiovascular effects of drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314919
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 545-550 
    Details
    ISSN: 1432-1041
    Keywords: Ramipril ; Piretanide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0–4 h) and ramiprilat (0–24 h) (from 15.8 to 19.8 ng·ml−1·h, and from 63.4 to 74.6 ng·ml−1·h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73 % of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196113
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  • 10
    Electronic Resource
    Electronic Resource
    Effect of α1-adrenoceptor antagonists, prazosin and urapidil, on a finger skin vasoconstrictor response to cold stimulation (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 371-375 
    Details
    ISSN: 1432-1041
    Keywords: Prazosin ; Urapidil ; Vasoconstrictor response ; laser Doppler flow ; finger tip blood flow ; cold stimulation ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of α-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different α1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these α1-adrenoceptor antagonists in human subjects. Method: In thirteen healthy male subjects (20–42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). Results: Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The α1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. Conclusion: These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative α1-adrenoceptor blocking potency of drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00203780
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  • 11
    Electronic Resource
    Electronic Resource
    An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 459-463 
    Details
    ISSN: 1432-1041
    Keywords: Key words Corticosteroids; systemic effects ; plasma cortisol suppression ; white blood cell count ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The systemic effects of single and multiple doses of inhaled fluticasone propionate (FP) and budesonide were examined in 24 healthy male volunteers (age range 18–29 years). The study was of an open, placebo-controlled, randomized, three-way crossover design. On each study day, multiple blood samples were taken over a 20 h period after drug administration (after a single dose and after the last of seven doses) and area under the curve (AUC0–20) for plasma cortisol and white blood cell (WBC) counts was calculated. Results: The present study shows that multiple dosing with FP 1.0 mg b.i.d. for 3.5 days (seven doses) resulted in a marked cortisol suppression from placebo which, at 55%, was more than double that seen with a single dose (25% suppression). Multiple dosing with budesonide 0.8 mg b.i.d. resulted in a 34% suppression in plasma cortisol compared with a suppression of 26% with a single dose. The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts. Conclusion: The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose. This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050050
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  • 12
    Electronic Resource
    Electronic Resource
    Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 513-518 
    Details
    ISSN: 1432-1041
    Keywords: Ramipril ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15 %, by ramiprilat plasma AUC, 44 %. Ramiprilat formation from intravenous ramipril was 53 % and from oral ramipril 28 %. Urinary recovery of oral ramipril was 23 %, i. v. ramipril 49 %, and i. v. ramiprilat 68 % of the given dose. Maximum ACE inhibition was highest (100 %) after i. v. ramiprilat; it was 99 % after i. v. ramipril and 84 % following oral ramipril. ACE inhibition over 24 h was highest after i. v. ramipril, 2 % less with i. v. ramiprilat and 34 % less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44–66 %.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193704
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  • 13
    Electronic Resource
    Electronic Resource
    Oral bioavailability of CHF1194, an inclusion complex of piroxicam and β-cyclodextrin, in healthy subjects under single dose and steady-state conditions (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 531-536 
    Details
    ISSN: 1432-1041
    Keywords: Piroxicam ; β-Cyclodextrin ; pharmacokinetics ; healthy volunteers ; multiple dose ; adverse event
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CHF1194 is an inclusion complex of β-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, β-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-β-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of β-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5′-hydroxypiroxicam and β-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80–125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5′-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with β-cyclodextrin. This may be of therapeutic interest as it might accelerate the onset of pain relief. The pharmacokinetics of piroxicam was linear after the doses used here, suggesting that long term treatment with CHF1194 should not require any change in dosing regimen. Even after 14 days of repeated administration of CHF1194, β-cyclodextrin could not be detected in plasma or urine, suggesting that in man the unchanged oligosaccharide was absorbed to a very small extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193707
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  • 14
    Electronic Resource
    Electronic Resource
    Insulin concentrations and insulin sensitivity after short-term amiloride in healthy subjects (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 469-472 
    Details
    ISSN: 1432-1041
    Keywords: Amiloride ; Insulin sensitivity ; hyperinsulinemic euglycemic clamp ; glucose utilization ; glucose production ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have evaluated the short-term effects of amiloride on insulin action in vivo, since amiloride is known to impair insulin action in vitro. Seven healthy subjects were treated according to a randomized, double-blind, cross-over protocol. The treatment periods were 3 days each with amiloride 15 mg daily and placebo. Insulin action on glucose turnover was assessed directly after each treatment period with the hyper-insulinaemic euglycaemic glucose clamp technique. At the two insulin concentrations studied (∼ 30 mU·l−1 and ∼ 200 mU·l−1), the glucose infusion rate required to maintain constant euglycaemia did not differ after either amiloride or placebo. The rates of glucose production and utilization were also similar, whereas the so-called insulin sensitivity index at the lower insulin concentration was significantly reduced (by about 15 %) after amiloride. Moreover, amiloride produced significantly higher fasting insulin and C-peptide concentrations, whereas fasting glucose and NEFA concentrations were unaltered. In conclusion, these data suggest that short-term amiloride slightly impairs insulin sensitivity with respect to glucose uptake. However, overall glucose homoeostasis does not appear to be affected, probably due to a compensatory rise in plasma insulin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191913
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  • 15
    Electronic Resource
    Electronic Resource
    Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 39-47 
    Details
    ISSN: 1432-1041
    Keywords: Dilevalol ; Propranolol ; intrinsic sympathomimetic activity ; healthy volunteers ; pulsed Doppler ; regional haemodynamics ; plasma renin activity ; plasma atrial natriuretic factor ; plasma norepinephrine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers. At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (−27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (−7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (−20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h). After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine. We conclude that the β2-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the β-adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the β-adrenoceptor antagonist activity of dilevalol was apparent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193476
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  • 16
    Electronic Resource
    Electronic Resource
    Effect of moxonidine on urinary electrolyte excretion and renal haemodynamics in man (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 203-208 
    Details
    ISSN: 1432-1041
    Keywords: Moxonidine ; Renal haemodynamics ; imidazoline receptors ; natriuresis ; blood pressure ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Moxonidine and related compounds have been recently introduced into antihypertensive therapy. It is thought that these drugs exert their blood pressure lowering effect through interaction with nonadrenergic receptors in the central nervous system, i.e. imidazoline receptors, although the contribution of specific interaction with α2-receptors is still under debate. Imidazoline receptors have recently been documented in the renal proximal tubule. In experimental studies, interaction of imidazolines with these receptors decreased the activity of the Na+/H+ antiporter and induced natriuresis. To quantitate the effect of the imidazoline receptor agonist moxonidine on renal sodium handling and renal haemodynamics in man, we examined ten healthy normotensive males (aged 25 ± 4 years) in a double blind placebo-controlled study using a crossover design. Subjects were studied on a standardized salt intake (50 mmol per day). On the 7th and 10th study day they were randomly allocated to receive either i.v. placebo or i.v. 0.2 mg moxonidine. Urinary electrolyte excretion, lithium clearance (as an index of proximal tubular sodium handling), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial blood pressure (MAP), plasma renin activity (PRA) and plasma noradrenaline (NA) levels were assessed. Injection of moxonidine did not increase fractional sodium excretion or lithium clearance. Specifically, antinatriuresis was not observed after injection of moxonidine despite a significant decrease in MAP from 91 to 85 mmHg and a significant increase in PRA. MAP and PRA did not change with administration of placebo. Injection of moxonidine did not affect GFR and RVR; ERPF decreased slightly but not significantly. Acute administration of 0.2 mg i.v. moxonidine decreased blood pressure in healthy volunteers on standardized salt intake, but did not affect natriuresis, proximal tubular sodium reabsorption or glomerular filtration rate. The absence of an antinatriuretic response despite a decrease in blood pressure suggests a direct facilitation of natriuresis by moxonidine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198299
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    Renal and endocrine effects of flosulide, after single and repeated administration to healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 193-201 
    Details
    ISSN: 1432-1041
    Keywords: Renal function ; Prostaglandins ; Flosulide ; non-steroidal anti-inflammatory drug ; renin-angiotensin-aldosterone ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Two double-blind, placebo-controlled, balanced cross-over studies were carried out successively in 8 male normotensive volunteers to investigate the acute and chronic effects of two doses of a novel non-steroidal anti-inflammatory drug flosulide (5 mg b.d. and 25 mg b.d.), on the renin-angiotensin-aldosterone system, linking this to changes in the urinary excretion of prostaglandins. Plasma renin and aldosterone were determined on Days 2 and 9, with the subject supine, after 1 h of rest in the sitting position following 1 h of walking, and 3 h after oral intake of 40 mg furosemide, also in the sitting position. Twenty-four hour urine samples were collected on Days 1 and 8 for the measurement of the electrolytes, aldosterone pH1 and the urinary prostaglandins PGE2, PGF2α, 6-keto-PGF1α and TxB2. Results: After the first day of treatment with 25 mg b.d. flosulide, the increase in body weight was close to significance (0.86 vs -0.08 kg with placebo). A dose-and time-dependent decrease in both active and inactive plasma renin were observed, whereas the fall in plasma and urinary aldosterone was statistically significant only after the higher dose of flosulide. These changes in the renin-angiotensin-aldosterone system were observed in the absence of oedema. Two out of eight volunteers experienced a strong and immediate reduction in the excretion of prostaglandins but overall the two doses tested did not produce a statistically significant inhibition in renal prostaglandins, especially following repeated dosing. The inhibitory effect of flosulide on renal prostaglandin synthesis was found to be less pronounced after repeated treatment, as documented on Day 9 by the lower inhibition of 6-keto-PGF1α and TxB2. Conclusion: These two studies in normal volunteers, in spite of some methodological limitations, were helpful in order to select doses of flosulide which should be effective and safe in patients during Phase II trials, by examining the inhibitory effect of the drug on renin synthesis and renal prostaglandin synthesis.
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    URL: http://dx.doi.org/10.1007/BF00192379
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    Pharmacokinetics of nicardipine enantiomers in healthy young volunteers (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 289-292 
    Details
    ISSN: 1432-1041
    Keywords: Key words Nicardipine; enantiomers ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P 〈 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose.
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    URL: http://dx.doi.org/10.1007/s002280050292
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  • 19
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    Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 441-449 
    Details
    ISSN: 1432-1041
    Keywords: Key words Angiotensin II ; Valsartan; AT1 receptor antagonist ; healthy volunteers ; pharmacokinetics ; renin-angiotensin system ; blood pressure ; passive tilting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet. Methods: This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. Results: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t½λ1 〈 1 h), followed by a slower terminal elimination phase (t½λ2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of −3.6 and −2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (−2.0 mmHg) and day 8 (−4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats · min−1 on day 1 and by 2.9 beats · min−1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion. Conclusions: Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.
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    URL: http://dx.doi.org/10.1007/s002280050317
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  • 20
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    Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 471-477 
    Details
    ISSN: 1432-1041
    Keywords: Key words Felodipine ; metoprolol; combined extended release formulation ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding Cmax of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination.
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    URL: http://dx.doi.org/10.1007/s002280050321
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  • 21
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    Comparison of the cardiovascular effects of nifedipine and nicardipine in the presence of atenolol (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 201-206 
    Details
    ISSN: 1432-1041
    Keywords: Nifedipine ; Nicardipine ; Atenolol ; cardiac output ; impedance cardiography ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A placebo controlled double blind crossover study was performed in 12 healthy volunteers to compare the cardiovascular effects of single oral doses of nifedipine (5, 10 and 15 mg) and nicardipine (20 and 30 mg) in the presence of atenolol 100 mg. Haemodynamic measurements were made by transthoracic electrical bioimpedance cardiography (TEBC) 2 h following drug administration during passive tilting, graded bicycle exercise (30–150 W), and recovery from exercise. In the absence of calcium channel blockade, atenolol reduced mean blood pressure, heart rate, and cardiac index, and increased stroke volume, peripheral resistance, pre-ejection period, and ventricular ejection time, particularly during and after exercise. In comparison with atenolol alone, addition of nifedipine or nicardipine reduced peripheral resistance but did not produce significant changes in stroke volume, cardiac output, dZ/dt[max], pre-ejection period (PEP), Ventricular ejection time (VET), PEP/VET, or Heather index at any point in the experiment. Similar reductions in peripheral resistance were produced by nifedipine 10 mg and nicardipine 20 and 30 mg. These apparently equivalent doses of nifedipine and nicardipine had similar effects on stroke volume, cardiac index, PEP/VET and Heather index. Thus the increases in ventricular performance previously demonstrated in association with nifedipine and nicardipine therapy were not observed in the presence of β-adrenoceptor blockade. Under these conditions no important differences have been observed in the cardiovascular effects of these two calcium channel blockers.
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    URL: http://dx.doi.org/10.1007/BF00315430
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  • 22
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    Effect of loperamide on jejunal electrolyte and water transport, prostaglandin E 2-induced secretion and intestinal transit time in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 239-243 
    Details
    ISSN: 1432-1041
    Keywords: Loperamide ; Intestinal perfusion ; absorption ; transit time ; healthy volunteers ; intestinal transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit. In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2–8 mg·l−1). The volunteers were pretreated with 1 mg·l−1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg·l−1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT). Loperamide 2 mg·l−1 converted the minor secretion after perfusion with the standard solution (water −1.45 ml·min−1, Na −0.09 and Cl −0.04 mmol·min−1) to absorption (water 0.93 ml·min−1, Na 0.23, Cl 0.25 mmol·min−1) within 15 min. Higher doses of loperamide did not increase absorption. The addition of PgE2 induced net secretion of water (−4.48 ml·min−1) and electrolytes (Na −0.57, Cl −0.51 mmol·min−1). Loperamide 4 mg·l−1 significantly diminished the PgE2-induced net secretion by approximately 50%. Loperamide dose dependently increased the MTT from 6 (2 mg·l−1) to 13.3 min (8 mg·l−1). MTT was still delayed 60 min after a wash out period (10.5 min). It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.
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    URL: http://dx.doi.org/10.1007/BF00315436
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    Plasma insulin during physiological and pathophysiological changes in atrial natriuretic factor (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 453-455 
    Details
    ISSN: 1432-1041
    Keywords: Insulin ; Atrial natriuretic factor ; natriuresis ; healthy volunteers ; renal function ; sodium metabolism ; water metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Changes in plasma insulin in response to a physiological or pathophysiological elevation in circulating atrial natriuretic factor (ANF) have been investigated. Plasma insulin, glucose, immunoreactive (ir) ANF, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), absolute and fractional excretion of sodium (FENa), have been measured in 14 volunteers before and during infusion of low doses of ANF or vehicle (V). Each subject received single-blind in a randomized sequence at 2 week-intervals: V alone, or ANF 4, 8 and 16 ng·kg−1·min−1, indused over 90 min. Plasma irANF was increased 2.5- to 11-fold during the ANF infusion as compared to the test with the vehicle. Plasma insulin did not change during V administration (baseline vs V: 22 vs 21 μU·ml−1) and was unchanged during ANF at 4, 8 and 16 ng·kg−1·min−1 (19, 19, 21 μU·ml−1, respectively). Blood pressure, ERPF and GFR were not affected, and diuresis, FENa and urinary Na excretion were increased significantly and dose-dependently during ANF, but not V infusion. Compared to baseline, ANF 4, 8 and 16 ng·kg−1·min−1 increased urinary Na excretion by 147, 241 and 446 μmol·min−1, respectively. The findings indicate that, in normal humans, an acute increase in irANF within or slightly above the physiological range, which modified natriuresis and diuresis, did not alter circulating plasma insulin.
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    URL: http://dx.doi.org/10.1007/BF00280135
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    Placebo controlled comparison of acute effects of ebastine and clemastine on performance and EEG (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 55-59 
    Details
    ISSN: 1432-1041
    Keywords: Ebastine ; Clemastine ; H1-receptor antagonist ; psychomotor performance ; healthy volunteers ; vigilance ; cognitive performance adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of single oral doses of 10 and 20 mg ebastine were compared with placebo and 2 mg clemastine in a double-blind cross-over study in 16 healthy male volunteers. Clemastine produced the known pattern of changes, namely impairment of psychomotor performance, drowsiness, and a selective effect on cognitive processes. Earlier encoding in a perceptual stage was slowed whereas abstract classification processes were not affected. Electrophysiological measures of vigilance showed a general decrease in vigilance especially 2.5 and 4.5 h after dosing. In contrast at no time was any effect of ebastine different from that of the placebo. Ebastine 10 and 20 mg differed positively from clemastine in its effect on pursuit tracking, subjective rating of drowsiness and general discomfort. Ebastine 10 mg also differed positively from clemastine in the EEG features of vigilance. It is concluded that 10 and 20 mg ebastine were free from sedative adverse effects.
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    URL: http://dx.doi.org/10.1007/BF00314920
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    A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)·Pro·NH2 (BW443C)] in healthy volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 67-71 
    Details
    ISSN: 1432-1041
    Keywords: BW443C ; enkephalin ; opioid peptide ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg−1 for 60 min and increasing to a maximum of 2.0 µg·kg−1·min−1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 µg·kg−1·min−1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN. Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations 〉0.8 µg·ml−1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60–90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations. The disposition of the peptide was adequately described by a 2-compartment model with a mean ± SD plasma clearance of 123±18 ml·min−1 and a half-life of 2.0±0.4 h.
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    URL: http://dx.doi.org/10.1007/BF01061420
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  • 26
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    Beta-blockade antagonism of tyramine-induced rise in blood pressure (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 263-266 
    Details
    ISSN: 1432-1041
    Keywords: tyramine ; propranolol ; pressure response ; blood pressure ; beta-adrenoceptor blockers ; healthy volunteers ; indenolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect β-adrenoceptor blockade on the pressor response to tyramine has been investigated in 6 healthy volunteers, each submitted to an i.v. tyramine pressor test before and after 7 days of propranolol 40 mg b.d. or indenolol 60 mg o.d. Tyramine was given as i.v. boluses of 1–6 mg, alternating with saline, in a randomized, single blind fashion. Prior to treatment tyramine caused a temporary, dose-dependent increase in systolic and diastolic blood pressure, whilst the heart rate remained unaffected. Both propranolol and indenolol reduced the pressor response to tyramine, as shown by a significant increase in ED15, i.e. the dose of tyramine required to increase systolic blood pressure by 15%.
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    URL: http://dx.doi.org/10.1007/BF00540953
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  • 27
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    Effect of the calcium antagonists nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal motility in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 313-316 
    Details
    ISSN: 1432-1041
    Keywords: Calciumantagonists ; Oesophageal motility ; oesophageal pharmaco-manometry ; lower oesophageal sphincter pressure ; healthy volunteers ; dihydropyridines ; nifedipine ; nifedipine ; nisoldipine ; nitrendipine ; nimodipine ; side ; effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30 min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline (−15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24% by nifedipine and 17% by nimodipine, whereas the effects of nitrendipine (decrease of 15%) and nisoldipine (9%) were not significant. Nifedipine significantly decreased by 17% the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r=0.92, nitrendipine r=0.80 and nisoldipine r=0.79. Nimodipine showed no such correlation. It is concluded that among the calcium antagonists studied, nifedipine exerted the strongest effect on oesophageal smooth muscle function, so it appears to be the most suitable compound for the treatment of primary motor abnormalities of the oesophagus.
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    URL: http://dx.doi.org/10.1007/BF00314958
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    Non invasive study of systemic and regional haemodynamic and cardiac effects of a new calcium antagonist, SR 33557, in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 329-334 
    Details
    ISSN: 1432-1041
    Keywords: Calcium antagonist ; Doppler techniques ; regional haemodynamics ; cardiac effects ; healthy volunteers ; SR 33 557 ; heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic and regional haemodynamic and cardiac effects of two oral doses (100 and 300 mg) of a new sulphone-indolizine calcium antagonist SR 33 557 (SR) and a placebo were non invasively investigated in a double-blind, cross-over study in 6 healthy male volunteers. Arterial pressure, heart rate, cardiac output, brachial and carotid artery diameters and flows and PR and QT intervals were studied. Stroke volume, total peripheral and forearm vascular resistance, regional cardiac output distribution indices and corrected QT intervals were calculated. SR did not produce any significant modification in systemic haemodynamics, although arterial pressure and cardiac output tended to decrease slightly after 300 mg. In contrast, at the regional level, ST produced strong vasodilatation and significantly increased brachial and carotid blood flow. SR-induced vasodilation affected only the arterioles, as shown by a significant decrease in forearm vascular resistance, but not the large arteries, as shown by lack of change in the brachial and carotid artery diameters. SR-induced vasodilation preferentially affected the brachial rather than the carotid vascular bed, resulting in a redistribution of cardiac output towards the musculo-cutaneous territories. SR caused a marked and long-lasting decrease in heart rate, but it did not affect the auriculo-ventricular conduction time.
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    URL: http://dx.doi.org/10.1007/BF00314962
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    Role of cytochrome P4502D6 in the metabolism of brofaromine (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 265-269 
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    ISSN: 1432-1041
    Keywords: Brofaromine ; Debrisoquine oxidation ; MAO-A inhibitor ; polymorphism ; quinidine ; healthy volunteers ; cytochrome P450 ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0−∞) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0–72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.
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    URL: http://dx.doi.org/10.1007/BF00315394
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    The effects of single doses of CL 284,846, lorazepam, and placebo on psychomotor and memory function in normal male volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 313-320 
    Details
    ISSN: 1432-1041
    Keywords: Lorazepam ; CL284,846 ; Psychomotor performance ; memory function ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of single doses of CL284,846 (20 mg), lorazepam (2 mg) and placebo on psychomotor performance, memory function and subjective feelings were assessed in 12 normal, healthy male volunteers. Each subject received each treatment in balanced order and a minimum of 6 days was left between treatments. The subjects performance on a comprehensive battery of tests of psychomotor performance, memory function and subjective ratings was assessed pre-treatment and at 1, 3 and 5 h post-treatment. In general, the effects of CL284,846 on memory were similar to those of lorazepam at 1 h post-treatment but, recovery was rapid with CL284,846. Impairments induced by lorazepam persisted throughout the post-drug testing sessions. This pattern of effects was repeated across most of the variables tested. However, at 1 h, CL284,846 produced less marked psychomotor impairment than lorazepam. The results of this study suggest that CL284,846 is a safe, rapid acting and effective sedative with some clear advantages over lorazepam with respect to unwanted cognitive and psychomotor impairments.
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    URL: http://dx.doi.org/10.1007/BF00265947
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    The assessment of the systemic effects of inhaled glucocorticosteroids (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 11-16 
    Details
    ISSN: 1432-1041
    Keywords: Budesonide ; Prednisolone ; calcium ; phosphate ; healthy volunteers ; osteoporosis ; mineral metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomized, double-blind crossover study, the effects of 0.8, 1.6 and 3.2 mg/day inhaled budesonide and 5, 10 and 20 mg/day oral prednisolone on mineral metabolism were compared. Twelve healthy subjects (4 m, 8 f) were treated for 1 week at each dosage level, the graduated dosages being given in ascending order. Budesonide and prednisolone were given twice daily and once daily, respectively, which reflects the schedules common in clinical practice. Serum calcium and the regulatory hormones of calcium metabolism (parathyroid hormone, vitamin D metabolites and calcitonin) were not changed either by prednisolone or budesonide. Prednisolone significantly increased 24 h and 08.00 h fasting urinary calcium excretion and decreased renal calcium reabsorption, while budesonide had little or no effect on urinary calcium loss and increased renal reabsorption at the highest dose level. Both drugs significantly increased renal phosphate reabsorption and serum phosphate levels, but prednisolone caused greater increases than budesonide. In conclusion, during short-term treatment with the dosages used, inhaled budesonide had less effect on calcium and phosphate metabolism than oral prednisolone, and so it may have a lesser action on the skeleton of the type contributing to osteoporosis during long-term treatment.
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    The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 27-33 
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    ISSN: 1432-1041
    Keywords: Nicorandil ; vasodilator ; tolerance study ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 μg·kg−1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing. All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 μg·kg−1). Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (〈20%) systemic clearances and larger values of Cmax and AUC. Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 μg·kg−1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 μg·kg−1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 μg·kg−1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.
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    Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 41-47 
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    ISSN: 1432-1041
    Keywords: Buspirone ; pharmacokinetics ; renal impairment ; hepatic impairment ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (Cmax) and area under the curves (AUC) of buspirone and 1-PP on Days D 5 and 10 were higher than on Day D 1. The trough levels (Cmin) and AUCs (D 5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher Cmax and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers. There was no correlation between the average plasma concentrations of buspirone ( $$\bar C$$ ) and the degree of renal impairment judged by creatinine clearance. An excellent correlation was observed between $$\bar C$$ of buspirone and serum albumin (r=0.862, and P〈0.0001) as well as between $$\bar C$$ and bromsulphalein clearance (r=0.678, P〈0.0003). In view of high intra-and inter-subject variability in buspirone concentrations, definitive dosing recommendations for patients with compromised renal or hepatic function could not be made, but such patients should initially be dosed cautiously with buspirone.
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    Plasma thiamine concentrations after intramuscular and oral multiple dosage regimens in healthy men (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 219-222 
    Details
    ISSN: 1432-1041
    Keywords: Thiamine ; pharmacokinetics ; analytical method ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel liquid chromatographic method for the determination of thiamine in plasma has been developed and has been used to study plasma thiamine concentrations after multiple dosage regimens for 11 days. The method involves purification, concentration and analytical separation of thiochrome on-line, using a switching column system. Ten healthy men were given 500 mg thiamine i.m. once a day (Group 1) and ten were given 250 mg p.o. every 12 h (Group 2). The times to reach steady state (7 and 5.6 days for Groups 1 and 2, respectively) were not different (P〉0.05). The mean elimination half-life was 1.8 days. The mean minimum steady-state concentration after the oral regimen (23 μg·l−1) was 78% of that after the intramuscular regime (29 μg·l−1).
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    No effect of cisapride on paracetamol absorption after oral simultaneous administration (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 235-236 
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    ISSN: 1432-1041
    Keywords: Cisapride ; Paracetamol absorption ; gastric emptying ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have measured the effect of oral cisapride on paracetamol absorption in 12 healthy volunteers in a double-blind placebo-controlled study. Volunteers received paracetamol plus placebo, paracetamol plus cisapride 10 mg and paracetamol plus cisapride 20 mg. Mean plasma paracetamol AUC at 60 min were 1070, 1051 and 1031 μg·min·ml−1 and maximum paracetamol concentrations were 31.5, 29.3 and 27.4 μg·ml−1 respectively (no significant differences). There was no difference also in time to maximum paracetamol concentration [median (range) 30 (15–120), 30 (15–90) and 30 (15–60) min, respectively].
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    The effect of oxprenolol dosage time on its pharmacokinetics and haemodynamic effects during exercise in man (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 171-176 
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    ISSN: 1432-1041
    Keywords: Oxprenolol ; β-adrenoceptor blockade ; circadian rhythm ; haemodynamics ; pharmacokinetics ; exercise ; healthy volunteers ; kinetic-dynamic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effect of dosage time of oxprenolol (Trasicor®) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses. There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P=0.04) and for elimination half-life (P=0.006). Both were lowest after administration at 14.00 h (163 (77) l and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) l, and 1.7 (0.6) h). The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P=0.03). The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and Emax did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.
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    The pharmacokinetics and pharmacodynamics of metoprolol after conventional and controlled-release administration in combination with hydrochlorothiazide in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 161-163 
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    ISSN: 1432-1041
    Keywords: Metoprolol ; controlled-release formulation ; hydrochlorothiazide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers ; efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied a controlled-release formulation containing metoprolol 100 mg and hydrochlorothiazide 12.5 mg. We compared the pharmacokinetics of both substances and the pharmacodynamics of metoprolol with those of a conventional combination tablet. The controlled-release formulation gave less variable plasma metoprolol concentrations, Cmax 138 nmol·l−1 and Cmin 74 nmol·l−1, whereas for the conventional formulation the mean Cmax of metoprolol was 629 nmol·l−1 and the Cmin 20 nmol·l−1. Despite lower relative systemic availability (68%) for metoprolol from the controlled-release formulation and a smaller AUC, metoprolol from the controlled-release formulation produced a greater total effect, calculated as the area under the curve of the effect on exercise heart rate vs. time (303 vs. 259%·h; P〈0.05). Hydrochlorothiazide was rapidly absorbed from both formulations and the plasma concentration profiles were almost superimposable. Controlled-release metoprolol with hydrochlorothiazide combines effective β1-adrenoceptor blockade for 24 h without affecting the pharmacokinetics of hydrochlorothiazide.
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    The acute effects of amiloride and potassium canrenoate on digoxin-induced positive inotropism in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 195-196 
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    ISSN: 1432-1041
    Keywords: Digoxin ; Amiloride ; Canrenoate ; inotropism ; healthy volunteers ; potassium sparing diuretics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00315506
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    Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 411-415 
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    ISSN: 1432-1041
    Keywords: Moxisylyte ; pharmacokinetics ; intracavernous administration ; healthy volunteers ; adverse events ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The concentration-time profiles of specific metabolites of moxisylyte, an α-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). Results: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. Conclusion: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.
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    Central effects of repeated administration of atenolol and captopril in healthy volunteers (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 23-28 
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    ISSN: 1432-1041
    Keywords: Atenolol ; Captopril ; Central effects ; short term administration ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The central effects of atenolol (50 mg tds) and captopril (50 mg tds) ingested for a period of seven days were studied in ten healthy volunteers. A placebo and two active control drugs, methyldopa (250 mg tds) and oxazepam (10 mg), were included in the design. Oxazepam was ingested on the seventh day only, with a placebo being taken on the preceding six days. On the seventh day, central effects of the drugs were tested at 10.00–11.00 h (session 1), immediately before the subjects' last dose of each drug and at 2.5–3.5 h after the final dose of each drug (1330–1430 h, session 2). Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. Recordings of the EEG and body sway were carried out. Neither atenolol nor captopril altered performance at any of the skills tested. There were no effects on subjectively assessed alertness or mood with captopril, while atenolol significantly increased wakefulness in session 2 and when the two sessions were meaned. Similarly, captopril did not modify body sway, while with atenolol there was a significant decrease in activity in the frequency range 1.0–2.75 Hz from session 1 to session 2. Both captopril and atenolol modified the electrical activity of the brain, with captopril increasing delta and theta activity and atenolol reducing delta, alpha and beta activity. Methyldopa significantly increased the number of involuntary rest pauses in the finger tapping task, and the choice reaction time from session 1 to session 2. There was a decrease in passivity during the first session and an increase in wakefulness in session 2 with methyldopa. This drug also decreased body sway in the frequency range 1.0–2.75 Hz activity in session 2, while oxazepam decreased bodys was at 1.0 to 2.75 Hz and increased activity at 2.5–3.0 Hz in session 2. Oxazepam reduced delta, theta and alpha content of the EEG. The present study has been unable to demonstrate any development of adverse central effects with captopril over a period of 7 days of drug ingestion. With atenolol adverse effects were present following short term dosing but were not more pronounced than with acute ingestion seen in previous studies. However effects on the electrical activity of the brain with atenolol remained after 7 days suggesting that the changes reported previously with single ingestions do not disappear.
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    Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 151-157 
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    ISSN: 1432-1041
    Keywords: Entacapone ; catechol-O-methyltransferase ; pharmacokinetics ; healthy volunteers ; adverse effects ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) by entacapone, and the pharmacokinetics of entacapone after single oral (5–800 mg) and IV (25 mg) doses have been examined in an open study in 12 healthy young male volunteers. Oral entacapone dose-dependently decreased the activity of S-COMT in RBCs with a maximum inhibition of 82% after the highest dose (800 mg). The inhibition of S-COMT in RBCs was reversible and the activity recovered within 4–8 h. Entacapone showed linear pharmacokinetics over the dose range studied: Cmax and AUC were correlated with the dose of the drug. Oral absorption of entacapone was fast, with a tmax ranging from 0.4 to 0.9 h, depending on the dose. Systemic availability of entacapone varied between 30 and 46%. Entacapone was rapidly eliminated by metabolism with a half-life of 0.27–0.30 h after oral doses of 5 to 50 mg. After doses from 100 to 800 mg the disposition was best described by two phases with a t1/2α of 0.27–0.37 h and t1/2β of 1.59–3.44 h. Over the dose range studied, the single oral and IV doses of entacapone were well tolerated. No haematological, biochemical or haemodynamic adverse effects were seen. The results show that entacapone is an orally effective and reversible COMT inhibitor in man and has simple, linear pharmacokinetics.
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    Dose proportionality of iopromide pharmacokinetics and tolerability after IV injection in healthy volunteers (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 339-343 
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    ISSN: 1432-1041
    Keywords: Iopromide ; X-ray contrast medium ; pharmacokinetics ; tolerability ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Twelve healthy male volunteers participated in a single-blind, randomised, placebo-controlled cross-over study of IV iopromide in doses of 15 g iodine or 80 g iodine infused over a period of 15 min. The volunteers were observed for three days during which time blood samples, urine and faeces were collected. The terminal disposition phase half-life of iopromide was 2 h and 1.9 h, and the total clearance was 110 and 103 ml·min-1 at the lower and at the higher dose levels, respectively. The steady state volume of distribution was 16 and 17 l, indicating predominantly extracellular distribution of iopromide. Statistical analysis (one-sided t-test) showed that all the target parameters (AUC, half-life and urinary excretion) were equivalent at both dose levels, indicating dose proportionate, first order kinetics of iopromide over the large dose range tested. Iopromide was well tolerated after both doses.
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    Single dose pharmacokinetics of sumatriptan in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 543-548 
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    ISSN: 1432-1041
    Keywords: Sumatriptan ; pharmacokinetics ; single dose ; bioavailability ; dose proportionality ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Sumatriptan is classified as a vascular 5HT1 receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration. The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h. Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.
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    Azithromycin does not alter the effects of oral midazolam on human performance (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 49-52 
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    ISSN: 1432-1041
    Keywords: Azithromycin ; Erythromycin ; Midazolam ; drug interaction ; healthy volunteers ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance. In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500mg+250mg). In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial. Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam. In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect. Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS). Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active. The corresponding, scores in the azithromycin + midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min. The combination differed from midazolam 15 mg in producing less drowsiness and mental slowness. In Study II, mean plasma midazolam concentrations (μg·1-1) after erythromycin + midazolam 10 mg were 0 (baseline), 168 (30 min) and 113 (90 min), which were higher than the values (0, 79 and 41) after placebo + midazolam. The corresponding concentrations (μg·1-1) after azithromycin + midazolam (0, 85 and 46) were similar to those found after placebo + midazolam. Erythromycin but not azithromycin enhanced the objective and subjective effects of midazolam. Our results suggest that as azithromycin, unlike erythromycin, does not interfere with midazolam metabolism, it also does not enhance the effects of midazolam.
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    The effect of food on the interaction of ofloxacin with sucralfate in healthy volunteers (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 67-69 
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    ISSN: 1432-1041
    Keywords: Ofloxacin ; sucralfate ; food ; drug interaction ; absorption ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the effect of food on the interaction of ofloxacin with sucralfate. Six healthy men took a single oral dose of ofloxacin (200 mg) on 4 occasions: alone after overnight fasting or after breakfast (non-fasting), and with sucralfate fasting or non-fasting. There were no significant differences in the plasma concentration-time profiles of ofloxacin after ofloxacin alone between fasting and non-fasting conditions. On the other hand, the peak plasma concentration and AUC of ofloxacin after co-administration with sucralfate while fasting fell by 70 and 61 % compared with ofloxacin alone; the changes non-fasting were 39 and 31 % respectively. The interaction of ofloxacin with sucralfate was markedly reduced by food, but still could not be disregarded.
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  • 46
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    Pharmacological effects of concomitant administration of β-adrenoceptor blocker and agonist in normal subjects: characterization by heart rate response to exercise (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 467-471 
    Details
    ISSN: 1432-1041
    Keywords: Metoprolol ; Denopamine ; exercise ; heart rate response ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of a combination regimen of metoprolol and β1-adrenoceptor agonist denopamine on resting and exercise heart rate have been studied in 10 normal volunteers. Maximal ramp upright bicycle exercise was performed three times at 1-week intervals. Two hours before each exercise test, 5 mg metoprolol plus 20 mg denopamine, 5 mg metoprolol plus a denopamine placebo, or two placebos were orally administered in a double-blind fashion. During exercise after placebo administration, heart rate increased in parallel with the exercise intensity. Compared to the placebo values, resting heart rate was significantly decreased by an average of 10 beats · min−1 by 5 mg metoprolol, whereas it was not altered by the combination regimen. During exercise, however, both the combination regimen and metoprolol alone showed a significant negative chronotropic effect, decreasing peak exercise heart rate by an average of 14 and 21 beats · min−1, respectively. Peak oxygen uptake was also significantly decreased by both regimens. We conclude that concomitant administration of 5 mg metoprolol and 20 mg denopamine exerts an effective β-adrenoceptor blocking action during exercise but a minimal effect at rest in normal subjects. The combination regimen appears to have a favourable pharmacological profile for β-adrenoceptor blocker therapy in patients with chronic heart failure.
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    Comparison of the effects of atropine in vivo and ex vivo (radioreceptor assay) after oral and intramuscular administration to man (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 45-49 
    Details
    ISSN: 1432-1041
    Keywords: Atropine ; M2-cholinoceptors ; effect kinetics ; radioreceptor assay ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of an oral dose of atropine (0.03 mg/kg body weight) and an IM (0.02 mg/kg) dose on the heart rate and salivary flow in seven healthy adult volunteers were compared to see whether the oral dose was sufficient to inhibit vagal reflexes of the heart. Atropine concentrations in plasma were determined by an M2-selective radioreceptor assay, and the in vitro occupancy of porcine cardiac M2-cholinoceptors was measured in parallel. In ligand-binding studies, atropine has been shown to have a comparable affinity for human and porcine cardiac M2-cholinoceptors (Ki 4.0 and 5.9, respectively). Slight changes in heart rate after oral administration were not significant. After IM administration, however, the heart rate increased significantly, by a maximum of 22 beats·min−1 after 45 min. The slight increase in heart rate after the oral dose corresponded to a receptor occupancy in vitro near the lower limit of detection, whereas the significant increase in heart rate after the IM dose corresponded to a receptor occupancy of up to 47%. The maximum reduction in salivary flow was similar after the oral and IM doses (84.3 and 87.5%, respectively). The almost complete inhibition of salivary flow could be explained by the lower vagal tone in the salivary glands compared with to the heart. The difference in the effect on heart rate was probably due to lower absorption of the oral dose. Thus, an oral dose greater than 0.03 mg atropine/kilogram body weight is required to compensate for low gastrointestinal absorption and to overcome the high vagal tone of the heart.
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    Pharmacokinetic characteristics and tolerability of a novel intravenous immunoglobulin preparation (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 237-242 
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    ISSN: 1432-1041
    Keywords: Intravenous immunoglobulin G ; Antihepatitis B ; pharmacokinetic parameters ; tolerability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In two independent trials 10 and 12 healthy volunteers received the novel intravenous immunoglobulin (IVIG) preparations BT 511 and BT 507, respectively. BT 511 contains 5 g human plasma proteins per 100 ml, more than 95% of which are immunoglobulins of the G class (IgG). BT 507 contains in addition 61 IU antibody against hepatitis B surface antigen (anti-HBs)·ml−1. In trial I volunteers received 4.0 ml/kg (n+4) and 8.0 ml·kg−1 (n+6) BT 511 to study the tolerability and the magnitude of the increase in immunoglobulins in plasma as well as their decline over 1 month. After administration of the lower dose, plasma IgG increased from 10.7 to 14.7 g·l−1 directly after the infusion. Following the 8.0 ml·kg−1 dose a more pronounced increase from 12.4 to 21.2 g·l−1 was observed. No adverse events occurred. After 1 month IgG concentrations had almost reached baseline values at 12.2 g·l−1 in the 4.0 ml·kg−1 group, but were still significantly increased at 15.2 g·l−1 after the high dose. There was a linear correlation between the maximal IgG plasma concentration and the subsequent decline of IgG during the 29-day observation period. After administration of BT 507 maximal anti-HBs concentrations of 1778 mU·ml−1 occurred 1.4 h after termination of the infusion. The terminal elimination half-life was 22.4 days, and total clearance and volume of distribution were determined to be 0.122 ml·min−1 and 5.41, respectively. The pharmacokinetic parameters calculated for anti-HBs as an indicator of IgG were in accordance with the pharmacokinetic behaviour of native IgG.
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    Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 115-120 
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    ISSN: 1432-1041
    Keywords: Key words Valsartan; pharmacokinetics ; deconvolu‐tion ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of orally and intravenously administered valsartan were determined in two studies. In a first pilot study, three i.v. doses of valsartan were given in an ascending manner (5, 10 and 20 mg) to evaluate tolerability and basic pharmacokinetics of the i.v. formulation. In a second study, the absolute bioavailability of 80 mg valsartan from a capsule and a buffered solution was compared with a 20 mg i.v. dose. Methods: The concentrations of valsartan in plasma and urine were measured using HPLC. The disposition of valsartan after an i.v. dose was characterized by biphasic decay kinetics, with a distribution phase (half-life 1.0 h), followed by a longer elimination phase (half-life 9.5 h). The volume of distribution at steady state was 16.9 l, and the total body clearance 2.2 l · h−1. 29% of the i.v. dose was recovered unchanged in the urine. Results: Plasma levels peaked 2 h after oral administration of the 80 mg capsule. Thereafter, plasma levels declined biexponentially with a terminal t1/2 of 7.0 h. Cmax was reached 1 h after administration of the solution, and t1/2 was 7.5 h. On average 7.3% (capsule) and 12.6% (solution) of the dose was excreted in the urine as the unchanged drug. The fraction of dose absorbed and systemically available after oral administration was 0.23 for the capsule and 0.39 for the solution, based on AUC. Absorption appeared to follow two first-order processes. The first phase was rapid, with a half-life of 0.5 h and 0.9 h for solution and capsule, respectively. The slower absorption phase was characterized by a half-life of 6.5 h for the solution and 3.5 h for the capsule. Most of the drug was absorbed during the period 0.4 h to 3 h post-dosing, and 90% of the fraction absorbed from the capsule was absorbed within 5 h.
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    Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 171-173 
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    ISSN: 1432-1041
    Keywords: Key words Mefloquine; mefloquine enantiomers ; carboxylic acid metabolite ; blood concentrations ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To compare concentrations of the separate enantiomers of mefloquine (MQ), total racemic MQ and the carboxylic acid metabolite in different blood fractions at steady state. Setting: Human volunteer laboratory, Unit of Clinical Pharmacology, Karolinska Institute. Volunteers: Ten healthy adult Caucasian volunteers. Methods: Drug concentrations were determined by high-performance liquid chromatography (HPLC). Results: Trough concentrations of the (+)RS enantiomer were higher in venous whole blood than in plasma and serum (mean ratios, 1.41 and 1.38). For the other enantiomer, (−)SR, concentrations were lower in whole blood than in plasma (mean ratio 0.89) and for the metabolite this ratio was 0.5. Conclusion: Stereoselective distribution might be important for antimalarial activity and should be considered when pharmacokinetic studies are performed.
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    Effect of cholinergic agonists and antagonists on gallbladder volume in fasting man (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 151-153 
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    ISSN: 1432-1041
    Keywords: atropine ; bethanechol ; prostigmine ; gallbladder volume ; real-time ultrasonography ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of direct cholinergic stimulation and blockade on gallbladder volume, determined by real-time ultrasonography (RUS), was evaluated in twenty normal, fasting subjects. Eleven subjects received atropine sulphate or placebo and 9 subjects a series of 3 injection of prostigmine, bethanechol or placebo, randomly assigned, at intervals of 24 h. RUS was performed under basal conditions after fasting for 12 h and every 5 min after drug injection up to 45 min in the atropine study and up to 60 min after prostigmine and bethanechol. There was no significant variation from fasting gallbladder volume after placebo in either group. After atropine sulphate gallbladder volume at first decreased and then significantly increased. With bethanechol and prostigmine, the volume fell significantly to a trough after 30 to 35 min, and then it returned to the basal value within 60 min. It is suggested that cholinergic mediation is involved in maintaining fasting tone in the gallbladder and that cholinergic stimulation causes contraction of the gallbladder by a direct effect.
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    Absorption of an aqueous solution of a new synthetic somatostatin analogue administered to man by gavage (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 167-171 
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    ISSN: 1432-1041
    Keywords: somatostatin analogue ; oral formulation ; gastrointestinal absorption ; SMS 201-995 ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To determine the local gastrointestinal absorption of a new synthetic somatostatin analogue (SMS 201-995 = Sandostatin), an intestinal tube was passed in eight healthy volunteers and on different days an aqueous solution was administered at four different locations: stomach, proximal duodenum, ligament of Treitz and jejunum. In a follow-up study, an oro-ileal tube was passed in six of the original volunteers and the drug solution was administered in to the terminal ileum. The aqueous solution of SMS was rapidly absorbed from the gastrointestinal tract after local application, and it was well tolerated. Absorption of the drug from the different sites was comparable, although there was a tendency to decreased peptide absorption after ileal administration. Absorption of the drug was quite variable between the subjects and the different locations. The dose-corrected systemic availability relative to subcutaneous administration in another study was 0.28%. However, significant plasma SMS concentrations were achieved, suggesting that oral delivery of the polypeptide may eventually be possible for long-term treatment of a variety of disorders.
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    Enoxacin — a potent inhibitor of theophylline metabolism (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 227-230 
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    ISSN: 1432-1041
    Keywords: enoxacin ; theophylline ; drug interaction ; healthy volunteers ; adverse effects ; pharmacokinetics ; renal tubular excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.
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    Effect of 6-hourly intermittent intravenous boluses of oxmetidine and ranitidine on gastric acidity and serum prolactin (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 267-271 
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    ISSN: 1432-1041
    Keywords: ranitidine ; oxmetidine ; gastric acidity ; bolus injection ; serum prolactin ; healthy volunteers ; gastric pH ; gastric juice volume
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect on 24-h gastric juice volume and pH of 30 min intravenous infusions of 200 and 400 mg oxmetidine and 50 mg ranitidine, administered at 6-hourly intervals, has been investigated in 12 healthy male subjects. After each infusion period a median intragastric pH 〉5 was obtained with all active treatments, which also caused a significantly elevated 24-h median pH versus placebo. The 24-h median pH following ranitidine did not differ significantly from that after either oxmetidine treatment. There was a sharp decrease in gastric volume secretion within 2 h of infusion of each active treatment. There was no significant difference between active treatments in the time required to reach an intragastric pH 〉5. No active treatment was able to maintain the pH 〉5 for longer than 4 h (average 3 h). It is concluded that in patients at risk of stress ulcer, continuous infusion therapy with H2-blockers should be employed both for pharmacokinetic and practical reasons. It should be accompanied by regular measurement of pH in order to monitor any fall in pH. Alternatively, shorter time intervals than 6 h should be used for bolus therapy.
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    Influence of smoking and gender on the disposition kinetics of metoprolol (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 355-361 
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    ISSN: 1432-1041
    Keywords: metoprolol ; smoking ; gender ; pharmacokinetics ; HPLC ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol. Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant-rate intravenous infusion over 20 min. The only significant difference between smokers (S) and nonsmokers (NS) was that S had a larger steady-state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability (f). No differences were observed between males (M) and females (FM) for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, f was higher after the 200-mg dose compared to the 100-mg dose. These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations of Johnsson et al. [1] who showed that f increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in f as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in f among subjects.
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    Effect of 40749 RP on basal and sham feeding stimulated gastric secretion in man (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 479-482 
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    ISSN: 1432-1041
    Keywords: 40749 RP ; gastric acid secretion ; gastric antisecretory agent ; sham feeding ; healthy volunteers ; vagal stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 40749 RP, a pyridyl-2-tetrahydrothiophene derivative, is known to be a potent inhibitor of the gastric acid response to pentagastrin, betazole and a meal. In 6 healthy young volunteers, a single oral dose of 2 mg · kg−1 greatly reduced the gastric acid secretory response to sham-feeding. By contrast, neither gastric pepsin nor the plasma PP response were altered by the drug. No change was observed in plasma gastrin, motilin, VIP or somatostatin concentrations. The results show that 40749 RP is also active on the pure vagus-stimulated gastric acid secretion. The lack of effect upon gastric pepsin and plasma PP suggests that 40749 RP is not likely to act on the basolateral cholinergic receptor and that it affects further cellular steps involved in hydrogen ion secretion.
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    Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. S9 
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    ISSN: 1432-1041
    Keywords: metoprolol ; controlled-release formulation ; pharmacokinetics ; pharmacodynamics ; exercise heart rate ; healthy volunteers ; efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and pharmacodynamic properties of a new multiple-unit, controlled-release (CR) formulation of metoprolol1 (metoprolol succinate, 95 mg once daily), which has almost constant (zero-order) release properties over most of a 24-h dose interval, have been compared with those of conventional metoprolol tablets (metoprolol tartrate, 100 mg once daily and 50 mg twice daily), in 12 healthy male volunteers. The steady-state plasma concentrations of metoprolol after five days of treatment varied less throughout the day with the CR than with the conventional formulation. This was associated with a considerably lower peak plasma concentration and the achievement of a significantly higher plasma concentration at the end of the dose interval. Similarly, the effect on exercise-induced tachycardia was maintained at a relatively constant level throughout the day after treatment with the CR formulation. A significantly greater effect 24 h after administration was achieved with the CR formulation, when compared with once-daily dosing with metoprolol tablets, 100 mg. Twice-daily dosing with metoprolol tablets, 50 mg, produced a similar β1-blocking effect at the end of the dose interval to that observed with metoprolol CR. Although the steady-state plasma concentrations indicated significantly lower systemic availability for the CR formulation, compared with both regimens of metoprolol tablets, the total effect over the dose interval, expressed as the area under the efficacy curve (AUEC), was similar for the three treatments. The relationship between steady-state plasma concentrations and the pharmacodynamic efficacy at corresponding times, indicated that plasma concentrations were more effectively utilized after the administration of the CR formulation than after the conventional tablet regimens. The results of this study clearly indicate the potential benefits offered by the new metoprolol CR formulation, under all circumstances where a constant degree of β1-selective blockade, without plasma peaks and troughs, is preferred.
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    The influence of cholestyramine on the elimination of tenoxicam and piroxicam (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 283-289 
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    ISSN: 1432-1041
    Keywords: piroxicam ; tenoxicam ; cholestyramine ; accelerated drug elimination ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of tenoxicam and piroxicam in eight healthy young volunteers. Each subject received on two occasions single intravenous injections of 20 mg tenoxicam and on another two occasions single oral doses of 20 mg piroxicam. Both medications were followed by multiple oral doses of either cholestyramine or plain water (placebo). Compared with placebo cholestyramine accelerated the elimination of both drugs. The average values of half-lives were reduced (tenoxicam: 31.9 h vs 67.4 h; piroxicam: 28.1 h vs 46.8 h) due to increases in clearance. Cholestyramine-mediated enhancement of drug elimination was most pronounced in the subjects with a comparatively low baseline drug clearance. Thus, intersubject variability in clearance was smaller when the drug administrations were followed by the anion-exchange resin. The twofold acceleration of tenoxicam elimination in the present study in man contrasts with a much larger effect (five-fold) seen in experiments with dogs. This points to a much easier access of unchanged tenoxicam to the intestinal lumen in the dogs than in man. Comparing the pharmacokinetics of tenoxicam and piroxicam in the same volunteers revealed a high degree of correlation in clearance and half-lives and similar intersubject variabilities in mean kinetic variables.
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    Comparative effects of rifabutin and rifampicin on hepatic microsomal enzyme activity in normal subjects (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 595-599 
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    ISSN: 1432-1041
    Keywords: rifampicin ; rifabutin ; microsomal enzyme induction ; healthy volunteers ; antimicrobial agent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The comparative enzyme inducing effects of rifabutin and the chemically related drug rifampicin have been investigated in 8 normal subjects. Rifampicin 600 mg daily for 7 days caused considerable shortening of the antipyrine half-life and a marked increase in antipyrine clearance, associated with an increased rate of conversion to norantipyrine and, to a lesser extent, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine. The urinary excretion of 6-β-hydroxycortisol was also markedly increased, while plasma GGT activity showed only a slight albeit statistically significant elevation. In the same subjects, rifabutin in the proposed therapeutic dosage (300 mg daily) for 7 days also enhanced the metabolic elimination of antipyrine, with preferential stimulation of the demethylation pathway, and increased the excretion of 6-β-hydroxycortisol, but the magnitude of the effects was signifiantly less than after rifampicin. No significant change in plasma GGT was seen. The results indicate that, contrary to the findings in animals, rifabutin does have enzyme inducing properties in man, although at the dosages assessed they were considerably less than those of rifampicin.
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    Lack of effect of cimetidine on the pharmacokinetics and metabolism of a single oral dose of metronidazole (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 65-68 
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    ISSN: 1432-1041
    Keywords: metronidazole ; cimetidine ; pharmacokinetics ; drug interaction ; drug metabolism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time course of the effect of cimetidine on the pharmacokinetics of metronidazole was investigated in 6 healthy volunteers. Cimetidine 1.0 g/day was administered for 9-days and metronidazole 500 mg was administered orally on the second and eighth days, and in a control experiment. During cimetidine treatment the plasma kinetics of metronidazole and its partial clearance by renal excretion of the unchanged compound, glucuronidation, hydroxylation and oxidation to its acetic acid metabolite were not significantly different from the control values. The results indicate that cimetidine does not influence the pharmacokinetics or metabolism of a single oral dose of metronidazole.
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    Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 69-75 
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    ISSN: 1432-1041
    Keywords: L-carnitine ; pharmacokinetics ; intravenous and oral doses ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 and 6 g was studied in 6 healthy subjects on a low-carnitine diet. Carnitine was more rapidly eliminated from plasma after the 6 g dose. Comparing the doses, the t1/2β of the elimination phase (β) was 6.5 h vs 3.9 h, the elimination constant 0.40 vs 0.50 h−1 and the plasma carnitine clearance was 5.4 vs 6.11 · h−1 for the 2 g and 6 g doses, respectively, showing dose-related elimination. Saturable kinetics were not found. The apparent volumes of distribution after the two doses were not significantly different and were of the same order as the total body water. Urinary recoveries of the 2 g and 6 g doses were 70% and 82%, respectively, during the first 24 h. Following the oral doses, there was no significant difference between the areas under the plasma carnitine concentration-time curves. Urinary recovery was 8% and 4% for the 2 g and 6 g doses during the first 24 h. Oral bioavailability was 16% for the 2 g dose and 5% for the 6 g dose. The results suggest that the mucosal absorption of carnitine was already saturated by the 2 g dose.
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    Therapeutic doses of codeine have no effect on acetaminophen clearance or metabolism (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 109-111 
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    ISSN: 1432-1041
    Keywords: acetaminophen ; codeine ; clearance ; metabolite formation ; glucuronidation ; pharmacokinetics ; healthy volunteers ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In nine healthy volunteers, the clearance and metabolism of acetaminophen 1000 mg i.v. was evaluated with and without two concomitant oral doses of codeine in order to investigate a possible interaction. Plasma acetaminophen was followed for 720 min and urine was collected for 24 h after each dose for determination of metabolites. When codeine was coadministered, the average total clearance of acetaminophen and its clearance by glucuronidation, sulphation and mercapturate formation were 0.58 to 1.12-times the control values. It is concluded that therapeutic doses of codeine do not influence the clearance or metabolism of acetaminophen.
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    Inhibitory effect of oral WEB 2086, a novel selective PAF-acether antagonist, on ex vivo platelet aggregation (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 237-240 
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    ISSN: 1432-1041
    Keywords: platelet activating factor (PAF) ; WEB 2086 ; platelet aggregation ; PAF-antagonist ; dose response ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary WEB 2086 is a novel PAF-acether antagonist, whose pharmacological action in man has only been preliminarily defined. Twelve healthy male volunteers received oral doses of 5, 30 and 90 mg and over the following 24 h inhibition of 5 × 10−8 M PAF-acether-induced platelet aggregation ex vivo was studied as an indicator of pharmacological activity. WEB 2086 inhibited PAF-acether-induced platelet aggregation in all the doses tested, with the maximum effect 1 to 2 h after administration. After 2 h 5- 30- and 90-mg doses caused, respectively, 87, 98 and 100% inhibition. The magnitude and duration of the inhibitory effect was dose-dependent, with a significant action still detectable 10 h after administration of all three doses, and 12 h after administration of the two highest doses (30 and 90 mg). The subjects did not complain of any significant adverse effect and all completed the study.
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    The behaviorally active peptide ACTH 4-10: Measurement in plasma and pharmacokinetics in man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 371-377 
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    ISSN: 1432-1041
    Keywords: ACTH 4-10 ; radioimmunoassay ; plasma extraction ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A specific radioimmunoassay for the quantitative measurement of ACTH 4-10 and a procedure for its extraction from plasma have been developed. Its pharmacokinetics was studied in eight healthy male volunteers given ACTH 4-10 125 µg/kg body weight as a bolus i.v. injection, by infusion and intranasally. Following the i.v. bolus, plasma levels rapidly declined biexponentially, with half-lives of 0.39±0.05 min for the α-phase and 3.84 ± 1.5 min for the β-phase (mean±SD). The constant rate i.v. infusion yielded steady-state levels between 0.74 and 5.06 ng/ml plasma. Administered as intranasal spray, absorption of intact ACTH 4-10 was low and variable (maximal bioavailability 7.6%). The results are discussed in relation to the dose-dependent effects of ACTH 4-10 on the auditory evoked potential.
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    Effect of antipyrine coadministration on the kinetics of acetaminophen and lidocaine (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 413-417 
    Details
    ISSN: 1432-1041
    Keywords: antipyrine ; acetaminophen ; lidocaine ; drug interactions ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic interactions between antipyrine and acetaminophen were evaluated in 7 healthy volunteers. On 3 occasions subjects received:1, antipyrine 1.0 g intravenously (i.v.);2, acetaminophen 650 mg i.v.;3, antipyrine 1.0 g and acetaminophen 650 mg i.v. simultaneously. Between Trials 1 and 3, antipyrine elimination t1/2 (17.2 vs 17.4 h), clearance (0.44 vs 0.43 ml·min−1·kg−1) and 24-h recovery of antipyrine and metabolites (313 vs 293 mg) did not differ significantly. Between Trials 2 and 3, acetaminophen Vz was reduced (1.14 vs 1.00 l·kg−1), t1/2 prolonged (2.7 vs 3.3 h), clearance reduced (4.8 vs 3.6 ml·min−1·kg−1), and fractional urinary recovery of acetaminophen glucuronide reduced. Eight additional subjects received 50 mg of lidocaine hydrochloride i.v. in the control state, and on a second occasion immediately after antipyrine 1.0 g given i.v. The two trials did not differ significantly in lidocaine Vz (2.6 vs 2.7 l·kg−1), t1/2 (2.0 vs 2.4 h) or clearance (15.0 vs 13.5 ml·min−1·kg−1). Although acetaminophen does not alter antipyrine kinetics, acute administration of antipyrine appears to impair acetaminophen clearance, possibly via inhibition of glucuronide formation. However, antipyrine has no significant effect on the kinetics of a single i.v. dose of lidocaine.
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    The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 59-65 
    Details
    ISSN: 1432-1041
    Keywords: indoramin ; 6-hydroxyindoramin ; debrisoquine ; hydroxylators ; genetic polymorphism ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five poor metabolisers (PM) and seven extensive metabolisers (EM), of debrisoquine, all healthy volunteers, received 50 mg indoramin orally following an overnight fast. Plasma concentrations of indoramin and 6-hydroxyindoramin were determined by HPLC with fluorimetric detection. In PM subjects, mean values of Cmax (158 ng/ml) and AUC(0–24) (2556 ng·h·m−1) for indoramin were substantially elevated and t1/2β (18.5 h) prolonged by comparison with values in the EM subjects (21.6 ng/ml, 151 ng·h·ml−1 and 5.2 h respectively). For 6-hydroxyindoramin, on the other hand, Cmax (12.4 ng/ml) and AUC(0–8) (47.5 ng·h·ml−1) in PM subjects were significantly lower than in the EM subjects (28.2 ng/ml and 94.7 ng·h·ml−1). There was a tendency to a higher incidence of side-effects in the PM group. Although the difference did not achieve statistical significance (0.1〉p〉0.05), all the PM subjects experienced sedation compared to only two in the EM group. Differences in blood pressure and pulse rate between the two groups were small. It is concluded that the oxidative metabolism of indoramin is subject to genetic polymorphism, which is probably under the control of the same gene locus as that influencing debrisoquine oxidation. The clinical consequences are discussed.
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    URL: http://dx.doi.org/10.1007/BF00610381
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    Psychomotor, respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 139-146 
    Details
    ISSN: 1432-1041
    Keywords: buprenorphine ; amitriptyline ; interaction ; psychomotor performance ; respiration ; pituitary hormones ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Actions and interactions of buprenorphine (BUP) and amitriptyline (AMI) on performance and respiration were studied double-blind and cross-over in 12 healthy volunteers. After one-week pretreatments with AMI or placebo, the subjects received on Day 8 placebo, BUP or AMI so that the final treatments were 1) placebo, 2) acute AMI 50 mg, 3) acute BUP, 4) subchronic AMI + acute BUP and 5) subchronic AMI. The subacute treatments were started at two-week intervals. A Mapleson D rebreathing circuit including a pneumotachograph and an infrared capnograph was employed to study drug effects on respiration. Minute volume and end-tidal carbon dioxide as well as psychomotor performance were measured and the blood samples taken on Day 8 before the drug intake and 2 and 4 h thereafter. The performance tests included tracking, choice reaction, flicker fusion, exophoria, nystagmus, digit symbol substitution and the subjective assessment of mood. BUP depressed respiration, and subchronic AMI increased this depression. Both BUP and acute AMI 50 mg each alone impaired various measures of performance and rendered the subjects drowsy, feeble, mentally slow and muzzy but subchronic AMI did not enhance BUP effects. BUP increased plasma prolactin levels similarly after both pretreatments. The results suggest that both BUP and AMI moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.
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    Circadian changes in the pharmacokinetics and cardiovascular effects of oral propranolol in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 619-624 
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    ISSN: 1432-1041
    Keywords: propranolol ; isomers ; chronopharmacokinetics ; cardiovascular effects ; circadian changes ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Four subjects were synchronized with activity from 07 to 23 h and were given a single oral dose of 80 mg racemic propranolol at fixed times (08, 14, 20 and 02 h) at weekly intervals. ANOVA revealed significant circadian changes in the peak propranolol concentration (Cmax), with a maximum at 08 h and a minimum at 02 h after drug intake; tmax was not dependent on the circadian phase. The elimination half-life varied significantly with the time of day, being shortest at 08 h (3.3 h) and longest at 20 h (4.9 h). The stereospecificity of the propranolol pharmacokinetics was not dependent on the time of drug intake. No circadian variation was found in the maximum decrease in heart rate, but the time to peak effect was dependent on the time of drug intake; tmax was 2.3 h at 08 h and 7.0 h at 02 h. Thus, the time to peak drug concentration did not coincide with the time to peak effect on heart rate at different times of day. Circadian changes were also found in the systolic blood pressure and in the double product. The results show a significant daily variation in the pharmacokinetics and cardiovascular effects of propranolol. However, chronokinetics cannot explain the circadian changes in the effects of the drug. It is concluded that circadian variation in sympathetic tone and vascular reactivity is mainly responsible for the circadian changes in the effects of propranolol.
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    URL: http://dx.doi.org/10.1007/BF00542498
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    Lack of effect of the benzodiazepine antagonist flumazenil (Ro 15-1788) on the performance of healthy subjects during experimentally induced ethanol intoxication (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 273-276 
    Details
    ISSN: 1432-1041
    Keywords: flumazenil ; ethanol ; alcohol intoxication ; benzodiazepine antagonist ; interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Flumazenil is a specific benzodiazepine antagonist. This study was designed to determine whether it also reverses CNS depression due to acute alcohol intoxication. Intoxication was experimentally induced in 6 healthy volunteers by intravenous infusion of ethanol. Individual constant ethanol plasma concentrations in the range 1.47±0.04 g · l−1 to 1.71±0.03 g · l−1 were maintained over 6 h. Two doses of flumazenil (0.1 or 0.2 mg · kg−1) and placebo were administered intravenously in a randomized, double-blind, two-way cross-over fashion. A battery of psychometric tests and subjective ratings of mood and performance were performed at baseline and at regular intervals during the study. Before the administration of flumazenil the characteristic symptoms and signs of ethanol intoxication were present in all subjects. Performance (measured by visual analogue scales), reaction time, digit symbol substitution test, and a tracing test, were markedly impaired by ethanol. After the injection of flumazenil three volunteers reported some subjective improvement in performance. However, in none of the subjects was there a difference between either dose of flumazenil and placebo in terms of an improvement in the objective psychometric variables.
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    Single and multiple dose pharmacokinetics of tenoxicam in the elderly (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 563-566 
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    ISSN: 1432-1041
    Keywords: tenoxicam ; pharmacokinetics ; elderly ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fourteen elderly subjects (10 women, 4 men) with a mean age of 81 (SD 6.7) years and in need of anti-inflammatory drug treatment were given a single dose of 20 mg tenoxicam. After a drug-free interval of 5 weeks, multiple dose treatment with 20 mg tenoxicam once daily for 56 days was initiated. The single and multiple dose kinetics of tenoxicam were investigated after HPLC determination of tenoxicam in the plasma. The elimination half-life of tenoxicam ranged from 44 to 132 h (mean 71.9 h) with no significant difference between the single and multiple dosage regimens. Tenoxicam reached maximum plasma concentrations after 1.4 and 1.1 h, with values of 3.6 and 15.5 µg·ml−1, for the single and multiple dosage regimen respectively. The corresponding trough values (24-h values) were 1.8 and 11.7 µg·ml−1. A mean accumulation ratio of 5.1 was calculated. The mean increase in the area under the plasma concentration time curves at steady-state was 21% more than predicted from the initial single dose. This deviation from linearity was considered to be of minor clinical significance. The kinetics of tenoxicam in elderly were similar to that published for young healthy volunteers.
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    Effect of acute administration of propranolol and atenolol on baroreflex function in normal man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 607-612 
    Details
    ISSN: 1432-1041
    Keywords: propranolol ; atenolol ; baroreflex function ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute administration of the β-adrenoceptor antagonists propranolol (80 mg) and atenolol (50 mg) on baroreflex function were investigated in healthy volunteers. Two h after administration both propranolol and atenolol significantly prolonged the supine R-R interval (1126, 1128 ms respectively) compared to placebo (1012 ms); systolic arterial pressure also fell (102.9, 102.0 mm Hg respectively) compared to placebo (112.6 mm Hg). Baroreflex function, assessed using glyceryl trinitrate to deactivate the baroreceptors was unchanged by these drugs compared to placebo. Baroreflex sensitivity (slope of the linear regression line relating R-R interval to systolic blood pressure) using phenylephrine to activate the baroreceptors, was also unchanged (17.2, 17.9 ms/mm Hg respectively) compared to placebo (19.9 ms/mm Hg). However both regression lines were shifted (p〈0.05) to the left compared to placebo.
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    Interaction of alcohol with maprotiline or nomifensine: Echocardiographic and psychometric effects (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 593-599 
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    ISSN: 1432-1041
    Keywords: maprotiline ; nomifensine ; ethanol ; drug interaction ; echocardiography ; psychometry ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight healthy volunteers received low doses of maprotiline and nomifensine up to 50 mg b. d. for 15 days in a double-blind, cross-over, placebo controlled study, during which echocardiography and psychomotor testing were carried out before and after the intake of alcohol 1 g/kg. Maprotiline increased heart rate and cardiac output and reduced peripheral resistance compared to placebo and nomifensine. Nomifensine alone was associated with a slight decrease in heart rate. Alcohol alone caused a significant increase in diastolic blood pressure, but did not otherwise modify the cardiovascular measures. The antidepressants did not augment the effects of alcohol. Antidepressants alone had no effect on psychomotor skills, but alcohol always impaired performance. No additional effects of alcohol were produced by the antidepressants. It appears that practically important peripheral or central consequences are unlikely to follow drinking a moderate amount of alcohol during regular therapy with low therapeutic doses of catecholamine reuptake inhibiting antidepressants. Experimental studies of the interaction of antidepressants and alcohol in patients with chronic heart disease seem to be justified.
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    The relationship between pharmacokinetics and pharmacodynamics of enoximone in healthy man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 631-635 
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    ISSN: 1432-1041
    Keywords: enoximone ; heart failure ; inotropic activity ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The relationship between the pharmacokinetics and pharmacodynamics of enoximone, a new positive inotropic agent, was investigated in 6 healthy men. The volunteers received single oral and i.v. doses of 3 and 1 mg/kg, respectively, and placebo in a double-blind cross-over trial. Plasma concentrations of enoximone and its sulphoxide metabolite, effects on the corrected electromechanical systole (QS2c), the impedance cardiogram (dZ/dt)/RZ index, blood pressure and heart rate were determined over an 8-h period. Peak effects on QS2c and the (dZ/dt)/RZ index were obtained after approximately 1 h. During the first hour, the cardiac effects lagged behind the high plasma concentrations. Thereafter, the effects on QS2c were closely correlated with the plasma concentrations both of enoximone and its sulphoxide derivative (r≥0.90). The concentration-effect curves of both substances were parallel and were independent of the route of administration. The inotropic activity was not related to the drug level in hypothetical peripheral compartments. The results suggest that determination of plasma enoximone 1 h after administration and thereafter may be useful in assessing the haemodynamic activity of the drug. Should this observation also be present in a clinical situation, plasma enoximone measurements might be a valuable tool in management of patients suffering from heart failure.
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    Inhibition of pentagastrin-stimulated gastric acid secretion and plasma levels of the new histamine H2-receptor antagonist ramixotidine dihydrochloride (CM 57755) in human volunteers (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 467-470 
    Details
    ISSN: 1432-1041
    Keywords: ramixotidine ; cimetidine ; CM 57755 ; H2-receptor antagonist ; gastric acid secretion ; healthy volunteers ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The new competitive histamine H2-receptor antagonist, ramixotidine 2 HCl (CM 57755), has been tested in healthy male volunteers for its ability to inhibit pentagastrin-stimulated gastric acid secretion. In the first study, in 8 subjects, pentagastrin 6 µg·kg−1 was injected s.c., 90 min after the following 4 oral treatments given in random order at weekly intervals: placebo, 100, 200 and 400 mg CM 57755. Gastric contents were collected over 15-min periods during the 2 h after pentagastrin stimulation. In a second, similar study, 8 subjects received placebo, 0.5 and 1.0 g CM 57755 and 800 mg cimetidine, 120 min before a 2 h i.v. infusion of 6 µg·kg−1·h−1 pentagastrin. Cumulative gastric secretion in placebo-treated subjects was 46±14 and 62±11 mmol H+·2 h−1 (mean±SD), respectively, in the first and second studies. It was significantly reduced only after 400 mg CM 57755 in the first study. In the second study either dose of CM 57755 and cimetidine caused a significant reduction in gastric acid secretion. Average plasma levels of ramixotidine were dose-related after 0.2 and 1.0 g and ranged from 0.3 and 1.6 µg/ml, respectively, at 60 min to 0.5 and 3.7 µg/ml at 180 min. The peak cimetidine level averaged 3.6 µg/ml at 150 min. Individual CM 57755 plasma levels throughout the test period were fairly consistent with the inhibition of cumulative gastric acid secretion scored concurrently in each subject. No subjective side-effects attributable to the treatments were reported, and no abnormal findings were seen in the ECG or in laboratory tests.
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    Drug interactions with urate excretion in man (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 499-502 
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    ISSN: 1432-1041
    Keywords: uric acid ; ampicillin ; benzbromarone ; pyrazinamide ; probenecid ; healthy volunteers ; drug excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of pyrazinamide and ampicillin on the uricosuric response to probenecid and benzbromarone were studied in six normal subjects. The amount of uric acid was calculated for the 24 h volume of urine and the urate and creatinine clearances were determined for each of three urinary collection periods in order to calculate the percentage Curate/Ccreatinine. Ampicillin alone caused a significant uricosuria in the 0–2 h (p〈0.025) and 8–24 h (p〈0.025) periods. Benzbromarone caused a significant reduction in all the parameters. These observations suggest that high concentrations ampicillin compete with uric acid for reabsorption, but that its delayed uricosuric action can be ascribed to the binding of this dipeptide to a charge-mediated receptor site on the brush border membrane of proximal tubular cells. It would also appear that benzbromarone is secreted by the pyrazinamide-sensitive mechanism for urate secretion as it can cause a paradoxical retention of urate, but leaves the other probenecid-sensitive secretory transport process unoccupied as indicated by the fact that it does not change the kinetics of ampicillin.
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    Safety and tolerance of single oral doses of trandolapril (RU 44.570), a new angiotensin converting enzyme inhibitor (1989)
    Springer
    European journal of clinical pharmacology 36 (1989), S. 17-23 
    Details
    ISSN: 1432-1041
    Keywords: trandolapril ; ACE-inhibition ; safety ; tolerance ; adverse effects ; healthy volunteers ; effect duration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The safety and tolerance of single oral doses of a new angiotensin converting enzyme (ACE) inhibitor, trandolapril have been examined in 90 healthy male volunteers, in a randomised, double blind, placebo-controlled study. The subjects were divided into 10 groups, each of 9 subjects and treatments (6 subjects on trandolapril and 3 on placebo per group) were allocated by unbalanced randomisation. Ten single, increasing oral doses were tested: 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 24 and 32 mg. The assessment criteria were clinical (monitoring of blood pressure, heart and respiratory rate, electrocardiogram, temperature and evaluation of behaviour and side effects) and routine laboratory tests. Blood pressure did not fall except for a slight drop in diastolic pressure during the first 4 h following the 32-mg dose. However, although an effect of the compound cannot be excluded, the reduction in blood pressure may have reflected intersubject variability. No orthostatic hypotension was observed. There was no change in the other vital signs, and in particular no increase in heart rate was observed. No serious adverse effect was encountered. The pharmacological activity of the compound was studied by assaying plasma ACE activity. Inhibition of ACE was linearly dose-dependant from 0 (placebo) to 2 mg, and above that dose, the inhibition was nearly total. ACE activity was markedly reduced within 30 min after administration of trandolapril, and maximal inhibition was observed from 2–4 h onwards, lasting for up to 24 h after dosing. For doses above 2 mg, inhibition was still 40% of the basal activity on Day 8 after dosing.
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    Pharmacokinetics of intravenous captopril in healthy men (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 367-370 
    Details
    ISSN: 1432-1041
    Keywords: captopril ; pharmacokinetics ; healthy volunteers ; i.v. application
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic characteristics of intravenously-administered captopril were investigated in 7 healthy men 20 to 33 years old. Capropril, labeled with14C, was given by injection over a 1 min period at mean doses of 2.78 mg (13.8 µCi), 5.67 mg (28.2 µCi) and 11.4 mg (56.8 µCi). Concentrations of unchanged captopril, captopril disulfide, and other metabolites (collectively) were determined in body fluids. Pharmacokinetic parameters were calculated for unchanged captopril, and it was shown that the disposition of intravenously-administered drug was linear with respect to dose over the dosage range studied.
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    Bioavailability and pharmacokinetics of oxazepam (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 385-389 
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    ISSN: 1432-1041
    Keywords: oxazepam ; pharmacokinetics ; i.v.-/oral administration ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t1/2β) 6.7 h, total clearance (CL) 1.07 ml·min−1·kg−1, volume of distribution (Vc) 0.27 l·kg−1 (0.21–0.49) and volume of distribution at steady-state (Vss) 0.59 l·kg−1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min−1·kg−1 and a distribution volume of 12.3 l·kg−1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t1/2β at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CLR) of the glucuronide metabolite was 1.10 ml·min−1·kg−1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.
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    Influence of renal failure, rheumatoid arthritis and old age on the pharmacokinetics of diflunisal (1989)
    Springer
    European journal of clinical pharmacology 36 (1989), S. 165-174 
    Details
    ISSN: 1432-1041
    Keywords: diflunisal ; pharmacokinetics ; healthy volunteers ; kidney failure ; rheumatoid arthritis ; aged subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose plasma kinetics of diflunisal was studied in healthy young and old subjects, in patients with rheumatoid arthritis, and in patients with renal failure. The plasma and urine kinetics of the glucuronidated metabolites of diflunisal were studied in the healthy elderly subjects and in the patients with renal failure. In addition, the multiple-dose plasma kinetics of diflunisal was assessed in healthy volunteers and in patients with rheumatoid arthritis. After a single dose of diflunisal the terminal plasma half-life, mean residence time and apparent volume of distribution were higher in elderly subjects than in young adults. No difference was observed in any pharmacokinetic parameter between age-matched healthy subjects and patients with rheumatoid arthritis. The elimination half-life of unchanged diflunisal was correlated with the creatinine clearance (r=+0.89) and its apparent total body clearance exhibited linear dependence on creatinine clearance (r=+0.78). In patients with renal failure, the terminal plasma half-life and mean residence time of diflunisal were prolonged. The renal and apparent total body clearances were lower, the mean apparent volume of distribution was higher and the mean area under the concentration-time curve extrapolated to infinity (AUC) was greater in the renal failure patients than in controls. The plasma concentration of the glucuronidated metabolites rapidly rose to levels above those of unchanged drug in renal patients, whereas they were lower than those of unchanged diflunisal in controls. The AUC (0–96 h) of diflunisal glucuronides in the patients was four-times that in controls, and the terminal elimination half-life of the glucuronides was prolonged in them. The renal excretion and clearance of diflunisal glucuronides were reduced when renal function was impaired. After multiple dosing, the pre-dose steady-state plasma-concentration increased with decreasing creatinine clearance (r=-0.79). When the plasma concentration exceeded 200 µmol·1−1, the elimination half-life was doubled, due to partial saturation of diflunisal conjugation. This finding suggests that lower doses could be used in long-term treatment. Thus, old age and arthritic disease appear to have little influence on the kinetics of diflunisal in the absence of renal functional impairment. Ordinary doses can be given for short term treatment of elderly patients with or without RA. In patients with renal failure, however, reduced doses of diflunisal are recommended.
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    Dose proportionality of nadolol pharmacokinetics after intravenous administration to healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 625-628 
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    ISSN: 1432-1041
    Keywords: nadolol ; pharmacokinetics ; 14C-nadolol ; healthy volunteers ; i.v. administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To support the increasing use of intravenous β-blockers during cardiovascular emergency and surgery, dose proportionality of pharmacokinetics of nadolol was evaluated after intravenous administration of 14C-nadolol at doses of 1, 2 and 4 mg to nine healthy volunteers. There were no observed differences in the excretion or the pharmacokinetics of nadolol with respect to the dose administered. Over a 72-h period after drug administration, an average of about 60% of the dose was excreted in the urine and about 15% was excreted in the feces. The range of values for total body clearance (219 to 250 ml·min−1), renal clearance (131 to 150 ml·min−1), mean residence time (10.5 to 11.3 h), half-life (8.8 to 9.4 h), and steady-state volume of distribution (Vss) (147 to 157 l) indicated that nadolol was extensively distributed and slowly cleared from the body. There was a linear correlation (r 2=0.97) between the area under the plasma concentration of nadolol versus time curve (AUC) and the dose. All pharmacokinetics parameters, except Vss, were slightly, but significantly, different at the 4 mg dose. Superposition of the dose-normalized average concentrations indicated that despite these minor differences in parameters, the pharmacokinetic behavior of nadolol was linear with respect to dose. Urinary excretion of nadolol was dose independent.
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    Acute effects of felodipine and nifedipine on hepatic and forearm blood flow in healthy men (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 529-533 
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    ISSN: 1432-1041
    Keywords: felodipine ; nifedipine ; calcium antagonists ; hepatic blood flow ; forearm blood flow ; healthy volunteers ; haemodynamic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute effects of oral administration of felodipine 10 mg and nifedipine 10 mg on heart rate, blood pressure, forearm blood flow and hepatic blood flow were studied in nine healthy men. Both drugs caused an increase in heart rate of 16 and 7 beats · min−1, respectively. Hepatic blood flow was significantly increased by 1.2 and 0.41 · min−1 after felodipine and nifedipine. There was also a decrease in diastolic blood pressure, 10 and 5 mm Hg, respectively, after felodipine and nifedipine. The forearm blood flow was increased by about 30 ml · 100 ml−1 · min−1 after felodipine, but nifedipine had no effect. The haemodynamic effects were most pronounced 50 min after drug administration.
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    Effect of high dose omeprazole on gastric pepsin secretion and serum pepsinogen levels in man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 173-176 
    Details
    ISSN: 1432-1041
    Keywords: omeprazole ; pepsinogen ; serum pepsinogen A ; serum pepsinogen C ; gastric pepsin ; urinary pepsinogen A ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To investigate the effect of omeprazole on serum and urinary pepsinogens and on gastric pepsin, 8 healthy male volunteers were studied before and after 9 days of treatment with omeprazole 60 mg/day p.o. Fasting serum samples and 24 h urine specimens were obtained, and gastric contents were aspirated at 15-min intervals, 4 prior to and 6 during pentagastrin 1.5 µg·kg−1·h−1 i.v. during intra-gastric perfusion with NaCl 0.9% and phenol red 3 mg·ml−1 as an inert recovery marker. Basal and pentagastrin-stimulated volume and acid secretion were significantly decreased. The basal and pentagastrin stimulated pepsin output remained unchanged but pepsin concentration in gastric secretion was increased. Administration of omeprazole resulted in a significant increase in the serum PGA and PGC levels. The 24-h urinary excretion of PGA increased, but that of PGC remained unchanged, and so did the renal clearances of creatinine and pepsinogen A. The renal clearance of pepsinogen C decreased. It was concluded that omeprazole did not affect gastric pepsin output, but, due to the decreased volume output, the concentration of pepsin in the gastric secretion was increased. Omeprazole increased the serum levels of pepsinogen A and C because more pepsinogen was released into the systemic circulation. This might be due to greater back-diffusion of pepsinogen from the gastric mucosa into the systemic circulation as a result of the higher pepsinogen concentration in gastric secretion.
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    URL: http://dx.doi.org/10.1007/BF00609248
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    Psychopharmacological effects of sertraline in normal, healthy volunteers (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 221-223 
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    ISSN: 1432-1041
    Keywords: sertraline ; antidepressants ; critical flicker fusion ; psychopharmacology ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A double-blind, placebo controlled, cross-over study was carried out in 10 normal healthy volunteers to investigate the effects of sertraline 25 mg, 50 mg, 75 mg and 100 mg on aspects of cognitive functioning. Changes with respect to placebo in objective tests of psychomotor function (critical flicker fusion and choice reaction time) showed that sertraline had an alerting effect. The changes were not consistent with subjective reports of drowsiness.
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    URL: http://dx.doi.org/10.1007/BF00609258
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    Pharmacokinetics and tolerance of a new penem antibiotic, FCE 22101, in healthy volunteers after a single intravenous dose (1989)
    Springer
    European journal of clinical pharmacology 36 (1989), S. 633-635 
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    ISSN: 1432-1041
    Keywords: FCE 22101 ; penem antibiotic ; pharmacokinetics ; single dose ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical tolerance and pharmacokinetics of FCE 22101 (sodium (5R, 6S)-6-[(1R)-hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate), a new penem antibiotic, have been studied after giving a single i.v. dose of 4 mg·kg−1 to ten healthy male volunteers. The pharmacokinetics was estimated according to a two-compartment open model. The peak plasma concentration (Cmax) was 15.5 (1.08) µg·ml−1, mean (SEM). FCE 22101 was rapidly cleared from the systemic circulation [ $$t_{1/2\lambda _z } $$ =44.2 (4.2) min; CL=7.21 (0.47) ml·kg−1·min−1]. The mean apparent volume of distribution at steady-state was 246 (16.9) ml·kg−1. The mean residence time relative to the 10 min infusion was 39.4 (1.5)min. Urinary recovery of FCE 22101 showed wide inter-subject variation, ranging from 10.2 to 53.6% of the dose. No subject complained of adverse effects.
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    The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 617-619 
    Details
    ISSN: 1432-1041
    Keywords: clotiazepam ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the single dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets in a cross-over study in 6 healthy volunteers (median age 28 years). The formulations had similar systemic availability. Compared with oral tablets the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.
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    URL: http://dx.doi.org/10.1007/BF00562556
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    A lack of pharmacokinetic interaction between ranitidine and piroxicam (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 583-586 
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    ISSN: 1432-1041
    Keywords: ranitidine ; piroxicam ; interaction ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng·ml−1 for ranitidine alone and 466 ng·ml−1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml−1 and 2551 h·ng ml−1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 μ·ml−1 in the presence of placebo and 2.0 μg·ml−1 in the presence of ranitidine respectively; mean AUC was 133 h·μg ml−1 and 137 h·μg ml−1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.
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    URL: http://dx.doi.org/10.1007/BF00316100
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    Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 71-75 
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    ISSN: 1432-1041
    Keywords: Isosorbide-5-mononitrate ; sustained-release formulation ; pharmacokinetics ; cardiovascular effects ; chronopharmacology ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values. The pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) did not differ after morning and after evening dosing, tmax being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of IS-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN. The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.
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    Calcitonin gene-related peptide (CGRP) causes redistribution of blood flow in humans (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 491-494 
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    ISSN: 1432-1041
    Keywords: blood flow ; calcitonin ; calcitonin gene-related peptide ; duplex-scan ; laser Doppler ; healthy volunteers ; cerebral blood flow ; skin blood flow ; intestinal blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In normal human subjects (n=6), blood flow in the common carotid artery, assessed with an ultrasonic duplex-scanning unit, was increased up to 152% of basal levels by 60-min infusions of human calcintonin gene-related peptide I (αCGRP) 80 pmol·kg−1·h−1, but it was not affected by 20 pmol·kg−1·h−1 CGRP or 88 pmol·kg1·h−1 human calcitonin. In the superior mesenteric artery, on the other hand, blood flow was reduced by 80 pmol·kg−1·h−1 CGRP to 58% of the basal level, but not by 20 pmol·kg−1·h−1 CGRP or with 88 pmol·kg−1·h−1 calcitonin. Blood flow in the abdominal aorta remained largely unchanged under the same conditions. Skin blood flow, assessed by a laser Doppler unit, was increased up to 682% of the basal level by 80 pmol·kg−1·h−1 CGRP, but not by 20 pmol·kg−1·h−1 CGRP or calcitonin. Thus CGRP increased regional blood flow to the brain and the skin at the expense of the gastrointestinal tract.
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    The effect of ranitidine and cimetidine on imipramine disposition (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 285-290 
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    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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    URL: http://dx.doi.org/10.1007/BF00981125
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  • 90
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    Femoxetine and cimetidine: Interaction in healthy volunteers (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 299-302 
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    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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    URL: http://dx.doi.org/10.1007/BF00981127
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    A dose-ranging study to evaluate the β1-adrenoceptor selectivity of bisoprolol (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 135-139 
    Details
    ISSN: 1432-1041
    Keywords: Atenolol ; bisoprolol ; β-adrenoceptor ; cardioselectivity ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A dose-ranging study was performed to compare the β1-adrenoceptor selectivity of bisoprolol with that of atenolol and nadolol. Seven normal subjects (mean age 26 y) were given single oral doses of bisoprolol 5 mg (B5), 10 mg (B10), 20 mg (B20); atenolol 50 mg (A50), 100 mg (A100); nadolol 40 mg (N40); and placebo (PL), in a single blind randomised cross-over design. β2-adrenoceptor responses were assessed by attenuation of finger tremor and cardiovascular responses to graded isoprenaline infusions. Dose-response curves were constructed, and doses of isoprenaline required to increase finger tremor by 100% (IT100), heart rate by 25 beats/min (IH25), SBP by 25 mm Hg (IS25), cardiac output by 35% (IC35), and decrease DBP by 10 mm Hg (ID10), after each treatment were calculated. These indices were compared with placebo response and expressed as dose-ratios. Exercise heart rate (EHR) was used to assess β1-adrenoceptor blockade. There were dose-related increases in plasma concentrations of bisoprolol and atenolol. Reduction of EHR was significantly less with B5 (16.8%) in comparison with all other treatments: B10 21.9%, B20 23.1%; A50 22.5%, A100 22.6%; N40 22.9%. There were small but significant reductions in isoprenaline-induced tachycardia with bisoprolol and atenolol, although mean dose-ratios were considerably less in comparison with N40 (IH25 dose-ratios): B5 2.55, B10 3.18, B20 3.93, A50 2.91, A100 4.89, N40 17.23. There were similar patterns for the other isoprenaline responses. These results show that conventional doses of bisoprolol (10 mg) and atenolol (50 mg) produced equal antagonism of β1 and β2-adrenoceptors, and therefore possess equal degrees of β1-adrenoceptor selectivity. Increasing doses of bisoprolol and atenolol were associated with partial loss of selective β1-adrenoceptor blockade, although antagonism of β2-adrenoceptors was significantly less compared with the effects of nadolol.
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    A comparison of the effects of digoxin and digitoxin on systolic time intervals and colour vision (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 221-223 
    Details
    ISSN: 1432-1041
    Keywords: Digoxin ; digitoxin ; pharmacodynamic differences ; colour vision ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Animal studies suggest that for the same inotropism hydrophilic cardiac glycosides produce greater depression of atrioventricular (AV) conduction than lipophilic ones. This has been explained on the basis of a greater vagomimetic effect with hydrophilic agents and a greater sympathomimetic effect with lipophilic agents. In this randomized, cross-over study we investigated the effects of placebo, digoxin (relatively hydrophilic), and digitoxin (relatively lipophilic) in twelve healthy volunteers. For both drugs steady-state serum concentrations in the mid-therapeutic range were achieved. Both drugs produced the same positive inotropic effect as measured by systolic time intervals (QS2c). There was a trend for digoxin to have a greater effect on AV conduction than digitoxin. After atropine or propranolol there was no difference between the effect of the two cardiac glycosides on AV conduction. No significant effects on colour vision were seen. We conclude that, there do not seem to be pharmacodynamic differences between digoxin and digitoxin at mid-therapeutic serum concentrations.
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    Atropine and verapamil interactions in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 317-318 
    Details
    ISSN: 1432-1041
    Keywords: Verapamil ; atropine ; calcium antagonists ; anticholinergic ; heart-rate ; atrio-ventricular conduction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The calcium antagonist falipamil, a chemical congener of verapamil, has anticholinergic properties. It was decided to study the interaction of verapamil with the anticholinergic drugs, atropine and pirenzepine, using healthy male volunteers. After atropine alone a significant tachycardia developed at 2 min and remained significant up to 90 min. Verapamil pretreatment followed by atropine administration resulted in a significantly greater tachycardia. Pirenzepine alone caused a bradycardic response which was accentuated after verapamil pretreatment. It is postulated that short term verapamil administration is accompanied by reflex activation of the sympathetic nervous system which does not manifest with a tachycardia owing to combined influence of verapamil and vagus on the sino-atrial node. Reduction of vagal tone with atropine treatment results in sympathetic overriding of the sino-atrial suppression, thus causing an additive tachycardia. The clinical use of atropine for prolonged verapamil-induced atrio-ventricular conduction is supported by these results.
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    Electrocardiographic and hemodynamic effects of tocainide (W-36095) in man (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 15-19 
    Details
    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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    Pharmacokinetics of TRIS (hydroxymethyl-)aminomethane in healthy subjects and in patients with metabolic acidosis (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 257-264 
    Details
    ISSN: 1432-1041
    Keywords: TRIS buffer ; metabolic acidosis ; pharmacokinetics ; cellular uptake ; renal excretion ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg=1 mmol/kg; pH 7.4) and to 20 patients suffering from metabolic acidosis (109–376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,β=5.6 h) and patients with intact renal function (t0.5,β=16.3–45.6 h). The final volume of distribution (Vβ) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.
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    Monoamine oxidase inhibition by tranylcypromine: Assessment in human volunteers (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 301-308 
    Details
    ISSN: 1432-1041
    Keywords: tranylcypromine ; tryptamine excretion ; monoamine oxidase inhibition ; norepinephrine pressor test ; tyramine pressor test ; pharmacodynamic half-life ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The inhibition of monoamine oxidase (MAO) by tranylcypromine was studied in 6 healthy volunteers given increasing doses of 10, 15, 20 and 25 mg/day over a 4 week period. Measurements were made of urinary tryptamine excretion, blood pressure response to tyramine (TY) and norepinephrine (NE), and subjective self-rating. A significant increase in urinary tryptamine, indicating the onset of MAO inhibition, occurred in all 6 subjects once the cumulative dose of 40 mg TC had been administered. Thereafter, urinary tryptamine increased up to 7-fold, dose-dependently with large interindividual variation (78±27 to 549±252 µg/g creatinine). Within 4 days after stopping the drug, control values were reached again. The assessment of TY potentiation by comparison of equieffective doses (Sdose) became up to 10 times more sensitive when both the height and the duration of the increase in systolic blood pressure (SAUC) were taken into account. The increases in tyramine sensitivity found with the highest cumulative doses of TC (5.4±0.8 mg/kg; n=6) were Sdose from 8–16 and SAUC from 28–162, respectively. The pharmacodynamic half-life (Pd1/2) of TC approximated a mean first fast Pd1/2 of 1.3 d and a slower phase of 14.2 d. During treatment with the highest TC dose, resting blood pressure was significantly elevated from 120 to 128 mm Hg, and the pressor sensitivity to NE (SNE) in 4 of the 6 subjects rose, the mean was 1.7 (n=6). In 3 volunteers NE sensitivity was normalized within 4 days after stopping TC. There was a significant correlation between increasing vigilance with TC dose in 5 volunteers (r=0.81, n=15, p〈0.01). It is concluded that combination of the results of several tests has provided reliable information about the onset, extent and duration of MAO inhibition in healthy volunteers.
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    Effect of zopiclone on the arousal level of healthy volunteers assessed by the averaged photopalpebral reflex (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 469-474 
    Details
    ISSN: 1432-1041
    Keywords: zopiclone ; nitrazepam ; photopalpebral reflex (PPR) ; hypnotic effect ; side effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The averaged photopalpebral reflex (PPR) represents the mean of summed reflex contractions of the orbicularis oculi muscle in response to periodic photic stimuli. The latency of PPR can be used to assess a drug effect on human arousal level, since it is prolonged if there is a reduction in the arousal level of the subject. In the present study of the clinical effects of zopiclone, healthy male volunteers aged 18–22 years were given zopiclone 5 mg and 10 mg, nitrazepam 5 mg and 10 mg, or placebo, in a double-blind, cross-over design. Changes in the latencies of PPR were examined from 0.5 to 4 h after medication. Both zopiclone and nitrazepam prolonged the latency in a dose-dependent manner, but the prolongation induced by zopiclone appeared more rapidly, was slightly more marked and lasted for a shorter period than that induced by nitrazepam. Zopiclone produced slightly fewer subjective changes, such as vagueness of thought and weakness, than did nitrazepam. From these results, it is suggested that zopiclone possesses a potent hypnotic action which appears more rapidly and is slightly more potent and shorter lasting than that of nitrazepam. In addition, zopiclone may also exhibit fewer side effects, such as vagueness of thought and weakness than nitrazepam, and it may cause less “hang over”.
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    Alcohol and bupropion pharmacokinetics in healthy male volunteers (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 627-630 
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    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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    Influence of slow calcium-channel blockade on the cardiovascular effects of coffee (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 171-175 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614297
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    Electronic Resource
    Electronic Resource
    Pharmacokinetics of fenfluramine and norfenfluramine in volunteers given d- and dl-fenfluramine for 15 days (1985)
    Springer
    European journal of clinical pharmacology 29 (1985), S. 221-224 
    Details
    ISSN: 1432-1041
    Keywords: fenfluramine ; norfenfluramine ; isomers ; pharmacokinetics ; healthy volunteers ; chronic treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of accumulation and elimination of d- and l-fenfluramine (F) and norfenfluramine (NF) have been studied in 8 young healthy volunteers given daily doses of 60 mg of sugar-coated tablets of 20 mg dl-F hydrochloride (dl-F) t.i.d. and capsules of 15 mg d-F hydrochloride (d-F) b.i.d. for 15 days. Repeated doses of d-F plus l-F gave the same values for the parameters measured as did d-F administered alone. Steady-state concentrations of all compounds were achieved within 4–8 days. The predicted mean steady-state concentrations of d-F and elimination half-lives calculated from the results of a previous single dose study were similar to those measured at steady state in this study, confirming the lack of effect of the drug on hepatic microsomal enzymes and on kinetics after repeated dosing. d-NF concentrations were approximately half those of the parent drug and the half-life was almost twice as long. Steady state concentrations both of L-f and l-NF were consistently about 40–50% higher than of the d-isomers and there was a comparable in the half-life.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00547426
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