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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 63 (1985), S. 1170-1173 
    ISSN: 1432-1440
    Keywords: Trinitroglycerin ; Dinitroglycerin ; β-Blockade
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ten healthy volunteers ingested a single 18-mg oral dose of sustained release nitroglycerin (TNG) (Giulini-Pharma) on three occasions: once in the control state, once during coadministration of propranolol (80-mg three times daily), and once during coadministration of metoprolol (100-mg twice daily). The degree of beta adrenergic blockade was evaluated by the metaproterenol infusion test. Plasma concentration of TNG and its major metabolite, 1,2-dinitroglycerin (DNG), during 12 h after each dose were measured by gas chromatography-mass spectrometry. Intact TNG was not detected in the plasma of any patient. The major metabolite, DNG, was easily measurable in blood, and had a biphasic plasma concentration profile. Coadministration of the beta-blockers had no influence on any of the kinetic variables for DNG. The mean values during control, propranolol, and metoprolol trials of DNG elimination half-life were: 1.35, 1.10, and 1.09 h; total area under the curve: 42, 38, and 42 ng/ml × h; oral clearance: 6.6, 7.2, and 6.4 liters/min. Thus TNG when administered as a sustained release oral preparation is rapidly and completely transformed to DNG. There was no pharmacokinetic interaction between sustained release TNG and two commonly used beta-blocking agents, suggesting that any clinical interaction that may-occur between sustained release nitroglycerin and beta-blocking agents is pharmacodynamic rather than pharmacokinetic in nature.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 59 (1981), S. 501-507 
    ISSN: 1432-1440
    Keywords: Digoxin-concentration ; Bioavailability ; Digitalis-Intoxication ; Digoxin-Konzentration ; Glykosidintoxikation ; biologische Verfügbarkeit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei 463 chronisch digitalisierten Patienten, die während eines Jahres zur stationären Aufnahme kamen, konnten prospektiv verschiedene Faktoren, die die Serum-Digoxin-Konzentration zu beeinflussen vermögen, untersucht werden. Die meisten Patienten nahmen β-Acetyl- oder β-Methyldigoxin ein. Mit Alter, Geschlecht, Kreatinin-Clearance sowie gewichtskorrigierter Dosis ließen sich weniger als 7% der Gesamtvariabilität der Serum-Digoxinkonzentration erklären. Von diesen Parametern war die Kreatinin-Clearance, die mit zunehmendem Alter signifikant abfiel (r=−0,36;p〈0,001), der bedeutendste Faktor. Eine ST-Streckensenkung bestand bei der Mehrzahl der Patienten; sie wurde mit höherer Digoxin-Konzentration deutlicher. Dagegen konnte keine Beziehung zwischen QT- und PR-Intervall, QRS-Dauer oder AV-Zeit im EKG und den Digoxinspiegeln abgeleitet werden. Bei 75 Patienten mit Vorhofflimmern nahm die Ventrikelfrequenz mit höheren Digoxin-Konzentrationen zu. Gastrointestinale, neuromuskuläre oder zentralnervöse Symptome, die mit einer Digitalis-Überdosierung zu vereinbaren sind, wiesen keine signifikante Korrelation mit den Glykosid-Spiegeln auf. Serumdigoxinkonzentrationen sind isoliert betrachtet nur von begrenztem Wert und sollten nur im Kontext mit dem klinischen Bild interpretiert werden.
    Notes: Summary Factors influencing serum digoxin concentrations, and the relation of these levels to classical electrocardiographic (ECG) and clinical manifestations of toxicity, were assessed in a series of 463 consecutively hospitalized patients of mean age 58 years. The majority of patients were receiving beta-acetyldigoxin or beta-methyldigoxin. Age, sex, creatinine clearance, and weight-corrected dose collectively explained less than 7% of overall variability in serum digoxin concentrations; creatinine clearance, which declined significantly with age (r=−0.36,p〈0.001) was the most important of these determinants. ST-segment depression was present in the majority of patients and became more common at higher serum digoxin concentrations. However, PR interval, QRS duration, QT interval, or the presence of AV block were not associated with serum levels. Among 75 patients with atrial fibrillation, ventricular rate did not decline with increasing digoxin concentrations. The presence of gastrointestinal, neuromuscular, or psychiatric symptoms classically attributed to digitalis toxicity was not associated with serum digoxin concentration. Serum levels of digoxin appear to be of limited value in assessing the degree of digitalization.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 59 (1981), S. 899-903 
    ISSN: 1432-1440
    Keywords: Oxazepam ; Pharmacokinetics ; Sex differences ; Smoking habits ; Oxazepam ; Pharmakokinetik ; Geschlechtsunterschiede ; Rauchergewohnheiten
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei 31 Versuchspersonen (22 männliche, neun weibliche) wurde die Kinetik von Oxazepam nach einer einmaligen oralen Gabe von 30 mg gaschromatographisch bestimmt. Das mittlere Alter der beiden Versuchsgruppen lag bei 51 bzw. 44 Jahren (Bereich: 22–86 Jahre). Die kinetischen Variablen für die männlichen und weiblichen Versuchsgruppen lauten (in Klammern der Bereich): Eliminationshalbwertzeit: 7,5 h (3,2 h–19,8 h) bzw. 8,5 h (3,4 h–12,4 h); Verteilungsvolumen: 0,96 (0,44–2,91) bzw. 1,17 (0.60–-3,12) l/kg Körpergewicht; Clearance 1,48 (0,62–3,00) bzw. 1,70 (0,56–3,73) ml/min/kg; Zeitpunkt der maximalen Plasmakonzentration: 2,2 h (0,75 h–6,0 h) bzw. 1,7 h (0,75 h–3,0 h) nach Tabletteneinnahme; maximale Plasmakonzentration 646 (242–1195) bzw. 653 (447–854) ng/ml. Geschlechtsbedingte Unterschiede in der Kinetik ließen sich im Gegensatz zu anderen Benzodiazepinen, wie z.B. Diazepam oder Desmethyldiazepam, nicht nachweisen. Ebenso bestanden keine signifikanten Korrelationen zwischen den kinetischen Variablen und dem Alter der Probanden. Auch hierin unterscheidet sich Oxazepam von den meisten anderen Benzodiazepinen. Dagegen ließ sich eine signifikante Beziehung zwischen der Clearance und dem Zigarettenkonsum der Probanden ableiten: sie war bei den Rauchern mit 1,98 ml/min/kg deutlich höher als bei den Nichtrauchern (1,23 ml/min/kg) (p〈0,01). Im Gegensatz zu anderen Benzodiazepinen beeinflussen die Rauchergewohnheiten die Kinetik des Oxazepam mehr als die alters- oder geschlechtsgebundenen Faktoren.
    Notes: Summary The kinetics of single 30-mg oral doses of oxazepam were determined in 22 male and nine female volunteers aged 20–86 years. Oxazepam plasma concentrations were measured in multiple plasma samples drawn during 36 h after each dose. Mean kinetic variables in males and females, respectively, were: elimination half-life, 7.5 and 8.5 h; volume of distribution, 0.96 and 1.17 l/kg; clearance, 1.48 and 1.70 ml/min/kg. Sex differences were not significant, nor were any of the kinetic variables significantly related to age. However, oxazepam clerance increased significantly with heavier cigarette smoking (r=0.48,p〈0.01). Mean clearance in smokers (1.98 ml/min/kg) was significantly higher than in non-smokers (1.23 ml/min/kg,p〈0.01). Thus, smoking is a more important determinant of oxazepam clearance than age or sex.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 59 (1981), S. 889-897 
    ISSN: 1432-1440
    Keywords: Digoxin ; Digitoxin ; Pharmacokinetics ; Pharmacodynamics ; Digoxin ; Digitoxin ; Pharmakokinetik ; Pharmakodynamik
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Gesunde Versuchspersonen erhielten eine einmalige Gabe von 1,0 mg Digoxin (n=10) oder Digitoxin (n=12). Die Kinetik der Glykoside wurde anhand der Plasma-Konzentrationszeitkurve über 48 h (Digoxin) oder 14 Tage (Digitoxin) analysiert. Während der ersten 24 h nach der Glykosidapplikation erfolgten in häufigen Zeitabständen die Registrierung von EKG, Echokardiogramm und Blutdruck. Um unspezifische kardiovaskuläre Änderungen auszuschließen, wurden die pharmakodynamischen Parameter nach Kochsalzinjektion erneut bestimmt. Die kinetischen Variablen (±SE) für Digoxin lauteten: Verteilungsvolumen (Vd) 8,3±0,6 l/kg Körpergewicht, Eliminationshalbwertzeit (Elt 1/2) 49±5 h, Clearance 2,1±0,2 ml/min/kg Körpergewicht. Die Digoxingabe führte nur zu geringen Änderungen von Blutdruck, Herzfrequenz und korrigiertem QT-Intervall. Dagegen nahm die echokardiographisch bestimmte zirkumferentielle Faserverkürzungsgeschwindigkeit und Ejektionsfraktion nach Digoxin im Vergleich zu Placebo signifikant zu. Das Maximum der Inotropie-Änderung wurde 4–6 h nach Digoxin-Applikation registriert. Die Änderungen von mVcf und EF korrelierten signifikant mit den Plasma-Digoxinkonzentrationen. 24 h nach Digoxin-Injektion waren die Ausgangswerte von mVcf und EF wieder erreicht. Die kinetischen Variablen für Digitoxin lauteten: Vd 0,63±0,03 l/kg; Elt 1/2 7,3±0,4 Tage; Clearance 0,043±0,003 ml/min/kg. Wie die Gabe von Digoxin führte die Digitoxininfusion nur zu geringfügigen Änderungen von Blutdruck, Herzfrequenz und QT-Intervall. Dagegen nahmen mVcf und EF im Vergleich zur Kochsalzinfusion signifikant zu. Die maximalen Änderungen wurden 4–8 h nach der Digitoxin-Infusion gemessen und korrelierten mit den Plasma-Digitoxinkonzentrationen. Somit steigern Digoxin und Digitoxin die myokardiale Kontraktilität gesunder Versuchspersonen im Vergleich zu einer Placebo-Gabe, jedoch ohne Herzfrequenz und Blutdruck zu beeinflussen. Das Maximum der Kontraktilitätsänderung ist erst nach ca. 4 h erreicht und hängt wahrscheinlich mit der langsamen Verteilung der Glykoside zusammen.
    Notes: Summary Healthy volunteers received single 1.0-mg doses of intravenous digoxin (n=10) or digitoxin (n=12). Glycoside pharmacokinetics were determined from multiple plasma samples drawn over the 48 hours (for digoxin) or 14 days (for digitoxin) after the dose. Electrocardiogram, echocardiogram, and blood pressure were recorded at multiple time points 24 h after the dose. To control for nonspecific cardiovascular changes, pharmacodynamic measurements were repeated on a second occasion for 8 hours after an intravenous injection of saline. Mean (±S.E.) kinetic variables for digoxin were: volume of distribution (Vd), 8.3 (±0.6) l/kg; elimination half-life (t1/2), 49 (±5) h; clearance 2.1 (±0.2) ml/min/kg. Changes in blood pressure, ventricular rate, and corrected QT-interval attributable to digoxin were small. However, echocardiographically-determined mean rate of circumferential fibre shortening (mVcf) and ejection fraction (EF) increased significantly following digoxin when compared to saline infusion. Changes were maximal at 4–6 h after dosage, and were highly correlated with plasma digoxin concentration. mVcf and EF returned to baseline by 24 h post-dosage. Mean kinetic variables for digitoxin were: Vd, 0.63 (±0.03) l/kg; t1/2, 7.3 (±0.4) days; clearance, 0.043 (±0.003) ml/min/kg. Like digoxin, digitoxin infusion produced minimal change in blood pressure, ventricular rate, or QT-interval. However, mVcf and EF increased significantly when compared to saline control. Changes were maximal at 4–8 h after infusion, and were correlated with plasma digitoxin concentration; at 24 h post-dosage, mVcf and EF were still increased over baseline. Thus, digoxin and digitoxin significantly increase myocardial contractility in healthy humans, but without important change in heart rate and blood pressure. Changes in contractility are of slow onset, probably due to slow distribution of glycoside to sites of pharmacologic activity.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 62 (1984), S. 765-767 
    ISSN: 1432-1440
    Keywords: Oxazepam ; Pharmacokinetics ; Benzodiazepines ; Renal failure ; Hemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of a single 30-mg oral dose of oxazepam was evaluated in seven patients with chronic renal failure on maintenance hemodialysis and in seven healthy controls matched for age and sex. Based on total (free plus bound) serum oxazepam concentrations, elimination half-life was prolonged in renal patients compared to controls (22 vs 8 h,p〈0.001) and volume of distribution increased (3.0 vs 1.4 1/kg,p〈0.02). However, total clearance was similar between groups (1.8 vs 1.9 ml/min per kilogram). These findings were confounded by the increased oxazepam free fraction in serum of renal failure patients (10.3%) as compared to healthy controls (4.3%). Correction for differences in binding indicates similar distribution of unbound oxazepam between groups, but reduced clearance of pharmacologically active unbound oxazepam in renal patients (18 vs 45 ml/min per kilogram). Oxazepam dosage, therefore, may require downward adjustment for renal failure patients on hemodialysis.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 61 (1983), S. 379-380 
    ISSN: 1432-1440
    Keywords: Serum lidocaine concentrations ; Bronchoscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Serum lidocaine concentrations were measured in a series of ten patients during and after topical lidocaine spray anesthesia used for diagnostic fiberoptic bronchoscopy. Mean total dose of lidocaine ranged from 480–720 mg. Peak serum lidocaine concentrations averaged 3.6 ώg/ml (range: 1.9 to 7.4 µg/ml), and were attained shortly after the start of the procedure. Repeated topical administration of lidocaine spray therefore may lead to large cumulative doses and serum concentrations which are in the therapeutic or potentially toxic range.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 64 (1986), S. 1213-1216 
    ISSN: 1432-1440
    Keywords: Isosorbide mononitrate ; Isosorbide dinitrate ; Beta-blocker ; Pharmacokinetics ; Propranolol ; Metipranolol ; Metoprolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min,P〈0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1440
    Keywords: Pharmacokinetics ; Desmethyldiazepam ; Clorazepate ; Propranolol ; Smoking
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The influence of propranolol coadministration or of cigarette smoking on the kinetics of desmethyldiazepam following a single 20-mg intravenous dose of clorazepate dipotassium was evaluated in healthy volunteers. In Study One, intravenous clorazepate was given once in the control condition, and again during coadministration of propranolol, 80 mg twice daily. Compliance with the prescribed propranolol regimen was verified by measurement of serum propranolol concentrations (mean, 37 ng/ml). In control vs propranolol treatment conditions, there was no significant difference in desmethyldiazepam volume of distribution (1.27 vs 1.23 liters/kg) or in free fraction in serum (1.83 vs 1.80% unbound). There was a small although statistically significant prolongation of desmethyldiazepam half-life (55 vs 61 h,P〈0.05) and reduction in clearance (0.281 vs 0.247 ml/min/kg,P〈0.02) attributable to propranolol. In Study Two, desmethyldiazepam kinetics were compared in eight cigarette smokers (mean, 19 cigarettes/day) and in 11 nonsmoking controls matched for age, sex, and body weight. There was no significant difference between controls and cigarette smokers in desmethyldiazepam volume of distribution (1.29 vs 1.34 liters/kg), elimination half-life (55 vs 59 h), clearance (0.284 vs 0.276 ml/min/kg), or free fraction in serum (1.96 vs 1.92% unbound). Thus, propranolol slightly although significantly impairs the clearance of desmethyldiazepam and prolongs its halflife. Cigarette smoking has no apparent influence on desmethyldiazepam kinetics.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 62 (1984), S. 427-429 
    ISSN: 1432-1440
    Keywords: Nifedipine ; Pharmacokinetics ; Hemodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Serum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 µg/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3–12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 64 (1986), S. 636-641 
    ISSN: 1432-1440
    Keywords: Pharmacokinetics ; Pharmacodynamics ; Stereoselectivity ; Penbutolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics and dynamics of thed- andl-isomers of the beta-adrenergic blocking agent penbutolol were investigated in healthy human volunteers. In Study One, subjects received a single 40-mg oral dose ofl-penbutolol (the pharmacologically active stereoisomer), and matching placebo on two occasions. A mean peak serum penbutolol concentration of 268 ng/ml was reached at 0.9 h after dosing. Elimination half-life averaged 1.6 h, and total clearance 16.6 ml/min per kg body weight. Changes in blood pressure, ventricular rate, and rate of circumferential fiber shortening (Vcf) did not differ betweenl-penbutolol and placebo. In Study Two, subjects received 40 mgd-penbutolo,l-penbutolol, and placebo on three occasions. Total clearance ofd-penbutolol was higher than for thel-isomer (43.7 vs 15.9 ml/min/kg;P〈0.01); this was reflected in correspondingly increased area under the serum concentration curve for conjugates of the oxidized metabolite 4-hydroxy penbutolol (2.25 vs 0.66 µg/ml×h;P〈0.005). In contrast, direct conjugates ofl-penbutolol achieved higher serum concentrations than conjugates ofd-penbutolol. Alterations in blood pressure, ventricular rate, and Vcf ford-penbutolol,l-penbutolol, and placebo were quantitatively small. Thus the clearance of penbutolol after oral administration in humans is stereoselective, but the oxidative pathway is more stereosensitive than the parallel conjugative pathway. Penbutolol causes minimal alterations in parameters of cardiac function after single 40-mg doses in healthy humans.
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