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  • Articles  (105)
  • pharmacodynamics  (95)
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  • Springer  (105)
  • 1990-1994  (95)
  • 1975-1979  (10)
  • Chemistry and Pharmacology  (105)
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  • Articles  (105)
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  • 1
    Electronic Resource
    Electronic Resource
    Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 123-126 
    Details
    ISSN: 1432-1041
    Keywords: Steroid 5α-reductase inhibitor ; Testosterone metabolism ; MK-0434 ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A four-period, two-panel, single-rising-dose study (0.1–100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5α-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h and maintained through 48 h post treatment. The maximum reduction was approximately 50 % and occurred at all doses above 5 mg (10, 25, 50 and 100 mg). MK-0434 appeared to have no effect on serum testosterone at these single doses. Rising single doses of MK-0434 were associated with an increase in Cmax and AUC but the changes were less than proportional to dose, most likely due to nonlinear absorption. MK-0434 given in single doses up to 100 mg was without significant adverse effects in healthy male volunteers. In summary, MK-0434 is a well-tolerated, potent, orally active 5α-reductase inhibitor in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199874
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  • 2
    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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  • 3
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 163-166 
    Details
    ISSN: 1432-1041
    Keywords: Medifoxamine ; pharmacokinetics ; pharmacodynamics ; elderly volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and psychomotor effects of medifoxamine, a 5 HT reuptake inhibitory antidepressant, were studied in healthy elderly volunteers after single and multiple dosing. The elimination half life (t1/2z) after single doses of 300 mg was 2.8 h — almost identical to that found in young volunteers. After seven days of dosing at 100 mg three times daily the mean corrected AUC after 300 mg significantly increased from 1.04 to 1.34 mg.h.l−1 and t1/2z increased to 4.0 h (NS). There were no significant changes in critical flicker fusion frequency, symbol digit substitution, continuous attention or choice reaction times.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199882
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  • 4
    Electronic Resource
    Electronic Resource
    Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 165-169 
    Details
    ISSN: 1432-1041
    Keywords: Fosinopril ; fosinoprilat ; CAPD ; ACE-inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng·ml−1, 4.8 h, and 3.19 μg·h·ml−1, respectively. Values for 1 CAPD patient with liver dysfunction were t1/2 of 65.4 h, Cmax of 182 ng·ml−1, tmax of 9 h, and AUC of 18.1 μg·h·ml−1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml·min−1. Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265911
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  • 5
    Electronic Resource
    Electronic Resource
    RU 41 656 does not reverse the scopolamine-induced cognitive deficit in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 225-231 
    Details
    ISSN: 1432-1041
    Keywords: RU 41 656 ; Scopolamine ; pharmacodynamics ; psychomotor performance ; memory ; drug interaction ; dementia model ; dopamine (D2) agonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The potential antagonism of a single oral dose of RU 41 656 10 mg on the memory and attention disturbances induced by scopolamine 0.6 mg s.c. have been investigated in a 3 period, placebo controlled, double blind, cross over study in 12 healthy, young volunteers. The effects of the compounds were evaluated by objective tests (Buschke selective reminding test, CFF, simple reaction time, tapping, arithmetical calculation) and subjective measurements (visual analogue scale, side effects questionnaire). Measurements were taken before treatment and 2, 4 and 7 h after RU 41 656. Scopolamine caused anterograde amnesia and sedative effects as which were not counteracted by RU 41 656.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315434
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  • 6
    Electronic Resource
    Electronic Resource
    Interaction of ORG 10172, a low molecular weight heparinoid, and digoxin in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 245-250 
    Details
    ISSN: 1432-1041
    Keywords: Org 10172 ; Digoxin ; heparinoid ; pharmacokinetics ; pharmacodynamics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Potential pharmacokinetic and pharmacodynamic interactions between a new low molecular weight heparinoid Org 10172 (bolus injection of 3250 anti-Xa units) and digoxin (0.25 mg once daily for 8 days) were studied in 6 healthy male volunteers using an open, randomised three-way cross-over design. Digoxin produced a slight increase in clearance of anti-Xa activity from 4.3 to 4.8 ml·min−1, while plasma anti-thrombin and thrombin generation inhibiting (TGI) activity remained unchanged. Digoxin did not affect the actions of Org 10172 on the clotting tests. In the presence of Org 10172 there was a reduction in the AUC of digoxin during one dosing interval after the seventh digoxin tablet from 20 to 17 ng·ml−1·h, and a significant reduction in the average serum digoxin conentration. Since renal digoxin clearance was not significantly changed this probably might be due to a change in the non-renal clearance of digoxin. Atrio-ventricular node conduction, as measured by PR-time intervals, remained unchanged during all three treatments. In conclusion, although the pharmacokinetics of Org 10172 and digoxin were slightly changed by the combination, it is probably safe to administer Org 10172 and digoxin simultaneously. The clinical relevance of the slight decrease in plasma anti-Xa activity levels cannot yet be defined.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315437
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  • 7
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 439-443 
    Details
    ISSN: 1432-1041
    Keywords: Alprazolam ; benzodiazepines ; pharmacokinetics ; pharmacodynamics ; sublingual dosage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study. The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes. Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography. Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P〈0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml−1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml−1. Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h. In general the two routes were significantly different from placebo but not from each other.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280132
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  • 8
    Electronic Resource
    Electronic Resource
    The pharmacokinetic and pharmacodynamic interactions of ramipril with propranolol (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 255-260 
    Details
    ISSN: 1432-1041
    Keywords: Ramipril ; Propranolol ; interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacodynamic effects of ramipril, propranolol, and their combination, as well as the effect of propranolol on the pharmacokinetics of ramipril in 12 healthy men (age 24 (SD 6) y, weight 72 (7) kg). Propranolol and placebo, ramipril and placebo, or propranolol and ramipril were given orally for four days in a crossover, double-blind fashion. The pharmacokinetics of ramipril and ramiprilat were investigated on day 4. Effects on plasma renin activity, ACE activity, and heart rate and blood pressure both before and after a standardized exercise test were measured on days 1 and 4. On day 4 the combination reduced the mean arterial pressure by 2.8 mmHg compared with propranolol alone and by 3.7 mmHg compared with ramipril alone. Ramipril had no effect on the bradycardia induced by propranolol. Propranolol reduced exercise mean arterial pressure by 9 mmHg (day 4) and heart rate by 7 beats.min−1 (day 4) compared with ramipril; this was not affected by co-administration of ramipril. On day 4 the average plasma renin activity was not significantly higher than after the combination. ACE activity was not affected by propranolol. The pharmacokinetics of ramipril and ramiprilat were not influenced by propranolol. The combination of ramipril and propranolol has additive pharmacodynamic effects that may be useful in the treatment of hypertension.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315392
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of famotidine in patients with reflux oesophagitis (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 357-360 
    Details
    ISSN: 1432-1041
    Keywords: Famotidine ; Reflux oesophagitis ; intraoesophageal long-term pH-metry ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics, pharmacodynamic effect and clinical efficacy of famotidine were studied in 10 patients with reflux oesophagitis Grades I and II. For the pharmacokinetic studies the patients received 20 mg famotidine i. v. The half-life of famotidine was 3.8 h, the total plasma clearance was 297 ml·min−1, and a steady state volume of distribution of 1.21·kg−1 was found. For pharmacodynamic assessment, intraoesophageal pH-metry was performed without and after acute treatment with famotidine 20 mg i. v. and following 3 weeks of oral famotidine 80 mg b. d. The resultant percentage total acid exposure time (pH〈4 within 24 h) were 23.9%, 19.0% and 19.2% (median), respectively (NS). At the end of 6 weeks of oral therapy, symptomatic and endoscopic improvement had occurred in 9 and 5 patients, respectively. Our study shows that the pharmacokinetics of famotidine in patients with reflux oesophagitis is comparable to that in healthy volunteers and peptic ulcer patients. The clinical response to the treatment appeared comparable to that found after other H2-receptor antagonists.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316472
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  • 10
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of quinaprilat after low dose quinapril in patients with terminal renal failure (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. S53 
    Details
    ISSN: 1432-1041
    Keywords: Quinapril ; Renal failure ; quinaprilat ; haemodialysis ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of the ACE inhibitor quinaprilat have been studied in six chronic haemodialysis (HD) patients and in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after a single oral dose of 2.5 mg quinapril. Mean tmax and Cmax values (SEM) for quinaprilat in interdialytic HD patients were 4.0 (0) h and 84 (8.4) ng · ml−1 respectively, and they did not differ significantly from those in CAPD patients (4.7 (0.7) h and 64 (5.7) ng · ml−1). Elimination half lives were 30 (10.1) h (HD) and 34 (7.3) h (CAPD). Cmax, tmax, t/12, and AUC were increased and CL was decreased compared to data reported previously after giving 2.5 mg to healthy subjects. Peritoneal clearance was calculated as 0.1 (0.1) ml · min−1, thus less than 0.5 % of the dose were removed within 24 h by CAPD. ACE activity was suppressed by more than 93 % between 4 and 24 h postdose (P 〈 0.001). It decreased in both groups with increasing plasma quinaprilat levels. Angiotensin II concentration compared to baseline was significantly decreased at 4 hours (−30.4±10 %) and 24 h (−30±9.9 %) (P 〈 0.05,n=11), while active plasma renin concentration was still significantly increased at 48 h postdose (+60.2±14.5 %,P 〈 0.01). Mean arterial pressure 24 h postdose was significantly (P 〈 0.05) decreased in HD (−12 mm Hg) and CAPD patients (− 20 mm Hg). Only two patients reported unwanted effects (fatigue, dizziness, nausea, and weakness). In conclusion, due to its long lasting effect on ACE activity and on blood pressure in terminal renal failure a starting dose of quinapril 2.5 mg o. d. may be used in hypertensive HD and CAPD patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01428395
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  • 11
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315499
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  • 12
    Electronic Resource
    Electronic Resource
    Population approaches in drug development (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 389-391 
    Details
    ISSN: 1432-1041
    Keywords: Population approach ; Drug development ; software ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis. The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development. The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191898
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  • 13
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 537-543 
    Details
    ISSN: 1432-1041
    Keywords: Lisinopril ; Dose adjustment ; ACE inhibitors ; pharmacokinetics ; pharmacodynamics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e. g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n=8; endogenous creatinine clearance [CLCR]: 18 ml·min−1·1.73m−2) and in healthy subjects with normal renal function (n=16; CLCR: 107 ml·min−1·1.73m−2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1–2.2 mg) was adjusted to the individual CLCR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (C max) in patients was lower than in volunteers (30.7 vs 40.7 ng·ml−1, while the mean area under the concentration-time curve (AUC 0–24 h) was higher (525 vs 473 ng·h−1·ml−1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9–2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose. Despite substantial dose reduction, blood pressure and proteinuria decreases were observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196112
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  • 14
    Electronic Resource
    Electronic Resource
    Relation between plasma concentrations and cardiovascular effects of oral oxprenolol in man (1975)
    Springer
    European journal of clinical pharmacology 8 (1975), S. 3-9 
    Details
    ISSN: 1432-1041
    Keywords: Oxprenolol ; plasma concentrations ; cardiac effects ; blood pressure ; oral dosing ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Oxprenolol, 40, 80 and 160 mg, was administered orally to seven healthy volunteers. Over the following eight hours repeated measurements were made of the plasma concentrations and effects on heart rate, myocardial contractility (PEPC) and systolic and diastolic blood pressure in recumbency, in the upright position and during physical effort at a work load of 120 watts on a bicycle ergometer. The maximum plasma levels and the area beneath the plasma concentration curves increased roughly in proportion to the dosage increment. No evidence of first-pass inactivation in the liver was found. The half-life of the drug in plasma was approximately 80 minutes, irrespective of the dose administered. Oxprenolol slowed heart rate, prolonged PEPC and lowered systolic blood pressure, by comparison with values recorded after a placebo. The effects were generally least marked in the recumbent position and most marked during effort, when a clear-cut dose-response relation was found. The pharmacodynamic effects of oxprenolol were compared with its concentration in plasma. Marked beta-receptor blockade still persisted eight hours after dosing, although at this time, after doses of 40 and 80 mg, the drug could not be detected in plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00616408
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  • 15
    Electronic Resource
    Electronic Resource
    The pharmokinetics of isradipine in hypertensive subjects (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 209-211 
    Details
    ISSN: 1432-1041
    Keywords: Isradipine ; hypertension ; pharmacokinetics ; pharmacodynamics ; clinical trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0–8) were 6.0 ng · ml−1, 1.5 h and 15.1 h · ng · ml−1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0–8) were 3.7 ng · ml−1, 1.2 h and 12.2 h · ng · ml−1 respectively indicating that the drug does not accumulate over time. Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265988
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  • 16
    Electronic Resource
    Electronic Resource
    Analgesic, central, cardiovascular and endocrine effects of the enkephalin analogue Tyr-D.Arg-Gly-Phe(4NO2)-Pro-NH2 (443C81) in healthy volunteers (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 213-218 
    Details
    ISSN: 1432-1041
    Keywords: enkephalin analogue (443C81) ; analgesia ; cold pain ; healthly volunteers ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, central, cardiovascular and endocrine effects of two i.v. doses of 443C81 were investigated in 12 healthy male volunteers. Its effects were compared with those of placebo and the classical opiate dipipanone given orally using a double dummy design. 443C81 produced dose-related analgesia; dipipanone 10 mg had a greater effect than the high dose 443C81. In contrast to dipipanone, 443C81 did not cause significant miosis or reduce minute volume on rebreathing CO2 and there was no evidence of sedation. Dry mouth was reported frequently and associated with reduced salivation after all active treatments. Both 443C81 and dipipanone increased circulating prolactin and growth hormone and reduced cortisol levels. This novel enkephalin appears to possess analgesic activity and some other properties of opiates but is devoid of clinically relevant narcotic effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315018
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  • 17
    Electronic Resource
    Electronic Resource
    The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 163-168 
    Details
    ISSN: 1432-1041
    Keywords: Tolbutamide ; diabetes mellitus ; non-insulin dependent ; pharmacokinetics ; pharmacodynamics ; glucose ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group). In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration. In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response. In the subset with a fasting blood glucose concentration of less than 8 mmol·l−1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280071
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  • 18
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    Relationship between pharmacokinetics and hemodynamic tolerance to isosorbide-5-mononitrate (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. S53 
    Details
    ISSN: 1432-1041
    Keywords: nitrates ; pharmacokinetics ; pharmacodynamics ; nitrate tolerance ; isosorbide-5-mononitrate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Healthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen 11 was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml. There was a significant negative correlation between the magnitude of hemodynamic effect remaining on the 5th day (measured by the area under the finger pulse curve) and the trough plasma concentration. Thus, the maintenance of minimum plasma concentrations of IS-5MN of 300 ng/ml or higher produces a rapid development of hemodynamic nitrate tolerance, whereas no tolerance was found when the plasma concentrations were allowed to decline below 100 ng/ml before the next dose was given. A significant attenuation of hemodynamic effects was found when minimum plasma concentrations were between 100 and 230 ng/ml. The degree of attenuation in this concentration range increased with increasing trough plasma concentrations.
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    URL: http://dx.doi.org/10.1007/BF01417565
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    Comparison of the pharmacodynamic effects of furosemide and BAY g 2821 and correlation of the pharmacodynamics and pharmacokinetics of BAY g 2821 (muzolimine) (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 341-344 
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    ISSN: 1432-1041
    Keywords: Muzolimine ; pharmacodynamics ; pharmacokinetics ; furosemide ; saluresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a biometrically planned, double-blind study on 12 Oedema-free male patients the saluretic effect of muzolimine 30 mg was compared with furosemide 40 mg. The plasma level of muzolimine was determined and correlated with its pharmacodynamics. In terms of excretion during the 12-hour observation period muzolimine 30 mg had as great a cumulative effect as furosemide 40 mg. There was a significant difference in the time-response curve. During the first two hours furosemide 40 mg had more saluretic effect than muzolimine 30 mg. Between two and four hours there was no significant difference between the two substances. Between four and six hours, however, muzolimine was somewhat more effective than furosemide, although the difference did not reach the level of significance. After 6 h there was no longer any difference between the two compounds. The half-life of the fall in concentration of muzolimine in plasma was 3.7 up to 10 h after its administration. The time-response curve of the increased urine excretion correlated well with the time course of the concentration of muzolimine in plasma.
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    URL: http://dx.doi.org/10.1007/BF00562448
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  • 20
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    Indobufen (K 3920), a new inhibitor of platelet aggregation: Effect of food on bioavailability, pharmacokinetic and pharmacodynamic study during repeated oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 329-333 
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    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; food effect on bioavailability ; repeated administration ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.
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    URL: http://dx.doi.org/10.1007/BF00558436
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  • 21
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    Pharmacokinetic, bioavailability and pharmacodynamic study of indobufen (K 3920), an inhibitor of platelet aggregation, after a single dose in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 323-327 
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    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; single dose ; bioavailability ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers received single iv and oral doses of 2-[p-(1-oxo-2-isoindolinyl)phenyl] butyric acid 100 mg (indobufen; K 3920), an inhibitor of platelet aggregation. Plasma levels and urinary excretion of the drug were determined by GLC. Collagen-induced platelet aggregation was assessed turbidimetrically at various intervals after administration. The plasma half-life of the drug was 7–8 h and more than 70% of the administered dose was recovered within 48 h in urine, as unchanged drug and as the glucuronide of indobufen. After oral administration of tablets of two different formulations, the drug was completely absorbed, but one formulation showed faster absorption. The maximal inhibitory effect on platelet aggregation was observed 1 to 4 h after iv administration, and it had decreased by 8 h. After tablets, peak effect and the time of the peak were similar, but activity was significantly prolonged, in accordance with the higher plasma levels found at 8 h. The data suggest that the effect of indobufen on platelets is reversible, and that for this drug platelets behave as a compartment that slowly equilibrates with plasma.
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    URL: http://dx.doi.org/10.1007/BF00558435
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  • 22
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    Investigation of a possible pharmacokinetic interaction between ibopamine and isosorbide-5-mononitrate (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 549-552 
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    ISSN: 1432-1041
    Keywords: Ibopamine ; Isosorbide-5-mononitrate ; pharmacokinetics ; drug interaction ; healthy volunteers ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between isosorbide-5-mononitrate (5-ISMN) and epinine, the active metabolite of ibopamine, has been investigated in 8 healthy male subjects given single doses of 200 mg ibopamine and 20 mg 5-ISMN, separately and together. The plasma 5-ISMN concentration-time profile was the same whether 5-ISMN was administered concomitantly with ibopamine or alone [AUC(o-t): 2.24 μg·ml−1·h after 5-ISMN alone, 2.16 μg·ml−1·h after 5-ISMN + ibopamine]. The plasma concentrations of total and free epinine and the urinary recovery of total epinine, homovanillic acid and dihydroxyphenylacetic acid, too, were not different when ibopamine was administered alone or concomitantly with 5-ISMN. The intake of ibopamine did not change the blood pressure and heart rate. The decrease in diastolic blood pressure induced by 5-ISMN was not influenced by concomitant intake of ibopamine. The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between 5-ISMN and ibopamine.
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    URL: http://dx.doi.org/10.1007/BF00314867
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    Metamizole-furosemide interaction study in healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 593-598 
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    ISSN: 1432-1041
    Keywords: Metamizole ; Furosemide ; prostaglandins ; drug interaction ; adverse effects ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and pharmacodynamic interactions between metamizole (dipyrone) and furosemide were investigated in 9 of 12 healthy female subjects able to complete the study. They received oral metamizole 3×1 g for 3 days or placebo (cross-over) and on the last day of both study periods furosemide 20 mg IV. On the last two days a balanced sodium diet (120 mEq) and on Day 3 an oral water load (600 ml) were given. Metamizole significantly inhibited basal urine flow, whereas the fractional excretion of sodium and chloride and the 12 h-GFR remained unchanged. Metamizole significantly reduced furosemide clearance (175 vs 141 ml · min−1), furosemide-stimulated plasma renin activity (1.42 vs 0.79 ng AI · ml−1 · h−1) and the urinary excretion of prostacyclin metabolites and of prostaglandin F2α (by 70–81%). The renal clearance and terminal half-life of furosemide, peak renal chloride and volume excretion were unchanged. Thus, metamizole did not interact with the renal excretion and the diuretic effect of furosemide, although prostaglandin synthesis was significantly reduced.
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    URL: http://dx.doi.org/10.1007/BF00265921
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    Intracolonic bioavailability of human calcitonin in man (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 527-531 
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    ISSN: 1432-1041
    Keywords: Calcitonin ; Colonic administration ; Bioavailability ; pharmacokinetics ; pharmacodynamics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Human calcitonin (hCT) injected into the lumen of the descending colon of normal human subjects was absorbed within minutes and could be recognized intact in plasma as shown by RIA in combination with reverse-phase HPLC. The absorption was low and variable, with bioavailabilities ranging from 0.01% to 2.7% relative to intravenously administered hCT (area under the concentrationtime curve). With intravenous hCT serum calcium was lowered and the fractional urinary excretion of calcium, phosphorus, sodium and chloride was significantly stimulated. With the intracolonic hCT, the fractional urinary excretions of calcium, sodium and chloride were also marginally stimulated relative to intracolonic vehicle (placebo). In conclusion, hCT is absorbed intact from the colon, but the bioavailability is low and highly variable.
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    URL: http://dx.doi.org/10.1007/BF02285096
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    Pharmacodynamics of salmon calcitonin in humans: New markers of pharmacological activity (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 229-233 
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    ISSN: 1432-1041
    Keywords: Salmon calcitonin ; pharmacodynamics ; adenosine ; pO2 IM dosing ; nasal spray dosing ; cytosolic calcium ; neutrophils ; platelets ; lymphocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to define the pharmacodynamic profile of salmon calcitonin (sCT) in humans, several markers of the biological activity of the drug have been studied, namely cAMP, adenosine and pO2 in venous blood, and the cytosolic free calcium level in circulating cells. Different dosages and routes of administration (1.5 IU. kg−1 and 0.75 IU kg−1 IM, and 1.5 IU. kg−1 via nasal spray) were compared. sCT caused an increase in cAMP, adenosine and pO2, and a decrease in cytosolic free calcium in neutrophils, lymphocytes and platelets. The peak times of all these parameters ranged between 109 and 182 min, and 101 and 168 min after IM and nasal spray administration respectively. There was greater variability in the values after IM than nasal spray of administration of sCT. It is concluded that adenosine and p02 in venous blood, and cytosolic free calcium in circulating cells are valuable markers of the activity of sCT and that sCT decreases the cytosolic free calcium level in neutrophils, lymphocytes and platelets. Pharmacodynamic analysis of the biological effects of the drug is highly reliable and valuable in predicting its pharmacological profile. sCT administration via a nasal spray is able to produce significant biological effects, although they are less marked than after IM dosing.
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    URL: http://dx.doi.org/10.1007/BF02333015
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    Effects of a sauna on the pharmacokinetics and pharmacodynamics of midazolam and ephedrine in healthy young women (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 377-381 
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    ISSN: 1432-1041
    Keywords: Midazolam ; Ephedrine ; Sauna ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of a sauna on the pharmacokinetics and pharmacodynamics of single doses of ephedrine 50 mg and midazolam 15 mg have been studied in 6 young healthy women in a placebo-controlled, double-blind study. The sauna (3 × 10 min; temperature 80–100°C; relative humidity 30–50%) modified the pharmacokinetics of both drugs: it retarded the absorption of midazolam estimated as Ka values, and it reduced the mean plasma midazolam concentrations at 2 h; ephedrine, was absorbed more rapidly and the maximum plasma concentration occurred earlier than in the control sessions. Changes in the pharmacodynamics due to the sauna were consistent with the pharmacokinetic findings: midazolam decreased flicker recognition and induced exophoria significantly less during the early sauna period than in the control session, whereas ephedrine made the volunteers subjectively more alert at that time. Later, at 2.5 and 3.5 h (1 h 20 min and 2 h 20 min after cessation of the sauna), and despite the equalisation of the plasma levels, midazolam caused significantly more exophoria after the sauna than in the control situation. This indicates an influence of a sauna on drug pharmacodynamics in the post-sauna adaptive phase. The results suggest that exposure to a sauna may alter both drug pharmacokinetics and pharmacodynamics.
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    URL: http://dx.doi.org/10.1007/BF00265959
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    Captopril does not interact with the pharmacodynamics and pharmacokinetics of digitoxin in healthy man (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 445-447 
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    ISSN: 1432-1041
    Keywords: Captopril ; Digitoxin ; impedance cardiography ; drug interaction ; healthy volunteers ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronic oral administration of 0.07 mg digitoxin o. d. for up to 58 days to 12 healthy volunteers caused a small drop in mean heart rate HR (95 % CI: −7.9 to −1.6 beats · min−1), in mean diastolic blood pressure (95 % CI: −8.3 to −0.4 mm Hg), shortening of the QTc-interval (95 % CI: −42 to −19 ms), shortening of the HR-corrected pre-ejection period PEPc (95 % CI: −16 to −1 ms) and electromechanical systole QS2c (95 % CI: −25 to −1 ms), and an increase in the impedance cardiographic Heather index (dZ/dtmax/RZ, 95 % CI: 0.3 to 4.3) relative to the baseline measurements before digitalisation. The concomitant administration of 25 mg oral captopril b. d. did not significantly alter these responses relative to the concomitant double-blind administration of placebo, nor did it alter the pharmacokinetic characteristics of plasma digitoxin at steady state. Thus, no relevant change in the pharmacokinetic and pharmacodynamic characteristics of chronically administered digitoxin were induced by concomitant treatment with captopril.
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    URL: http://dx.doi.org/10.1007/BF02220626
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    Pharmacodynamics and pharmacokinetics of oral nitrendipine solution in hypertensive patients with advanced renal failure (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 129-134 
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    ISSN: 1432-1041
    Keywords: Nitrendipine ; Hypertension ; pharmacokinetics ; renal function ; hypertensive crisis ; pharmacodynamics ; blood pressure ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nitrendipine solution 5 mg·ml−1 in the dose of 5 mg was given orally to 20 patients with chronic renal failure and elevated diastolic blood pressure (≥110 mmHg), of whom 10 were on maintenance haemodialysis (endogenous creatinine clearance 〈5 ml·min−1) and 10 were at the predialysis stage (endogenous creatinine clearance 5–20 ml·min−1). The aim of the study was to investigate the influence of kidney function and/or dialysis treatment on the pharmacokinetic and pharmacodynamic profile of a solution of nitrendipine and to assess its antihypertensive efficacy. After 10 min there was a significant reduction in blood pressure from 188/113 to 173/100 (patients not dependent on dialysis) and from 197/112 to 161/94 mmHg (patients dependent on dialysis). The maximum fall in blood pressure (approximately 30%) was attained after 90 min in the dialysis patients and after 120 min in the non-dialysis group. Blood pressure increased again about 3 h after the administration of nitrendipine but it was still below baseline after 12 h. The terminal elimination half-life (4.1 h in the dialysis patients and 3.6 h in non-dialysis patients) was similar to that observed in patients with normal renal function. The pharmacokinetics of nitrendipine did not differ between the dialysis and non-dialysis groups. There was a correlation between plasma concentration and the blood pressure reduction. The maximum plasma concentration of nitrendipine was reached after 0.5 h (median) and did not differ between the two groups. The mean maximum plasma concentration was 14.8 μg·1−1 in the study population as a whole, with comparable means in the dialysis (17.3 μg·1−1) and non-dialysis (12.4 μg·1−1) groups. The nitrendipine solution proved to be effective in lowering acutely elevated blood pressure in patients with advanced renal failure and renal hypertension, and was well tolerated. The pharmacokinetics was not affected by renal impairment or by dialysis.
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    URL: http://dx.doi.org/10.1007/BF00315493
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    Pharmacodynamic modeling of cortisol suppression from fluocortolone (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 581-583 
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    ISSN: 1432-1041
    Keywords: Fluocortolone ; cortisol ; pharmacodynamics ; pharmacokinetics ; adrenal suppression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of fluocortolone on cortisol suppression was characterized using a ‘direct suppression pharmacodynamic model’. The model incorporates the physiologic circadian secretion of cortisol under normal and treatment conditions, together with pharmacokinetic data from single fluocortolone doses of 20, 50, and 100 mg. A mean IC50 value (fluocortolone plasma concentration at which the circadian secretion of cortisol is inhibited by 50%) of 15.5 ng·ml−1 was found. This analysis shows how use of pharmacodynamic modeling can characterize dose-proportionality data to provide an in vivo measure of drug potency.
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    URL: http://dx.doi.org/10.1007/BF00315319
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    Pharmacodynamic studies in man of theβ-adrenoceptor antagonist DL 071 IT (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 87-90 
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    ISSN: 1432-1041
    Keywords: beta-receptor blockade ; DL 071 IT ; oxprenolol ; pharmacodynamics ; exercise test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary DL 071 IT, a new potent non-selectiveβ-adrenergic blocking drug with intrinsic sympathomimetic activity and weak membrane stabilizing activity, was evaluated alone and in comparison with oxprenolol, in six volunteers, at rest and during an exercise test. Heart rate and systolic pressure were monitored for up to 7 h after oral administration of the drugs. Exercise heart rate and systolic pressure were significantly reduced by both drugs, but only DL 071 IT caused a significant reduction in resting heart rate. As compared to oxprenolol, DL 071 IT has a longer duration of action and is from 5.0 to 13.5 times more potent.
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    Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 237-256 
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    ISSN: 1432-1041
    Keywords: Non-steroidal anti-inflammatory drugs ; Enantioselective ; Enantiomers ; pharmacodynamics ; pharmacokinetics ; stereoselective
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00266343
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    Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics on felodipine — and its potential clinical relevance (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 313-317 
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    ISSN: 1432-1041
    Keywords: Dihydropyridine ; Felodipine ; availability ; flavonoids ; dietary interaction ; pharmacokinetics ; pharmacodynamics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of drinking grapefruit juice on the acute pharmacokinetic and haemodynamic actions of the dihydropyridine calcium antagonist felodipine given as a 5 mg plain tablet has been studied in nine, healthy, middle-aged males. Compared to water, grapefruit juice caused an increase in Cmax from mean 6 to 16 nmol · l−1, and in the AUC from 23 to 65 nmol · h · l−1. The change in AUC corresponded to an increase in the systemic availability of felodipine from 15 to 45%, assuming no change in its clearance. This change was probably caused by inhibition of the oxidation of felodipine to the inactive dehydrofelodipine by flavonoids in grapefruit juice. The interaction with grapefruit juice is believed to be a class effect for the dihydropyridines, as oxidation of the dihydropyridine ring to the corresponding pyridine derivative is a major metabolic route for all these drugs. The higher plasma concentrations of felodipine taken with grapefruit juice resulted in a greater change in blood pressure measured in the morning 3 h after dosing (−9%) than did water (0%).
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    Disposition kinetics and concentration-effect relationship of metipranolol in patients with cirrhosis and healthy subjects (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 337-340 
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    ISSN: 1432-1041
    Keywords: Metipranolol ; Liver cirrhosis ; pharmacokinetics ; pharmacodynamics ; beta-adrenoreceptor blockade
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics and heart rate reducing effect of deacetylmetipranolol (DMP), the active form of the β-adrenoreceptor blocking agent metipranolol (MP), administered as a single 40 mg oral dose have been compared in 6 patients with cirrhosis and 6 healthy volunteers. The mean maximal DMP concentration was significantly higher and the time to reach the peak level shorter in the patients compared to the healthy subjects. There was also a significantly higher AUC of DMP, a shorter half-life of the rapid phase of the decline in DMP concentrations, a smaller central compartment and lower apparent DMP clearance in patients. A correlation with the albumin level was observed in cirrhotics for individual values of apparent DMP clearance (r=0.92) and AUC (r=-0.89). The maximal reduction in heart rate was recorded in patients at plasma DMP levels which were already significantly lower than the peak levels. Median inhibitory concentrations (IC50) and maximum possible heart rate reductions (Δ HRmax), obtained by fitting individual plots of the plasma DMP concentration-effect relationship to the inhibitory Emax model in the postdistributional phase of DMP disposition were significantly higher in cirrhotics than in healthy subjects. It is conjectured that down-regulation of adrenoreceptors due to chronic sympathetic activation in hepatic cirrhosis contributes to decreased sensitivity to the reduction in heart rate following a single dose of the beta-blocker.
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    Effect of cetirizine, ketotifen and chlorpheniramine on the dynamics of the cutaneous hypersensitivity reaction: a comparative study (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 359-362 
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    ISSN: 1432-1041
    Keywords: Cetirizine ; Ketotifen ; pharmacodynamics ; cutaneous hypersensitivity reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Allergic cutaneous challenge causes mast cell and basophil mediator release which recruit inflammatory cells to the site of antigen administration. This secondary cell infiltration and mediator release is responsible for the changes seen during the late phase of allergic diseases. In this randomised, double-blind, cross-over, placebo controlled study, it was demonstrated that, at steady-state drug concentrations, chlorpheniramine reduced the wheal-and-flare reaction by about 50% compared to the 75% reduction, on average, by cetirizine and ketotifen. Cetirizine significantly reduced eosinophil vacuolisation at all observation periods, i. e. 2, 6, 10 and 24 h, and also inhibited basophil accumulation significantly at 10 h (75% reduction), while chlorpheniramine had a negligable effect on these variables. These changes would indicate that the late phase reaction was modified, especially as eosinophil vacuolisation is known to correlate with late phase intensity, T-lymphocyte infiltration and subsequent tissue damage. It further supports previous speculation that cetirizine inhibit late histamine release by acting on basophils. The extent of induration in the late phase reaction did not differ significantly among the three treatments. Cetirizine and ketotifen, noticeably although not significantly, reduced eosinophil and lymphocyte recruitment. As these two antihistamines differ structurally and in regard to receptor specificity, it is possible that they exert their actions on other, unspecified, receptors.
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    Elevated plasma nilvadipine concentration after single and chronic oral administration to patients with chronic liver disease (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 475-479 
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    ISSN: 1432-1041
    Keywords: Calcium channel blocker ; Nilvadipine ; blood pressure ; liver disease ; pharmacokinetics ; pharmacodynamics ; cirrhosis ; hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fourteen normotensive patients with liver disease (6 with cirrhosis and 8 with chronic hepatitis) and 7 healthy volunteers were given a single oral dose of nilvadipine 2 mg. In addition, nilvadipine 4 mg was administered orally twice daily for several months to 6 hypertensive patients with mild liver dysfunction and 18 hypertensives with normal liver function. A significant increase in plasma nilvadipine was found in the patients with cirrhosis as compared both to the normal and chronic hepatitis subjects; the time to peak concentration was similar among the three groups. The peak plasma nilvadipine concentration was closely correlated both with the serum albumin level and the retention of indocyanine green. Changes in blood pressure, pulse rate and various vasoactive hormones following a single oral dose of nilvadipine did not differ between the groups. Thus, an increase in plasma nilvadipine relative to the level in normal subjects was demonstrated in patients with cirrhosis following a single oral dose, as well as in patients with slight liver dysfunction following long-term oral administration.
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    URL: http://dx.doi.org/10.1007/BF00314853
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    Pharmacokinetics and effects of levodopa in advanced Parkinson's disease (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 385-389 
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    ISSN: 1432-1041
    Keywords: Levodopa ; Parkinson's disease ; pharmacokinetics ; pharmacodynamics ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant ke0 using model-independent analysis. The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was 〉4–5 μg·ml−1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min. The patients remained clinically stable during the period of the intraduodenal infusion.
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    Moexipril does not alter the pharmacokinetics or pharmacodynamics of warfarin (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 291-293 
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    ISSN: 1432-1041
    Keywords: Moexipril ; Warfarin ; pharmacokinetics ; pharmacodynamics ; drug-interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The potential effect of moexipril, a new converting enzyme inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of warfarin has been investigated. Ten healthy male volunteers received in a randomised crossover fashion a single oral dose of 50 mg warfarin sodium alone and together with the first dose of 6 days of oral treatment with moexipril 15 mg o.d. Mean oral plasma clearance of (R)-warfarin was 175 ml·h−1 in the absence and 181 ml·h−1 in the presence of moexipril, and the corresponding values for (S)-warfarin were 248 ml·h−1 and 249 ml·h−1. Apparent volume of distribution, peak plasma concentration, time to reach peak concentration and area under the plasma concentration-time curve both of (R)- and (S)-warfarin were not significantly affected. Moexipril did not alter the maximum prothrombin time (20.3 versus 20.1 s, respectively in the absence and presence of moexipril), time to maximum response (48.0 versus 50 h) and area under the prothrombin time versus time curve. The results suggest that a clinically important interaction between moexipril and warfarin is unlikely to occur in patients treated with both drugs.
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    URL: http://dx.doi.org/10.1007/BF00315400
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    The pharmacokinetics and pharmacodynamics of 12 weeks of glyburide therapy in obese diabetics (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 459-463 
    Details
    ISSN: 1432-1041
    Keywords: Glyburide ; Diabetes mellitus ; pharmacokinetics ; pharmacodynamics ; obesity ; type II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics and pharmacodynamics of glyburide during long-term therapy in 20 patients with type II diabetes mellitus. The patients were divided according to body mass index (BMI) into an obese group [n=12, age 55(13) y, BMI 36.2(9.2) kg·m−2, total body weight (TBW) 100(23) kg], and a non-obese group [n=8, age 61(13) y, BMI 24.5(2.1) kg·m−2, TBW 73(7) kg]. The dosages of glyburide were titrated to achieve specified therapeutic goals based upon serum glucose concentrations or to a maximum dosage of 20 mg per day. The pharmacokinetics of glyburide were determined at week 12 of treatment. On the study day, the patients took a 2.5 mg liquid test dose of glyburide with a Sustacal meal challenge. The elimination rate constant (λz), clearance (CL), and apparent volume of distribution (Vz) were 0.08 h−1, 3.3 l·h−1, and 47.0 l in the obese group, and 0.07 h−1, 3.1 l·h−1, and 56.8 l in the non-obese group. These values were not statistically significantly different. However, there were differences between the groups when the volume and clearance were corrected by TBW or BMI but not by ideal body weight (IBW) or fat-free mass (FFM). Regression analysis between the pharmacokinetic variables and body weight status revealed statistically significant correlations between volume or clearance and body weight. However, due to large inter-patient variability, these relations were relatively weak and were considered to be non-predictive. In regard to the pharmacodynamic effects of glyburide, there were greater C-peptide and insulin responses at baseline and after 12 weeks of therapy in the obese than in the non-obese patients. However, there were no significant differences in glucose responses between the two groups. More non-obese patients needed the maximum dose (20 mg) of glyburide (7/8) compared with obese patients (6/12). These findings suggest that obese patients may be more sensitive to the effects of glyburide. Alternatively, our obese patients may have had less serious disease than our non-obese patients.
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    URL: http://dx.doi.org/10.1007/BF00315518
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  • 39
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    The influence of hypoglycaemic sulphonylureas on elimination and efficacy of phenprocoumon following a single oral dose in diabetic patients (1976)
    Springer
    European journal of clinical pharmacology 10 (1976), S. 31-36 
    Details
    ISSN: 1432-1041
    Keywords: Diabetes mellitus ; drug interaction ; phenprocoumon ; pharmacokinetics ; pharmacodynamics ; sulphonylureas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of various antidiabetic treatments on the kinetics and efficacy of a single oral dose of 12 mg phenprocoumon were studied in 71 hospitalized patients, 58 with adult-onset diabetes mellitus and 13 non-diabetic aged patients, and 13 healthy young volunteers. Treatment for one week or longer with insulin or the antidiabetic sulphonylureas tolbutamide, glibenclamide or glibornuride, altered neither the plasma level (1.29 – 1.40 µg/ml at zero time) nor the half-life of phenprocoumon (5.2 – 6.8 d) compared to treatment by diet alone. The mean half-life of phenprocoumon was significantly shorter in non-diabetic aged patients (4.2 d) than in diabetic patients of the same age (5.1 – 6.8 d), or in young healthy volunteers (5.7 d). The efficacy of a single dose of phenprocoumon (maximal reduction of Quick-values by 34 – 47% after 48 to 72 hrs) in diabetic patients treated with diet, or diet and antidiabetic drugs, was the same as in non-diabetic aged patients. In healthy young volunteers phenprocoumon was half as effective as in aged patients.
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    URL: http://dx.doi.org/10.1007/BF00561546
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  • 40
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    Individual variation in the response to phenprocoumon (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 351-358 
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    ISSN: 1432-1041
    Keywords: Phenprocoumon ; protein binding ; pharmacokinetics ; pharmacodynamics ; drug therapy ; myocardial infarction ; chronic disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In nine patients, the synthesis rate Rsyn of the vitamin K-dependent clotting factors was calculated from changes in prothrombin-complex activity after intravenous administration of a synthesis-blocking dose of phenprocoumon (PPC). The biological half-life of PPC was between 2.70 and 7.01 days. No correlation was found between the level of the free fraction of this strongly protein-bound drug and its biological half-life. There was a positive correlation (p〈0.01) between the size of the free fraction of PPC and the apparent volume of distribution of the drug. Four of the patients had had an acute myocardial infarction and they showed increased sensitivity to PPC. In them the plasma level of PPC sufficient to reduce Rsyn to 50% of R°syn was significantly lower, and the depression of individual vitamin K-dependent coagulation factors was more pronounced and prolonged, than in five other patients with chronic disease. The degradation rate of coagulation factors was also found to be higher in the patients with acute myocardial infarction. In four patients with chronic disease, anticoagulant therapy with PPC was continued in the out-patient clinic. The calculated oral maintenance dose of PPC, assuming complete absorption, first-order elimination kinetics and a linear relationship between the pharmacological effect and the logarithm of the PPC-plasma concentration, showed good agreement with the dose actually found to produce the desired PP% level.
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  • 41
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    Pharmacokinetics and pharmacodynamics of the ace inhibitor benazepril hydrochloride in the elderly (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 379-385 
    Details
    ISSN: 1432-1041
    Keywords: benazepril ; benazeprilat ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; elderly ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of a single oral dose benazepril·HCl 10 mg have been studied in 15 healthy volunteers aged 65 to 80 y. The kinetics of unchanged benazepril and its active metabolite benazeprilat did not differ significantly in males and females, so the combined kinetic data from all 15 elderly subjects were compared with a historical control group of 19–32 year-old healthy men treated in the same way. The disposition of benazepril was not affected by age. The time to maximum plasma concentration, tmax (0.5 h) and elimination half-life (0.6 h) in the elderly were the same as in young subjects. The kinetics of benazeprilat was slightly changed in the elderly; although its tmax (1.5 h) was not affected, Cmax and the AUC were 20–40% greater. The elimination half-life of benazeprilat during the first 24 h after doing in the elderly was increased by about 20% to 3.2 h. The renal plasma clearance of benazeprilat (18.1 ml·min−1) was about 20% smaller than in the young subjects. An average of 18.5% of the dose was recovered as benazeprilat in the 24 h urine from the elderly subjects, which was similar to the recovery in the young subjects. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 95%, respectively). Mean systolic and diastolic blood pressures in the elderly were reduced by a maximum of 37/16 mm Hg at 6 h, in association with a small rise in pulse rate. Treatment was generally well tolerated. Three of the 15 subjects reported clinical adverse experiences judged to be possibly drug related, namely headache, abdominal pain and cold extremities.
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  • 42
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    Subjective symptoms and pharmacokinetics/dynamics of metoprolol CR in elderly subjects — a comparison with atenolol (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 571-578 
    Details
    ISSN: 1432-1041
    Keywords: Atenolol ; metoprolol CR ; elderly subjects ; subjective symptoms ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind, randomised, cross-over study, the pharmacokinetic/dynamic effects and subjective symptoms of a new controlled-release (CR) formulation of metoprolol (50 and 100 mg) have been compared with atenolol (50 mg) and placebo in 20 elderly healthy subjects. The metoprolol CR formulation displayed an even plasma concentration-time profile over the dosage interval while atenolol produced a peak at 2–4 h. All three active treatments produced significant β1-blockade at 24 h compared to placebo. Four hours after dose intake, the degree of β1-blockade was significantly greater with conventional atenolol 50 mg than with either dose of metoprolol CR. Subjective well-being was examined with a self-administered questionnaire (MSE-profile), including three dimensions: Contentment, Vitality and Sleep. No significant differences were detected between placebo and either dose of metoprolol CR. At 2 h, following atenolol, a deterioration in Vitality was observed compared to placebo and metoprolol CR 100 mg. At the end of the dosage interval there was no longer any significant difference between the treatments. Perceived leg fatigue during exercise, evaluated 4 h after dosing, was more pronounced during treatment with atenolol than metoprolol CR 50 mg. The results suggest that the metoprolol CR formulation was not associated with significant effects on subjective well-being, whereas atenolol caused a deterioration at the time of the peak plasma concentration of the drug.
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    Pharmacological activity and safety of trandolapril (RU 44570) in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 149-153 
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    ISSN: 1432-1041
    Keywords: Trandolapril ; ACE inhibition ; pharmacodynamics ; duration ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacological activity and safety of the new angiotensin converting enzyme (ACE) inhibitor trandolapril (RU 44570) has been evaluated in ten healthy male volunteers given 2 mg once daily for seven days. Assessment criteria included evaluation of plasma ACE and renin activity and aldosterone levels in the supine and standing positions, monitoring of blood pressure, heart rate and electrocardiogram, routine blood and urine laboratory tests, and evaluation of adverse effects. Plasma ACE activity (both in the supine and standing positions) was significantly lower after the first dose and was almost completely suppressed after 7 days of treatment. Plasma renin activity with the subjects in both positions was significantly increased at the end of treatment. Plasma aldosterone did not vary significantly, except for an increase in the standing position after 7 days of washout. No significant changes occurred in blood pressure, heart rate, electrocardiogram, blood or urine laboratory tests. No adverse effects were reported, in particular, no orthostatic hypotension, cough or episodes of bronchospasm occurred. It is concluded that oral trandolapril 2 mg o.d. is an effective and long-lasting ACE inhibitor with a good safety profile on repeated dosing. Further studies are warranted to investigate its therapeutic application as well as its safety profile after long-term administration.
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  • 44
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    Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 65-68 
    Details
    ISSN: 1432-1041
    Keywords: Chlordesmethyldiazepam ; pharmacokinetics ; i.v./p.o. administration ; renal failure ; protein binding ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 2 mg IV dose of chlordesmethyldiazepam has been studied in 11 patients with renal failure on regular haemodialysis and in 11 age-matched healthy controls. The kinetics was also examined after a single 2 mg oral dose in 6 of the 11 renal failure patients. After intravenous administration the kinetics of total chlordesmethyldiazepam in renal patients and controls were the same. The unbound fraction of the drug in renal patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed a reduced apparent volume of distribution (47 vs. 140 l · kg−1) and a reduced clearance (5.0 vs. 10.5 ml · min−1 · kg−1) in the patients. The systemic availability of oral chlordesmethyldiazepam was good (82%) despite a relatively slow absorption rate.
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    Pharmacokinetics and pharmacodynamics of conventional and controlled-release formulations of metipranolol in man (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 243-247 
    Details
    ISSN: 1432-1041
    Keywords: metipranolol ; pharmacokinetics ; pharmacodynamics ; β-adrenoreceptor blockade ; radioreceptor assay ; controlled release form
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and β-adrenoceptor blocking effects of conventional and sustained-release metipranolol have been studied in 6 healthy male volunteers given a single oral dose of 40 mg. Plasma drug concentrations determined by TLC and a radioreceptor assay, and the inhibition of exercise-induced tachycardia, were monitored for 48 h. Relevant amounts of active metabolites other than deacetylmetipranolol were not found. Compared to conventionally formulated metipranolol, the controlled-release product had a prolonged mean residence time (10.7 vs 5.5 h), the peak drug concentration was halved and the time to peak drug concentrations was delayed. Relatively constant plasma concentrations (cideal = 6.5 ng/ml) and a clinically significant reduction of exercise-induced tachycardia were maintained throughout a 24 h dosing interval. An individual deacetylmetipranolol plasma concentration-effect relationship was evaluated using the Emax model. Mean parameters were Emax 26% and C50 2.9 ng/ml.
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    Difference in action between oral triazolam and zopiclone (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 47-51 
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    ISSN: 1432-1041
    Keywords: Triazolam ; zopiclone ; pharmacodynamics ; quantitative EEG ; saccadic eye movements ; psychometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of oral triazolam 0.25 mg and zopiclone 7.5 mg in 7 supine volunteers were compared by means of quantitative measurements of the EEG, saccadic eye movements, visual analogue scale (VAS) for alertness, critical flicker fusion frequency (CFF) and the Maddox wing. Zopiclone reached its maximum effect earlier (62 min) than triazolam (91 min; CFF). On linear regression analysis the average rate constant (regression coefficient) of onset of action of zopiclone was significantly greater than that of triazolam (0.29 vs. 0.17). Triazolam and zopiclone had similar effects, but zopiclone seemed to have a faster onset of action, probably indicating swifter absorption in supine subjects. Quantitative EEG evaluation gave parallel results to the other parameters used, but triazolam and zopiclone showed a dissimilar mechanism of action, as characterized by changes in the alpha frequency.
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  • 47
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    The effect of urapidil on responses to phenylephrine, angiotensin and isoprenaline in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 1-3 
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    ISSN: 1432-1041
    Keywords: Urapidil ; phenylephrine ; angiotensin ; isoprenaline ; dose-response ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg·h−1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 μg·min−1 before to 685 μg·min−1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has α1-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.
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    Pharmacokinetics and pharmacodynamics of cicaprost in healthy volunteers after oral administration of 5 to 20 μG (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 149-153 
    Details
    ISSN: 1432-1041
    Keywords: Cicaprost ; PGI2-mimetic drug ; pharmacokinetics ; pharmacodynamics ; volunteers ; dose titration ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a Phase I study, the tolerability, pharmacodynamics and pharmacokinetics of cicaprost have been investigated in 6 male volunteers given 5, 10, 15 and 20 μg as tablets of the β-cyclodextrin clathrate. Individual inhibition of platelet aggregation and changes in facial colour (measured by chromametry) were dose-dependent and reached a maximum 30 to 60 min post-dose. The maximum inhibition of platelet aggregation was about 40%. After 3 to 4 h pre-treatment values had returned. Blood pressure remained within the normal range. The peak plasma level of cicaprost was reached within 15 to 90 min after drug intake. Both Cmax-and AUC were individually dose-dependent. The terminal half-life in plasma of cicaprost was approx. 1 h, and its total clearance amounted to 4–7 ml·min−1·kg−1. The time courses of the plasma levels and of the pharmacodynamic actions were in agreement. Interindividual differences were observed in the occurrence of unwanted effects (e.g. headache). Thus, cicaprost is an orally available PGI2-mimetic, for which effects on platelet aggregation and vascular perfusion have been demonstrated in healthy volunteers after doses of 5 to 15 μg.
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    Are all cardiac glycosides pharmacodynamically similar? (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 317-320 
    Details
    ISSN: 1432-1041
    Keywords: cardiac glycosides ; digitalis ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    Sublingual captopril — a pharmacokinetic and pharmacodynamic evaluation (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 393-398 
    Details
    ISSN: 1432-1041
    Keywords: Captopril ; sublingual ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In this study we compared the pharmacokinetics and pharmacodynamics of captopril after sublingual and peroral administration. Single 25 mg doses of captopril were administered sublingually and perorally on two different occasions in a randomised cross-over fashion to eight healthy volunteers aged 22–35 years. The kinetics of unchanged captopril, plasma renin activity (PRA), BP and heart rate were studied over three hours after both peroral and sublingual administration of captopril. Mean pharmacokinetic parameters for unchanged captopril after sublingual administration were: Cmax, 234 ng·ml−1; tmax, 45 min; AUC (0–3 h), 15.1 μg·ml−1. min. Mean pharmacokinetic parameters for unchanged captopril after peroral administration were: Cmax, 228 ng·ml−1; tmax, 75 min; AUC (0–3 h), 17.0 μg·ml−1. min. tmax was significantly shorter when captopril was administered sublingually; all other pharmacokinetic parameters were equivalent. The plasma captopril concentrations achieved post drug administration led to increases in PRA and reductions in BP. tmax for PRA was 86 min for sublingual captopril and 113 min for perorally administered drug. Peak PRA values were, however, not significantly different. BP, as expected, was not reduced dramatically in these healthy volunteer subjects, however, in systolic BP vs time profiles, BP was significantly lower after volunteers received sublingual captopril. Heart rate increased slightly after captopril administration; there were no differences between the two routes of administration. Administration of captopril sublingually, therefore led to a more rapid attainment of plasma captopril concentrations and had a more rapid onset of pharmacological effect when compared with peroral administration.
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    Location of chromosomal control of GA-induced enzyme release by distal half-grains of wheat (1977)
    Springer
    Biochemical genetics 15 (1977), S. 47-57 
    Details
    ISSN: 1573-4927
    Keywords: wheat ; chromosomes ; gibberellin ; enzymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The three enzymes, α-amylase, peroxidase, and acid phosphatase, are among those released by the aleurone of bread wheat, Triticum aestivum, as a direct response to gibberellins (GA) from the embryo during germination. Aneuploid genotypes are used to investigate the chromosomal location, nature, and extent of genetic control of the release of these enzymes in endosperms after induction by exogenous GA. Ditelosomics demonstrate the effect of removal of known chromosome arms, and tetrasomics show the effect of duplication of chromosome pairs. Quantitative analysis demonstrates complex control systems over and above those previously found using zymogram techniques. For α-amylase, chromosome arms with net promoter effects and chromosomes with net inhibitor effects were found. These effects were not chromosome-dosage responsive, unlike the promoter-inhibitor system found for acid phosphatase control. Peroxidase levels in the endosperms were generally high in both types of aneuploids. With one exception, all chromosomes showing involvement as ditelosomics showed a similar effect as tetrasomics, indicating that in the euploid a balanced state restricting, rather than promoting, peroxidase levels existed.
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    Allelochemicals in soil from no-tillage versus conventional-tillage wheat (Triticum aestivum) fields (1990)
    Springer
    Journal of chemical ecology 16 (1990), S. 2277-2289 
    Details
    ISSN: 1573-1561
    Keywords: Allelochemicals ; no-tillage ; conventional-tillage ; soils ; wheat ; Triticum aestivum ; mass spectrometry ; Petri-dish bioassay ; fatty acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Putative allelochemicals found in the soil of no-tillage and conventional-tillage wheat plots near Stillwater, Oklahoma, were obtained by a mild alkaline aqueous extraction procedure, bioassayed to determine their biological activity, purified, and analyzed with a capillary gas chromatography-mass spectrometry-data analysis system. The most significant inhibition was found in bioassays of extracts from soil collected immediately after harvest in June, July, and August. No-tillage soils produced significant inhibition during the rest of the year also. Mass spectrometry showed fatty acids as the most abundant compounds. However, when bioassayed authentic samples of the five free fatty acids showed no significant biological activity toward wheat.
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    Allelopathic activity in wheat-conventional and wheat-no-till soils: Development of soil extract bioassays (1992)
    Springer
    Journal of chemical ecology 18 (1992), S. 2191-2221 
    Details
    ISSN: 1573-1561
    Keywords: Cover crops ; wheat ; Triticum aestivum ; soybean ; Glycine max ; soil extracts ; germination bioassays ; phenolic acids ; hydroxamic acids ; allelopathy ; slope analysis ; ivy-leaved morning glory ; Ipomoea hederacea ; crimson clover ; Trifolium incarnalum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The primary objective of this research was to determine if soil extracts could be used directly in bioassays for the detection of allelopathic activity. Here we describe: (1) a way to estimate levels of allelopathic compounds in soil; (2) how pH, solute potential, and/or ion content of extracts may modify the action of allelopathic compounds on germination and radicle and hypocotyl length of crimson clover (Trifolium incarnatum L.) and ivyleaved morning glory (Ipomoea hederacea L. Jacquin.); and (3) how biological activity of soil extracts may be determined. A water-autoclave extraction procedure was chosen over the immediate-water and 5-hr EDTA extraction procedures, because the autoclave procedure was effective in extracting solution and reversibly bound ferulic acid as well as phenolic acids from wheat debris. The resulting soil extracts were used directly in germination bioassays. A mixture of phenolic acids similar to that obtained from wheat-no-till soils did not affect germination of clover or morning glory and radicle and hypocotyl length of morning glory. The mixture did, however, reduce radicle and hypocotyl length of clover. Individual phenolic acids also did not inhibit germination, but did reduce radicle and hypocotyl length of both species. 6-MBOA (6-methoxy-2,3-benzoxazolinone), a conversion product of 2-o-glucosyl-7-methoxy-1,4-benzoxazin-3-one, a hydroxamic acid in living wheat plants, inhibited germination and radicle and hypocotyl length of clover and morning glory. 6-MBOA, however, was not detected in wheat debris, stubble, or soil extracts. Total phenolic acids (FC) in extracts were determined with Folin and Ciocalteu's phenol reagent. Levels of FC in wheat-conventionaltill soil extracts were not related to germination or radicle and hypocotyl length of either species. Levels of FC in wheat-no-till soil extracts were also not related to germination of clover or morning glory, but were inversely related to radicle and hypocotyl length of clover and morning glory. FC values, solute potential, and acidity of wheat-no-till soil extracts appeared to be independent (additive) in action on clover radicle and hypocotyl length. Radicle and hypocotyl length of clover was inversely related to increasing FC and solute potential and directly related to decreasing acidity. Biological activity of extracts was determined best from slopes of radicle and hypocotyl length obtained from bioassays of extract dilutions. Thus, data derived from the water-autoclave extraction procedure, FC analysis, and slope analysis for extract activity in conjunction with data on extract pH and solute potential can be used to estimate allelopathic activity of wheat-no-till soils
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    Genetic aspects of wheat gliadin proteins (1978)
    Springer
    Biochemical genetics 16 (1978), S. 831-853 
    Details
    ISSN: 1573-4927
    Keywords: Triticum aestivum L. ; wheat ; storage proteins ; gliadins ; gel electrophoresis ; endosperm ; dominant genes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Inheritance of gliadin components unique to three different varieties of common wheat (Triticum aestivum L.) was studied in F1 and F2 seeds of intervarietal crosses using protein patterns obtained by polyacrylamide gel electrophoresis in aluminum lactate buffer (pH 3.2). The patterns of F1 seeds of the crosses Cheyenne × Justin and INIA 66R × Justin evidenced all the bands present in the patterns of the parents; band intensities reflected gene dosage levels dependent on whether the contributing parent was maternal or paternal in accordance with the triploid nature of endosperm tissue. Most of the gliadin components examined segregated in accordance with control by a single dominant gene, but in two instances single bands in the one-dimensional electrophoretic patterns segregated in the F2 as expected if controlled by two genes. A method of two-dimensional electrophoresis was developed that resolved these apparently single bands into two components each, which could segregate independently. Linkage analysis provided evidence of codominant alleles and closely linked genes coding for gliadin protein components in both coupling and repulsion situations. The gliadin protein components seem to be coded for by clusters of genes located on chromosomes of homoeologous groups 1 and 6 in hexaploid wheats.
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    The amino acid sequence of a protein from wheat kernel closely related to proteins involved in the mechanisms of plant defence (1993)
    Springer
    The protein journal 12 (1993), S. 379-386 
    Details
    ISSN: 1573-4943
    Keywords: Amino acid sequence ; wheat ; wounding ; plant defence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The amino acid sequence of wheatwin1, a monomeric protein of 125 residues isolated from wheat kernel (variety S. Pastore), is reported. Wheatwin1 is highly homologous (95%) to barwin, a protein from barley seed, which was shown to be related to the C-terminal domain of two proteins encoded by the wound-induced geneswin1 andwin2 in potato and to a protein encoded by the same domain of the hevein gene (hev1) in rubber tree. Similarly to barwin, wheatwin1 contains six cysteine residues all linked in disulfide bridges and the N-terminal residue is pyroglutamate. Moreover, structural studies performed on wheatwin1 andwin1 protein by predictive methods demonstrated that these proteins and barwin are closely related in the secondary structure also. The high level of homology found with the product ofwin1,win2, andhev1 genes strongly suggests that barwin and wheatwin1 play a common role in the mechanism of plant defence.
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    The amino acid sequence and reactive site of a single-headed trypsin inhibitor from wheat endosperm (1994)
    Springer
    The protein journal 13 (1994), S. 187-194 
    Details
    ISSN: 1573-4943
    Keywords: Trypsin inhibitor ; wheat ; primary structure ; reactive site ; Bowman-Birk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The sequence of a trypsin inhibitor, isolated from wheat endosperm, is reported. The primary structure was obtained by automatic sequence analysis of the S-alkylated protein and of purified peptides derived from chemical cleavage by cyanogen bromide and digestion withStaphylococcus aureus V8 protease. This protein, named wheat trypsin inhibitor (WTI), which is comprised of a total of 71 amino acid residues, has 12 cysteines, all involved in disulfide bridges. The primary site of interaction (reactive site) with bovine trypsin has been identified as the dipeptide arginyl-methionyl at positions 19 and 20. WTI has a high degree of sequence identity with a number of serine proteinase inhibitors isolated from both cereal and leguminous plants. On the basis of the findings presented, this protein has been classified as a single-headed trypsin inhibitor of Bowman-Birk type.
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    Nitroglycerin dinitrate metabolites do not affect the pharmacokinetics and pharmacodynamics of nitroglycerin in the dog: A preliminary report (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 163-173 
    Details
    ISSN: 1573-8744
    Keywords: Nitroglycerin ; dinitrate metabolites ; 1,2-glyceryl dinitrate ; 1,3-glyceryl dinitrate ; pharmacodynamics ; metabolite inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Studies were carried out in conscious dogs to determine the effects of 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN) on nitrogtycerin (GTN) pharmacokinetics and pharmacodynamics. In the first set of experiments, steady state plasma levels (Css) of either 1,2-GDN or 1,3-GDN in three dogs were rapidly achieved by giving an iv bolus (77 μg/kg), followed immediately by an infusion (50 μg/min) of the same GDN. A single iv bolus dose of GTN (0.025 μg/kg) was given 50 min after beginning the GDN infusion and compared with plasma concentrations following a similar GTN dose in the absence of dosed GDNs. No significant differences in GTN AUC (p0.9) and CLapp (p 0.7) were found. In a second set of experiments, an infusion of nitroglycerin was begun in each of 4 dogs and continued for 160 min at an infusion rate of 100 gm/min. Steady state concentrations of GTN were achieved within 100 min, at which time the dog received, simultaneously, an iv bolus dose (5.14 mg) of one of the GDNs and an infusion dose (100 gmg/min) of the same GDN. For both dinitrate metabolites no significant differences (p 0.5) were found between control and interaction arterial and venous clearances, although venous GTN clearances tended to decrease in the presence of dosed GDNs. Steady state systolic blood pressure during GDN infusions could be further reduced when GTN doses were administered; however, the steady state systolic blood pressure decrease caused by GTN could not be further reduced by the GDN infusions. Results suggest that the GDNs do not inhibit nitroglycerin metabolism or hemodynamics at the dose levels studied here.
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    URL: http://dx.doi.org/10.1007/BF01059768
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    Semiparametric analysis of non-steady-state pharmacodynamic data (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 691-712 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; linear system analysis ; nonlinear system analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We present an approach to the analysis of pharmacodynamic (PD) data arising from non-steadystate experiments, meant to be used when only PD data, not pharmacokinetic (PK) data, are available. The approach allows estimation of the steady-state relationship between drug input and effect. The analysis is based on a model describing the time dependence of drug effect (E) on (unobserved) drug concentration (Ce) in an hypothetical effect compartment. The model consists of (i) a known model for the input rate of drug I(t), (ii) a parametric model; L(t, a) (a function of time t, and vector of parameters a), relating I to an observed variable X, (iii) a nonparametric model relating X to E. Ce is proportional to X. X(t) is given by I(X) * L(t, a)/AL, where L(t,α)=e −α 1 t * ∑ k=1 m , α2k e −α 2k+1 t, ∑ k=1 m α2k=1, AL=∫ 0 ∞ L(t) dt, and * indicates convolution.The nonparametric model relating X to Eis a cubic spline, a function of X and a vector of (linear) parameters β. The values of α and β are chosen to minimize the sum of squared residuals between predicted and observed E. We also describe a similar model, generalizing a previously described one, to analyze PK/PD data. Applications of the approach to different drug-effect relationships (verapamil-PR interval, hydroxazine-wheal and flare, flecainide and/or verapamil-PR, and left ventricular ejection fraction) are reported.
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    URL: http://dx.doi.org/10.1007/BF01080874
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    Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 567-589 
    Details
    ISSN: 1573-8744
    Keywords: prednisolone ; pharmacokinetics ; pharmacodynamics ; corticosteroids ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4−and 49.2−mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50 (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CLand Vss increasing with dose. Free prednisolone exhibited slight capacitylimited elimination and distribution as CLand Vss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity-in particular IC50-and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration-time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.
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    URL: http://dx.doi.org/10.1007/BF01064420
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    Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to rats: Absorption from various GI segments (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 1-17 
    Details
    ISSN: 1573-8744
    Keywords: bumetanide ; pharmacokinetics ; pharmacodynamics ; multiple peaks ; absorption from various GI segments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Bumetanide, 2, 8, and 20 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of bumetanide in rats (n=10–12). The absorption of bumetanide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of bumetanide after oral administration were also investigated. After iv dose, the pharmacokinetic parameters of bumetanide, such ast 1/2 (21.4, 53.8 vs. 127 min),CL (35.8, 19.1 vs. 13.4 ml/min per kg),CL NR (35.2, 17.8 vs. 12.6 ml/min per kg) andV SS (392, 250 vs. 274 ml/kg) were dose-dependent at the dose range studied. It may be due to the saturable metabolism of bumetanide in rats. After iv dose, 8-hr urine output per 100g body weight increased significantly with increasing doses and it could be due to significantly increased amounts of bumetanide exreted in 8-hr urine with increasing doses. The total amount of sodium and chloride exreted in 8-hr urine per 100g body weight also increased significantly after iv dose of 8 mg/kg, however, the corresponding values for potassium were dose-independent. After oral administration, the percentages of the dose excreted in 24-hr urine as unchanged bumetanide were dose-independent. Bumetanide was absorbed from all regions of GI tract studied and approximately 43.7, 50.0, and 38.4% of the orally administered dose were absorbed between 1 and 24 hr after oral doses of 2, 8, and 20 mg/kg, respectively. Therefore, the appearance of multiple peaks after oral administration could be mainly due to the gastric emptying patterns. The percentages of bumetanide absorbed from GI tract as unchanged bumetanide for up to 24 hr after oral doses of 2, 8, and 20 mg/kg (96.2, 95.4 vs. 98.2%) were not significantly different, suggesting that the problem of precipitation of bumetanide in acidic gastric juices or dissolution may not contribute significantly to the absorption of bumetanide after oral administration. Urine output per 100g body wt increased at oral doses of 8 and 20 mg/kg.
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    Pharmacodynamics of the antiarrhythmic disopyramide in healthy humans: Correlation of the kinetics of the drug and its effects (1976)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 4 (1976), S. 231-242 
    Details
    ISSN: 1573-8744
    Keywords: disopyramide ; antiarrhythmic ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects on heart rate, R-T' interval, and mean arterial blood pressure were studied in seven healthy male volunteers after intravenous (1 and 2 mg/kg) and oral (3 and 6 mg/kg) administration of the quinidine-like antiarrhythmic disopyramide phosphate, 4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide phosphate. The left ventricular ejection time was measured after intravenous administration of 2 mg/kg of drug. Simultaneously the plasma concentrations and urinary excretion of the parent drug and its main metabolite, the monodealkylated product, were monitored as a function of time. Heart rate increases of 20% were observed at 2 mg/kg i.v. and 6 mg/kg p.o. and peaked at 0–4 min and 2 hr after administration, respectively. R-T' interval increases of 40% and 9% were observed at 2 mg/kg and 1 mg/kg i.v., respectively, and peaked at 0–2 min after administration. R-T' interval increases of 12% and 4% were observed at 6 mg/kg and 3 mg/kg p.o., respectively, and peaked at 2.5 hr. The ejection time index was unchanged, and although a 5–10% increase in the mean arterial blood pressure was observed in the 11 hr after administration, there was no pattern consistent with size or mode of administration of the four different dosages.
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    Enhancement of Tissue Delivery and Receptor Occupancy of Methylprednisolone in Rats by a Liposomal Formulation (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1402-1410 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; methylprednisolone ; pharmacokinetics ; tissue distribution ; pharmacodynamics ; glucocorticoid receptors ; drug delivery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A liposomal formulation of methylprednisolone (L-MPL) was developed to improve localization of this immunosuppressant in lymphatic tissues. Liposomes containing MPL were formulated from a mixture of phosphatydylcholine and phosphatydylglycerol (molar ratio, 9:1) and sized by extrusion through a 0.1-µm membrane. Male Sprague–Dawley rats received a bolus dose of 2 mg/kg of L-MPL or free MPL in solution (control). Samples of blood, spleen, liver, thymus, and bone marrow were collected at intervals over a 66-hr period. Concentrations of MPL in plasma and organs and free cytosolic glucocorticoid receptors (GCR) in spleen and liver were determined. The plasma MPL profiles for free and L-MPL were bi- and triexponential. Although the alpha phase kinetics of both dosage forms were similar, L-MPL showed a substantially slower elimination phase than did free drug. Incorporation of MPL into liposomes caused the following increases: terminal half-life, from 0.48 (MPL) to 30.13 hr (L-MPL); MRT, from 0.42 to 11.95 hr, V ss, from 2.10 to 21.87 L/kg; and AUC, from 339 to 1093 ng · hr/mL. Uptake of liposomes enhanced significantly the delivery of drug to lymphatic tissues and liver; AUC tissue:plasma ratios for spleen increased 77-fold; for liver, 9-fold; and for thymus, 27-fold. The duration of GCR occupancy was extended 10-fold in spleen and 13-fold in liver by the liposomal formulation. Lymphatic tissue selectivity and extended receptor binding of liposome-delivered MPL offer promise for enhanced immunosuppression.
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    URL: http://dx.doi.org/10.1023/A:1018954704886
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    Histocultures of Patient Head and Neck Tumors for Pharmacodynamics Studies (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1493-1499 
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    ISSN: 1573-904X
    Keywords: chemosensitivity ; histoculture ; head and neck tumors ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This investigation was to establish a clinically relevant experimental model to evaluate the pharmacodynamics of drugs used for head and neck cancers. A total of 83 surgical samples of primary and lymph nodal metastatic tumors was obtained from 66 patients. Fragments of these tumors were cultured on a collagen gel matrix. The tumor cell labeling index (LI) was determined by [3H]thymidine incorporation and autoradiography. Seventeen tumors (20%) were contaminated. About 80% of the remaining 65 tumors were successfully cultured for at least 2 weeks. The cultured tumor fragments retained the morphology and architecture of the freshly removed specimens; both tumor and stromal cells were present. The tumor cell LI after 2–3 weeks in culture, determined from the most proliferative area of the tissue, averaged 77 ± 12% for primary tumors and 78 ± 12% for nodal metastases. The activity of three clinically active agents, 5-fluorouracil (FU), cisplatin (DDP), and mitomycin C (MMC), was evaluated in 47 tumors. All three drugs inhibited the tumor LI. The concentrations needed to produce a 50% inhibition of the tumor LI (IC50) were within the clinically achievable concentration range. The intertumor variation in the IC50 for FU (60-fold) was considerably greater than that for DDP and MMC (7- to 8-fold). The nodal metastatic tumors appeared to be less sensitive to FU than the primary tumors, while there were no apparent differences for DDP or MMC. Tumors from patients previously treated with chemotherapy and/or radiotherapy appeared less sensitive to FU and DDP than tumors from untreated patients, but the differences were not statistically significant. Interestingly, tumors from previously treated patients were significantly more sensitive to MMC than tumors from untreated patients. The maintenance of the morphology of the fresh tumor and the observed intertumor variability in IC50 values indicate the preservation of intra- and intertumor heterogeneity in the histocultures. In summary the viability and high success rate of growth of human head and neck tumors in organ-like culture and the chemosensitivity of the cultured tumors to clinically active agents at clinically achievable concentrations support the use of this experimental model for pharmacodynamic evaluation.
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    Introduction to Backpropagation Neural Network Computation (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 165-170 
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    ISSN: 1573-904X
    Keywords: neural network ; neurocomputing backpropagation ; modeling ; pattern recognition ; pharmacodynamics ; pharmacokinetics ; classification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Neurocomputing is computer modeling based, in part, upon simulation of the structure and function of the brain. Neural networks excel in pattern recognition, that is, the ability to recognize a set of previously learned data. Although their use is rapidly growing in engineering, they are new to the pharmaceutical community. This article introduces neurocomputing using the backpropagation network (BPN).
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    Simulation for the Analysis of Distorted Pharmacodynamic Data (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 545-548 
    Details
    ISSN: 1573-904X
    Keywords: Michaelis–Menten kinetics ; nonlinear mixed effect model (NONMEM) ; pharmacodynamics ; population pharmacokinetics ; statistical simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A simulation study was conducted to compare the performance of alternative approaches for analyzing the distorted pharmacodynamic data. The pharmacodynamic data were assumed to be obtained from the natriurertic peptide-type drug, where the diuretic effect arises from the hyperbolic (Emax) dose–response model and is biased by the dose-dependent hypotensive effect. The nonlinear mixed effect model (NONMEM) method enabled assessment of the effects of hemodynamics on the diuretic effects and also quantification of intrinsic diuretic activities, but the standard two-stage (STS) and naive pooled data (NPD) methods did not give accurate estimates. Both the STS and the NONMEM methods performed well for unbiased data arising from a one-compartment model with saturable (Michaelis–Menten) elimination, whereas the NPD method resulted in inaccurate estimates. The findings suggest that nonlinearity and/or bias problems result in poor estimation by NPD and STS analyses and that the NONMEM method is useful for analyzing such nonlinear and distorted pharmacodynamic data.
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    Inhibition of Rat Splenocyte Proliferation with Methylprednisolone: In Vivo Effect of Liposomal Formulation (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 848-854 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; methylprednisolone ; pharmacodynamics ; glucocorticoid receptors ; immunosuppression ; drug delivery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effect of a liposomal formulation of methylprednisolone (MPL) on the inhibition of lymphocyte proliferation in spleen cells was investigated following IV dosing in rats. Liposomes do not alter the suppressive action of MPL when placed in lymphocyte culture. Rat splenocytes were found to have greater sensitivity to MPL (EC50 = 7.9 nM) than do human peripheral blood lymphocytes (EC50 = 28 nM). In vivo studies in rats utilized 2 mg/kg IV bolus doses of liposomal MPL compared to drug in solution. Animals were sacrificed at various times post-dosing until 120 h, spleen was excised and, after incubation of lymphocytes with PHA, splenocyte blastogenic responses were assessed by measuring cellular incorporation of 3H-thymidine. The suppressive effect of liposomal MPL in comparison with free drug was significantly prolonged (〉120 h vs 〈 18 h). Inhibition effects versus time were described by a pharmacodynamic model using MPL concentrations in plasma as an input function. A nonlinear relationship was found between suppression of splenocyte proliferation and the concentration of bound glucocorticoid receptors in spleen. Only partial receptor occupancy accompanied complete lymphocyte suppression. The suppression of endogenous corticosterone in plasma for both treatments was similar with values from L-MPL rats returning to baseline after 24 h. These results demonstrate enhanced efficacy of local immunosuppression by targeting spleen with liposomal MPL.
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    Increased Sensitivity to the Anticonvulsant Effect of Valproate in Aging BN/BiRij Rats (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1046-1051 
    Details
    ISSN: 1573-904X
    Keywords: pharmacodynamics ; valproate ; aging ; anticonvulsive
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg · L−1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.
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    Receptor-mediated prednisolone pharmacodynamics in rats: Model verification using a dose-sparing regimen (1990)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 18 (1990), S. 189-208 
    Details
    ISSN: 1573-8744
    Keywords: prednisolone ; pharmacodynamics ; modeling ; glucocorticoid receptor ; tyrosine aminotransferase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Our receptor/gene-mediated model of corticosteroid action was tested and extended by examining the pharmacokinetics/dynamics of multiple low doses vs. a single higher dose of intravenously administered prednisolone in adrenalectomized male Wistar rats. Low-dose rats received 3 bolus doses (5 mg/kg) of prednisolone at 0, 0.5 and 1.0hr. High-dose animals were given a single 25 mg/kg dose of prednisolone. Both regimens were expected to produce equivalent net responses based on model predictions. Control rats were not dosed. The profiles of free hepatic cytosolic glucocorticoid receptors and the hepatic tyrosine aminotransferase (TAT) enzyme were examined. Plasma prednisolone concentrations showed bi-exponential decline for both doses using pooled animal data. Clearance of total plasma prednisolone was 4.16 and 3.21 L/hr per kg in low- and high-dose groups. Volume of distribution at steady state (∼1.50 L/kg) and central volume (∼0.6 L/kg) were similar for both groups. Receptor levels from 5–16 hr stabilized at 64% of the 0-hr control value. Receptor and TAT profiles were essentially superimposable for both dosing groups. Our previous model was used to simultaneously describe prednisolone plasma concentrations, hepatic receptors, and TAT activity. The ability of total plasma prednisolone (Cp), corticosteroid binding globulin (CBG)-free plasma prednisolone (CCBG), and free plasma prednisolone (CF) to describe the kinetics/dynamics were examined. The CF values produced optimum fitting of all receptor data. The similarity of the two dosing groups supports the view that appropriately timed doses of a steroid can be used in an optimally efficacious manner by first filling all receptor sites and then replacing steroid as receptors are expected to recycle from nuclear/DNA binding sites as the steroid is eliminated.
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    URL: http://dx.doi.org/10.1007/BF01062199
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    Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 147-169 
    Details
    ISSN: 1573-8744
    Keywords: computers ; pharmacokinetics ; pharmacodynamics ; infusions ; drug delivery ; computer driven ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Computer-controlled infusion pumps incorporating an internal model of drug pharmacokinetics can rapidly achieve and maintain constant drug concentrations in the plasma. Although these pumps offer more accurate titration of intravenous drugs than is possible with simple boluses or constant rate infusions, the choice of the plasma as the target site is arbitrary. The plasma is not the site of drug effect for most drugs. This manuscript describes two algorithms for calculation of the infusion rates necessary for a computer-controlled infusion pump to rapidly achieve, and then maintain, the desired target concentration at the site of drug effect rather than in the plasma.
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    URL: http://dx.doi.org/10.1007/BF01070999
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    Application of semilinear canonical correlation to the measurement of opioid drug effect (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 611-635 
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    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; plasma concentration-effect relation-ship ; anesthesia ; analgesic ; narcotic ; opioids ; alfentanil ; brain ; electroencephalograph ; spectral edge ; semilinear canonical correlation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To examine the relationship between the electroencephalograph (EEG) and plasma opioid concentration, one would like to collapse the high-dimensional EEG signal into a univariate quantity. Such a simplification of the EEG is desirable because a univariate quantity can be modeled using standard nonlinear regression techniques, and because most of the information in the EEG is redundant or unrelated to drug concentration. In previous studies of the EEG response to opioids, the manner in which a univariate component was extracted from the EEG was ad hoc.In this paper, this extraction was performed optimally using a new statistical technique, semilinear canonical correlation. Data from 15 patients who received an intravenous infusion of the semisynthetic opioid alfentanil were analyzed. The components of the EEG that were nearly maximally correlated with plasma drug concentration were found, based on a standard pharmacokinetic-pharmacodynamic model. Two new EEG components were produced from the powers in the frequency spectrum of the EEG: a weighted sum of the logarithms of the powers, and a weighted sum of the powers expressed as percentages of the total power. These components both had a median R2 of 0.84, compared to median R2sranging from 0.37 to 0.83 for five commonly used ad hocEEG components. The new components also had less variability in R2 between subjects.
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    URL: http://dx.doi.org/10.1007/BF01064422
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    Simultaneous pharmacodynamic modeling of the non-steady-state effects of three oral doses of 1,3-glyceryl dinitrate upon blood pressure in healthy volunteers (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 515-532 
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    ISSN: 1573-8744
    Keywords: glyceryl dinitrate ; nitroglycerin ; human ; blood pressure ; pharmacodynamics ; pharmacokinetic-pharmacodynamic modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The organic nitrate 1,3-glyceryl dinitrate (1,3-GDN) is one of the primary dinitrate metabolites of the antianginal agent nitroglycerin (GTN). Investigational New Drug Approval was sought to administer oral solution doses of 1,3-GDN to a small number (n=3) of healthy volunteers; each subject receiving three doses at 1.2, 2.4, and 3.6 mg. With volunteers confined to a semirecumbent posture for the duration of each treatment (4-hr period postdose), diastolic blood pressure (DBP) was recorded and plasma samples collected for 1,3-GDN concentration analysis. Appreciable concentration-related decreases in DBPwere observed, with maximal decreases from predose baseline values approximating 11 to 25 mm Hg. For each subject parametric pharmacodynamic modeling was performed with simultaneous analysis utilizing the DBPvs. time data from all three doses; an inhibitory Emax pharmacodynamic model was adopted. The temporal relationship between plasma 1,3-GDN concentrations and DBPdisplayed rapid equilibration. For subjects 1, 2 and 3,respectively, Emax was predicted as 12.9, 23.4, and 29.7 mm Hg, representing 21.5, 31.6, and 39.5% decreases in DBPfrom predose baseline values;plasma concentrations at half Emax (C50)were 2.75, 2.43, and 5.93 μg/L. Utilizing pharmacokinetic-pharmacodynamic modeling, 1,3-GDN plasma concentrations appear to relate to a systemic “effect measure” that is mechanistically representative of the therapeutic actions of organic nitrates as peripheral vasodilators. The establishment of a GDN plasma concentration-effect relationship together with the relatively high plasma levels of GDN achieved following GTN dosing supports the hypothesis that the GDNs contribute significantly to the hemodynamic effect observed with GTN.
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    URL: http://dx.doi.org/10.1007/BF01059112
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    Estimation of amobarbital plasma-effect site equilibration kinetics. Relevance of polyexponential conductance functions (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 617-634 
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    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; system approaches ; electroencephalogram ; amobarbital ; effect site equilibration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The time delay between drug plasma concentrations and effect has been modeled most commonly by the effect compartment approach, assuming first-order monoexponential equilibrium kinetics between plasma and effect site. So far this assumption has not been rigorously probed. The purpose of the present investigation was to model the delay between amobarbital plasma concentrations and EEG effect using a new approach based on system analysis principles. This approach models the equilibrium between plasma and effect site without assuming a specific kinetic structure. Assuming linear distribution kinetics between plasma and effect site, the relationship between the two variables may be described by a convolution type of linear operation, involving a conductance function ϕ(t),which is approximated by a sum of exponentials. Six male Wistarderived rats received an iv infusion of amobarbital at a rate of 10mg/kg per min until isoelectric periods of 5sec or longer appeared on the EEG. Frequent arterial blood samples were obtained and EEG was continuously quantified using aperiodic analysis. The amplitudes in the 2.5–30Hz frequency band were used as EEG effect measure. The delay between plasma concentrations and EEG effect was best modeled by a biexponential conductance function. The use of a biexponential conductance function resulted in a significant further reduction (41 ± 10%)in hysteresis when compared to a monoexponential function, indicating that the assumption of simple first-order monoexponential equilibration kinetics is inadequate. The use of a biexponential conductance function also resulted in a significantly different shape of the effect site concenration- EEG effect relationship and hence the estimated pharmacodynamic parameters, when compared with a monoexponential function. This relationship showed a biphasic behavior, with EEG effects being maximal at amobarbital concentrations of 29.6± 1.3mg/L. At 80.2±2.0mg/L the EEG effect was reduced 50%below baseline values. A comparison was made with the equilibration between amobarbital plasma and cerebrospinal fluid (CSF) concentrations. Six male Wistarderived rats received an iv infusion of amobarbital, 10mg per min for 15min. Arterial blood and CSF samples were taken simultaneously at regular intervals. The equilibration between plasma and CSF concentrations was best fitted by a monoexponential conductance function. Significant differences in equilibration profiles of CSF and effect site with the plasma site were observed. To reach 50%equilibrium the effect site requires 2.5±0.3min and the CSF 3.5±0.2min, to reach 95%the values were, respectively, 90± 27and 15± 1min. This suggests that CSF is kinetically distinguishable from the effect site.
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    URL: http://dx.doi.org/10.1007/BF01080870
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    Pharmacoimmunodynamics of methylprednisolone: Trafficking of helper T lymphocytes (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 319-331 
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    ISSN: 1573-8744
    Keywords: methylprednisolone ; helper T lymphocytes ; pharmacodynamics ; cell trafficking ; chronopharmacology ; immunosuppression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A two-compartment dosed model was used to characterize the cell trafficking behavior of helper T cells in response to various single doses of methylprednisolone. Steroids are assumed to inhibit the circadian-determined cell return from extravascular sites to blood in a classic inhibitory pattern reflected by an IC50.The rate of cell efflux from tissues is modeled with a cosine function having a period of 24 hr and a maximum at about 1 am. Nonlinear leastsquares regression employing differential equations was used to analyze helper T-cell data from three human studies from our laboratory. The IC50 value of methylprednisolone of 12–19 ng/ml approximates receptor KD values. Simulations were performed to demonstrate the log-linear role of steroid dose or AUCon the integral of effect of helper T cells over a wide range of methylprednisolone doses. This pharmacodynamic model allows flexibility for characterizing any type of steroid dosing regimen and is relevent in describing complex response data for corticosteroid immunosuppressive effects in man.
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    Receptor-mediated methylprednisolone pharmacodynamics in rats: Steroid-induced receptor down-regulation (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 333-355 
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    ISSN: 1573-8744
    Keywords: methylprednisolone ; methylprednisone ; pharmacodynamics ; steroid receptor ; down-regulation ; tyrosine aminotransferase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Several approaches to receptor down-regulation were examined to extend previous receptor/ genemediated pharmacokinetic/dynamic models of corticosteroids. Down-regulation of the glucocorticoid receptor was considered as an instantaneous event or as a gradual steroid-receptor-mediated process. Concentrations of plasma methylprednisolone, free hepatic cytosolic receptors, and the activity of hepatic tyrosine aminotransferase (TAT) enzyme were measured for 16 hr following administration of 0, 10, and 50 mg/kg methylprednisolone sodium succinate to 93 adrenalectomized rats. Receptor down-regulation was best described by a fractional decrement in the rate of return of free cytosolic glucocorticoid receptor. Predicted values for free receptor, bound receptor, nuclear bound receptor, and transfer compartments were in accord with the expected rank order values based on the high and low steroid doses. Model parameter estimates were independent of dose and described the rapid depletion of free cytosolic receptor, latephase return of cytosolic receptor to a new baseline level that was 20–40% lower than control, and the TAT induction/dissipation pattern following steroid dosing. The microscopic association and dissociation constants describing the steroidreceptor interaction were 0.23 L/nmole per hr (kon and 4.74 hr−1 (koff) for methylprednisolone compared to previously obtained values of 0.20 L/nmole per hr and 15.7 hr−1 for the related steroid prednisolone. The time course of TAT induction was similar to that observed previously for prednisolone. Efficiency of TAT induction was more closely related to steroid receptor occupancy than plasma methylprednisolone concentrations due to receptor saturability and receptor recycling.
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    Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 521-536 
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    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacodynamics ; cell trafficking ; corticosteroids ; glucocorticoid receptors ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A two-compartment closed model was used to characterize the movement of basophils between blood and extravascular sites resulting from methylprednisolone (MP) exposure. This model is consistent with the view that corticosteroids cause a decrease in the recirculation of these cells from peripheral compartments. Methylprednisolone (Solu-Medrol) was given to healthy males at doses of 10, 25, and 40 mg. Blood samples were collected and assayed for MP by HPLC for pharmacokinetic analysis. Whole blood histamine, an index of circulating basophils, was assessed by RIA over 32 hr. Nonlinear least-squares analysis was carried out to solve for the model parameters reflecting cell movement between compartments and sensitivity (IC50)to the steriod. This model quantitates the fall and return pattern of biologic response to corticosteroids with a minimal number of parameters which jointly fit several dose/response curves and yields a mean IC50 value of 8.1 ng/ml similar to receptor binding of MP. Properties of the temporal and integrated response curve and model extrapolations over a wide dose range were explored with simulations. Because corticosteroids exert similar effects on other cells in blood, this model may be applicable to various regulatory and immunosuppressive effects.
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    A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 537-552 
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    ISSN: 1573-8744
    Keywords: Modeling ; neuromuscular blocking drugs ; pharmacodynamics ; pharmacokinetics ; potency ; onset time
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To account for experimental data showing increased onset time with increased potency of neuromuscular blocking drugs, a pharmacokinetic-pharmacodynamic model is presented. It is characterized by a finite concentration of receptors (R)in the effect compartment. Transfer from central to effect compartment is linearly related to concentration gradient. A sigmoid Emax model is used to describe the relationship between receptor occupancy and effect. Plasma concentrations found in the literature are used. Differential equations are solved numerically for equipotent doses of drugs of different potencies. Because the density of receptors constitutes a significant drain of drug molecules for potent drugs, the model predicts an inverse relationship between speed of onset and potency. The concentration of receptors in the effect compartment Rwhich best fits experimental data obtained in humans is 0.28 Μmol/L. With this value of R,onset times are prolonged when the ED95 (dose for 95% blockade) is less than 0.1 Μmol/kg. It is concluded that, in the development of a short-acting nondepolarizing neuromuscular blocking drug, agents having an ED95 of 0.1 Μmol/kg or greater appear more promising.
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    The relationship between receptor-effector unit heterogeneity and the shape of the concentration-effect profile: Pharmacodynamic implications (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 449-468 
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    ISSN: 1573-8744
    Keywords: concentration-effect ; heterogeneity ; pharmacodynamics ; receptor ; E max model ; dose response ; shape factor ; effector unit ; Hill coefficient ; sigmoidalE max model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The apparent concentration-effect relationship is the ensemble of many effector units (such as individual cells or channels) that do not always exhibit a uniform stimulus-effect relationship. This concept is substantiated by many observations of heterogeneity in receptor-effector populations including hormone secreting cells, response to hormonal stimuli, activity pattern of second messengers, stimulus-evoked synaptic currents, and single ion channels. The relationship between drug concentration and magnitude of pharmacologic response is commonly described by the sigmoidalE max model which was derived from the Hill equation. The sigmoidicity factor (N) in this model is assumed to be a pure mathematical parameter without physiological connotations. This work demonstrates that the numerical value ofN (measured empirically) is the product of two factors: (i) the degree of heterogeneity of the effector subunits, i.e., the elemental component that upon drug stimulus contributes its pharmacological effect independently and does not interact with other subunits (it could range from a single receptor up to a whole tissue), and (ii) value ofN *—the shape factor of the subunits' concentration-effect relationship. A special case of this approach occurs whenN *〉5, which is an on-off case. HereN is determined by the distribution (density equation) of the subunit values. In case of heterogeneity of the microparameters of the effector subunits the apparentN will always have a lower value thanN *. According to this theory it can be concluded that without knowledge of the distribution of the microparameters no mechanistic interpretation can be deduced from the apparentN value. If in the futureN * can be determined by theoretical or experimental methods, the distribution function relatingN * toN can be calculated. The relevance of this theory is increased in view of the progress being made in advanced research techniques which may enable us to determine the concentration-effect relationship at the level of the individual effector unit.
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    URL: http://dx.doi.org/10.1007/BF02353789
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    Comparison of some control strategies for three-compartment PK/PD models (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 525-550 
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    ISSN: 1573-8744
    Keywords: Bayesian ; compartment model ; dose regimen design ; pharmacokinetics ; pharmacodynamics ; stochastic control ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In drug therapy, effective dosage strategies are needed to maintain target drug effects. The relationship between drug dose and drug effect is often described by pharmacokinetic/pharmacodynamic (PK/PD) models where typically the PK model has a multicompartment form and the PD model is the sigmoidal Emax model. The parameters in the PK/PD model are generally unknown in the individual patient, although prior knowledge may be available and can be updated after measurements of drug effect are taken during the therapy. This fact, together with the complexity of the PK/PD model, makes the control problem complex. This paper investigates several control strategies in the framework of a three-compartment PK model plus an effect site with a PD model. Using computer simulations under different assumptions, we show that a MAP (maximum a posteriori) Bayesian type of strategy is effective, nevertheless in high-risk situations a stochastic control strategy hedging against estimation errors provides better performance at computational cost.
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    URL: http://dx.doi.org/10.1007/BF02353793
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    Neural networks in pharmacodynamic modeling. Is current modeling practice of complex kinetic systems at a dead end? (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 397-412 
    Details
    ISSN: 1573-8744
    Keywords: neural networks ; pharmacodynamics ; pharmacokinetics ; modeling ; drug effect prediction ; alfentanil ; model testing ; system analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems, in particular the brain. Computational NN are classified as parallel distributed processing systems that for many tasks are recognized to have superior processing capability to the classical sequential Von Neuman computer model. NN are recognized mainly in terms of their adaptive learning and selforganization features and their nonlinear processing capability and are considered most suitable to deal with complex multivariate systems that are poorly understood and difficult to model by classical inductive,logically structured modeling techniques. A NN is applied to demonstrate one of the potentially many applications of NN for modeling complex kinetic systems. The NN was used to predict the effect of alfentanil on the heart rate resulting from a complex infusion scheme applied to six rabbits. Drug input-drug effect data resulting from a repeated, triple infusion rate scheme lasting from 30 to 180 min was used to train the NN to recognize and emulate the input-effect behavior of the system. With the NN memory fixed from the 30- to 180-min learning phase the NN was then tested for its ability to predict the effect resulting from a multiple infusion rate scheme applied in the subsequent 180 to 300 min of the experiment. The NN's ability to emulate the system (30–180 min) was excellent and its predictive extrapolation capability (180–300 min) was very good (mean relative prediction accuracy of 78%). The NN was best in predicting the higher intensity effect and was able to identify and predict an overshoot phenomenon likely caused by a withdrawal effect from acute tolerance. Current modeling philosophy and practice is discussed on the basis of the alternative offered by NN in the modeling of complex kinetic systems. In modeling such systems it is questioned whether traditional modeling practice that insists on structure relevance and conceptually pleasing structures has any practical advantages over the empirical NN approach that largely ignores structure relevance but concentrates on the emulation of the behaviorof the kinetic system. The traditional searching for appropriate models of complex kinetic systems is a painstakingly slow process. In contrast, the search for empirical models using NN will continue to improve, limited only by technological advances supporting the very promising NN developments.
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    Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 1-17 
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    ISSN: 1573-8744
    Keywords: furosemide ; protein-calorie malnutrition ; pharmacokinetics ; pharmacodynamics ; decreased gastric and liver first-pass metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of dietary protein deficiency on pharmacokinetics and pharmacodynamics of furosemide was investigated after iv bolus (1 mg/100 g) and oral (2 mg/100 g) administration of furosemide to male Sprague-Dawley rats fed on a 23% (control) or a 5% (protein-calorie malnutrition: PCM) protein diet ad lib.for 4 weeks. After iv administration, the mean values of CL R , V ss, and the percentages of dose excreted in 8-hr urine as furosemide were increased 81, 31, and 61%, respectively, in PCM rats when compared with those in control rats, however, CL NR was 54% decreased in PCM rats. The decreased CLNR in PCM rats suggested the significantly decreased nonrenal metabolism of furosemide. The urine volume per g kidney after iv administration was not significantly different between the two groups of rats although the amount of furosemide excreted in 8-hr urine per g kidney increased significantly in PCM rats. The diuretic, natriuretic, kaluretic, and chloruretic efficiencies reduced significantly in PCM rats after iv administration. After oral administration, the extent of bioavailability increased considerably from 27.6% in control rats to 47.0% in PCM rats, probably as a result of decreased gastrointestinal and hepatic first-pass metabolism. This was supported by a tissue homogenate study; the amount of furosemide remaining per g tissue after 30-min incubation of 50 μg of furosemide with the 9000 × gsupernatant fraction of stomach (42.4 vs. 47.9 μg) and liver (41.4 vs. 45.9 μg) homogenates increased significantly in PCM rats. No significant differences in CLR and t1/2 were found between the control and the PCM rats after oral administration. The 24-hr urine volume and the amount of sodium excreted in 24-hr urine per g kidney increased significantly in PCM rats, and this might be due to a significantly increased amount of furosemide reaching the kidney excreted in urine per g kidney.
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    Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 281-297 
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    ISSN: 1573-8744
    Keywords: atrial natriuretic peptide ; brain natriuretic peptide ; neutral endopeptidase ; NONMEM ; nonlinear mixed effect model ; pharmacodynamics ; phosphoramidon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of α-rat atrial natriuretic peptide (α-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of α-rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.
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    Pharmacokinetics and pharmacodynamics of nitroglycerin and its dinitrate metabolites in conscious dogs: Intravenous infusion studies (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 533-550 
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    ISSN: 1573-8744
    Keywords: nitroglycerin ; 1,2-glyceryl dinitrate ; 1,3-glyceryl dinitrate ; pharmacokinetics ; pharmacodynamics ; clearance ; systolic blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Intravenous infusions of nitroglycerin (GTN), 1,2-glyceryl dinitrate (1,2-GDN), and 1,3-glyceryl dinitrate (1,3-GDN) were given to four conscious dogs at 10 μg/min, 30 μg/min, 50 μg/min, and 70 μg/min of GTN and 20 μg/min and 100 μg/min of GDNs. The steady state plasma concentrations (Css)of GTN were reached after about 60 min whereas for 1,2-GDN and 1,3-GDN the Csswere reached at about 150 min after the infusion began. Except for one dog, the Cssof GTN were not proportional to infusion rate, however, all dogs together showed a good linear relationship between Cssof GTN and infusion rates with an average correlation coefficient of 0.917±0.102. Large variability in GTN clearance after various infusion rates was observed in all dogs. The Cssratios of 1,2-GDN/GTN and 1,3-GDN/GTN yield overall averages of 31.5 ±17.2 and 5.47 ±3.19,respectively. Average Cssratios of metabolites 1,2-GDN/1,3-GDN were 5.78±1.23. This ratio is different from those obtained after iv bolus and oral dosing indicating that the biotransformation of GTN to 1,2-GDN and 1,3-GDN differs for each dosing route. The clearances for 1,2-GDN and 1,3-GDN were not changed over the dose range of 20 μg/min to 100 μg/min. Terminal half-lives of 1,2-GDN and 1,3-GDN postinfusion were similar to those values obtained after a single bolus dose (45 min). It appears that all the GTN dose at steady state can be accounted for by the formation of measurable 1,2-GDN and 1,3-GDN. Large intra- and interdog variations in systolic blood pressure decrease (SPD) following infusions of GTN were observed, however, all dogs showed a clear systolic blood pressure decrease when the highest infusion rate (70 μg/min) was given. No significant systolic blood pressure drop was detected following 20 μg/min infusions of 1,2-GDN or 1,3-GDN. It was clear that systolic blood pressure in all dogs decreased following 100 μg/min infusions of 1,2-GDN or 1,3-GDN. When SPD values were plotted vs. log GTN concentrations following the infusion of 70 μg/min of GTN in all four dogs, a counterclockwise hysteresis was observed indicating the significant contribution of the active dinitrate metabolites to GTN pharmacodynamics.
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    Pharmacodynamic model for joint exogenous and endogenous corticosteroid suppression of lymphocyte trafficking (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 469-480 
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    ISSN: 1573-8744
    Keywords: pharmacodynamics ; T-helper cells ; T-suppressor cells ; CD4+ lymphocytes ; CD8+ lymphocytes ; corticosteroids ; methylrednisolone ; cortisol ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The circadian pattern of the immune system correlates with that of circulating T-helper cells and inversely with cortisol concentrations. Corticosteroids, both endogenous and exogenous, cause lymphocyte dimunition in blood by retention of cells in the lymphatic circulation. A physiologic pharmacodynamic model was developed to describe changes in circulating lymphocytes as a function of both endogenous cortisol and methylprednisolone concentrations. The model was applied to T-helper and T-suppressor cell data collected from six asthmatic men during baseline, after single-dose, and after 6 days of 20 mg daily methylprednisolone. The model described all phases of the study well. Baseline circadian rhythm of lymphocytes was related to cortisol concentrations. Multiple-dosing of methylprednisolone caused apparent tolerance and decreased the sensitivity of lymphocytes to corticosteroids by 116% and markedly reduced endogenous cortisol concentrations. A 60% increase in circulating T-helper cells was observed which could be accounted for by dual changes in receptor sensitivity and endogenous cortisol.
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    Comparison of four basic models of indirect pharmacodynamic responses (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 457-478 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamics ; indirect response ; effect compartment model ; sigmoidE max model ; methylprednisolone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma concentration and response-time profiles using computer simulations. It was found that the responses produced showed a slow onset and a slow return to baseline. The time of maximal response was dependent on the model and dose. In each case, hysteresis plots showed that drug concentrations preceded the response. When the responses were fitted with pharmacodynamic models based on distribution to a hypothetical effect compartment, the resulting parameters were dose-dependent and inferred biological implausibility. Indirect response models must be treated as distinct from conventional pharmacodynamic models which assume direct action of drugs. The assumptions, equations, and data patterns for the four basic indirect response models provide a starting point for evaluation of pharmacologie effects where the site of action precedes or follows the measured response variable.
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    URL: http://dx.doi.org/10.1007/BF01061691
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    Pulmonary Delivery of Powders and Solutions Containing Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) to the Rabbit (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1101-1109 
    Details
    ISSN: 1573-904X
    Keywords: rhG-CSF ; intratracheal instillation ; lung ; pharmacokinetics ; pharmacodynamics ; pulmonary absorption ; Tc-99m
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Two powder formulations (MMAD 〈4 µm) containing rhG-CSF were insufflated (IF) via an endotracheal tube at doses of 5, 75 or 500 µg/kg to New Zealand white rabbits. Doses of 5 and 500 µg/kg of solutions were administered by intratracheal instillation (IT), subcutaneous (SC) injection in the thigh and intravenous injection (IV) via the marginal ear vein. Blood samples were removed at regular intervals from an indwelling jugular catheter. Blood was analyzed directly for total white blood cell counts (WBC). Plasma was assayed for rhG-CSF by a specific ELISA. The distribution of radioactive dose in lung tissue was found after administering Tc99m HSA in solution or when incorporated into powders. The pharmacokinetics and pharmacodynamics were determined for all routes of administration. High dose IV concentration vs. time profiles declined biexponentially (t1/2 α = 0.6 ± 0.2 hrs, t1/2 β = 4.6 ± 0.2 hrs, n = 8). Clearance was dose dependent (11.6 ± 2.6 [500 µg/kg, n = 8] vs. 21.8 ± 3.3 ml/hr/kg [5 µg/kg, n = 5]). A normal systemic response was obtained after IF, indicating that rhG-CSF retains activity in the solid state. Dissolution and absorption of rhG-CSF from the powders were not rate limiting. The plasma concentration vs. time profiles peaked at similar times to those after IT (Tmax 1 -2 hrs) but were earlier than obtained after SC (Tmax 6-10 hrs). Powders were less efficiently dosed to the lung lobes after insufflation compared with instillates (14.7 ± 10.5 vs. 60.1 ± 10.6%), resulting in bioavailabilities ranging from 5 to 33%. Bioavailability after SC was 11.0 ± 7.0% and 95.3 ± 7.9% (n = 6) for the low and high doses, respectively.
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    URL: http://dx.doi.org/10.1023/A:1018924512928
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    Soil transformation of wheat and corn metabolites mboa and DIM2BOA into aminophenoxazinones (1993)
    Springer
    Journal of chemical ecology 19 (1993), S. 2453-2461 
    Details
    ISSN: 1573-1561
    Keywords: DIMBOA ; MBOA ; DIM2BOA ; M2BOA ; 2-amino-7-methoxy-3H-phenoxazin-3-one ; 2-amino-4,6,7-trimethoxy-3H-phenoxazin-3-one ; corn ; wheat ; soil microbial transformation ; phytotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The defensive cyclic hydroxamates 7-methoxy-2,4-dihydroxy-1,4(2H)-benzoxazin-3-one (DIMBOA) and 7,8-dimethoxy-2,4-dihydroxy-1,4(2H)-benzoxazin-3-one (DIM2BOA) of wheat and corn are transformed in nonsterile soil, via 6-methoxy-2(3H)-benzoxazolone (MBOA) and 6,7-dimethoxy-2(3H)-benzoxazolone (M2BOA) respectively, into 2-amino-7-methoxy-3H-phenoxazin-3-one and 2-amino-4,6,7-trimethoxy-3H-phenoxazin-3-one. The soil transformation is similar of that undergone by the rye metabolite 2(3H)-benzoxazolone (BOA) into 2-amino-3H-phenoxazin-3-one. The transformations to phenoxazinones are not observed in sterile soil. The 2-amino-3H-phenoxazin-3-one inhibits barnyard grass radicle elongation, but the methoxylated aminophenoxazinones are not significantly inhibitory.
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    URL: http://dx.doi.org/10.1007/BF00980682
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    Foliar chemicals of wheat and related grasses influencing oviposition by Hessian fly,Mayetiola destructor (Say) (Diptera: Cecidomyiidae) (1992)
    Springer
    Journal of chemical ecology 18 (1992), S. 1965-1980 
    Details
    ISSN: 1573-1561
    Keywords: Hessian fly ; Mayetiola destructor ; Diptera ; Cecidomyiidae ; oviposition stimulants ; wheat ; rye ; barley ; oat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract More than twice the number of mated female Hessian flies,Mayetiola destructor (Say) entered a zone within 1 cm of a paper strip treated with one plant equivalent (PE) of a chloroform extract of wheat foliar waxes compared to a strip treated with solvent only; females also stayed six times longer and laid 10 times more eggs on the strip treated with the wheat extract. Column chromatographic fractionation of the wheat extract and application of these fractions onto filter paper strips showed four fractions elicited significant numbers of eggs to be laid. Single, binary, and tertiary combinations of three of these fractions (two of the four fractions apparently contained similar compounds) were tested. The greatest numbers of eggs were laid on strips treated with the tertiary combination or the binary combination conaining the two most active fractions (3 and 6); three times the number of eggs were laid on strips treated with this binary combination than the sum of eggs laid on strips treated with these two fractions separately. A comparison of grasses and their extracts showed female Hessian flies laid greater numbers of eggs on wheat or rye than on barley or oat. Fractionated barley and oat extracts were tested for activity as for wheat, and a similar pattern was observed, i.e., the greatest numbers of eggs were laid on fractions 3 and 6. Dose-response tests, using these two fractions of wheat, barley, or oat showed the same threshold of activity for fraction 3 for all three extracts, i.e., 2 PE. In contrast, fraction 6 of wheat was active at the lowest dosage tested, 0.25 PE, while the same fraction of either barley or oat was not active until tested at a dosage of 2 PE. It appears that (at least) two chemicals in the foliar waxes of these grasses influence ovipositional behavior of female Hessian flies. Furthermore, given the similar foliar chemistry of these grasses and the strong synergistic interaction between fractions 3 and 6 shown for wheat extract, it is likely that the ovipositional preferences exhibited by female Hessian flies towards these grasses may be explained by quantitative differences in the amount(s) of the active chemical(s) in their respective fraction 6 (most polar fraction tested).
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    URL: http://dx.doi.org/10.1007/BF00981920
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    Hydroxamic acid glucosides in honeydew of aphids feeding on wheat (1992)
    Springer
    Journal of chemical ecology 18 (1992), S. 841-846 
    Details
    ISSN: 1573-1561
    Keywords: Rhopalosiphum padi ; Homoptera ; Aphididae ; wheat ; maize ; DIMBOA ; hydroxamic acids ; aphid honeydew
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract DIMBOA glucoside (2-O-/gb-D-glucopyranosyl-4-hydroxy-7-meth-oxy-1,4-benzoxazin-3-one), the main hydroxamic acid (Hx) in intact wheat plants, was detected in the honey dew ofRhopalosiphum padi feeding on seedlings of six wheat cultivars that differed in their concentration of Hx, suggesting that the chemical circulates in the phloem. Neither the aglucone (DIMBOA) nor its main breakdown product were found in any of the honeydew samples. Honey dew production by aphids caged on seedlings of the wheat cultivars and DIMBOA glucoside concentrations in the honeydew followed biphasic curves when plotted against Hx concentration, suggesting passive ingestion of the chemical from the phloem at low Hx concentrations and limited ingestion due to feeding deterrency by Hx in mesophyll cells at high Hx concentrations. The presence of plant toxins such as Hx glucosides in the phloem sap, the main ingesta of aphids, and in the mesophyll cells, has major implications for plant defense, through a feeding deterrent effect during stylet penetration, and deterrency (antixenosis) along with antibiosis during feeding.
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    URL: http://dx.doi.org/10.1007/BF00988324
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    Pharmacodynamics of Methylprednisolone Phosphate After Single Intravenous Administration to Healthy Volunteers (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 263-268 
    Details
    ISSN: 1573-904X
    Keywords: methylprednisolone phosphate ; pharmacokinetics ; pharmacodynamics ; lymphocytes ; intravenous ; granulocytes ; glucose ; healthy human subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of methylprednisolone were investigated after intravenous administration of methylprednisolone phosphate to healthy subjects at seven different doses (16 to 1000 mg). Forty different pharmacodynamic parameters were followed for 1 week. The pharmacodynamic data were analyzed as a function of time as well as cumulative effects in form of the areas under the effect–time curves. Statistically significant dose-dependent effects of methylprednisolone were observed for 15 pharmacodynamic parameters. Highly significant (P ≤ 0.0001) effects were increases in glucose levels, number of white blood cells, and segmented granulocytes as well as a decrease in the number of lymphocytes. For these pharmacodynamic effects an integrated pharmacokinetic/pharmacodynamic model was derived that translates the methylprednisolone plasma concentration–time profiles into effect– time profiles. This model allows prediction of pharmacodynamic effects for any single dose in the range studied at any time point.
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    URL: http://dx.doi.org/10.1023/A:1015864709082
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    Pharmacodynamics and Biophasic Drug Levels of Methionine Enkephalin (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 930-932 
    Details
    ISSN: 1573-904X
    Keywords: biophase ; mydriasis ; dose–effect curve ; methionine enkephalin ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Methionine enkephalin (Met-E) is a naturally occurring pentapeptide. It appears to mediate pain perception by blocking CNS pathways. Using rabbits, a log dose relationship was obtained between Met-E-induced dilation of the pupil (mydriasis) and constant intravenous infusion dose rates (14, 20, 28, 37, 56, 73, and 129 µg/min/kg). Steady-state dilation is reached within 9 min. Dose-effect curves (DEC) were fitted by a linear regression analysis of the log dose versus percentage dilation plots. Fitted DEC were used to determine temporal profiles for the relative biophasic drug level.
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    URL: http://dx.doi.org/10.1023/A:1015872016718
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    Pharmacodynamics of Insulin Following Intravenous and Enteral Administrations of Porcine-Zinc Insulin to Rats (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1003-1009 
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    ISSN: 1573-904X
    Keywords: insulin ; intravenous ; enteral ; pharmacokinetics ; bio-availability ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Previous work from this laboratory showed site-dependent variations in the apparent permeability of insulin as measured using the everted rat gut sac technique, with the greatest permeability in the distal jejunum and the lowest in the duodenum (5). To quantify better the rate and extent of insulin absorption from the small intestine, closed-loop in situ experiments were performed in nondiabetic rats. Results correlated with the everted gut sac technique in that the absolute bioavailability determined in situ was higher for insulin solution administered to the more distal region of the intestine (0.133%) than that absorbed from an earlier portion of the intestine (0.059%). While the difference in regional bioavailabilities was not significant (P = 0.08), the blood glucose response showed highly significant differences (P = 0.0015), with severe and prolonged hy-poglycemia resulting from insulin delivered to the distal jejunum/ proximal ileum. Insulin administered iv followed a two-compartment pharmacokinetic model. Whole-body elimination rate constants were similar for both iv and enteral insulin. Although therapeutic quantities of insulin were absorbed from the distal small intestine, absorption enhancers would be necessary to decrease the dose of insulin required.
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    URL: http://dx.doi.org/10.1023/A:1015894125611
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    Dose and Time-Course Evaluation of a Redox-Based Estradiol-Chemical Delivery System for the Brain. II. Pharmacodynamic Responses (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 1107-1112 
    Details
    ISSN: 1573-904X
    Keywords: estradiol ; estradiol delivery system ; blood–brain barrier ; pharmacodynamics ; gonadotropins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Clinically, brain-enhanced delivery and sustained release of estradiol (E2) are desirable for effective treatments of menopausal hot flushes and prostatic adenocarcinoma and for fertility regulation. Thus, we conducted studies to determine the dose- and time-dependent effects of a brain-enhanced estradiol-chemical delivery system (E2-CDS) on anterior pituitary hormones secretion in ovariectomized (OVX) rats. The E2-CDS has consistently demonstrated preferential retention of its intermediate metabolite (E2-Q+ ), with slow release of E2 in the brain but rapid clearance from peripheral tissues. Animals received a single iv injection of E2-CDS at doses of 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg on day 0. The responses of plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL) were then evaluated at 1, 7, 14, 21, or 28 days after drug administration. The E2-CDS caused a dose- and time-dependent suppression of LH and FSH throughout the time course studied. The maximum LH and FSH reduction occurred at 7 days postinjection. Plasma LH and FSH were significantly suppressed by 86 and 58% on day 7, respectively, and were suppressed by 35% (LH) or were at preinjection levels (FSH) at 28 days following the single injection of a 1.0-mg E2-CDS dose. An equimolar E2 dose suppressed LH and FSH by only 29 and 20% on day 7, respectively which were not significantly different from time 0 values. Plasma PRL increased significantly on day 14 with the 1.0-mg E2-CDS dose but levels returned to preinjection values by 28 days after drug administration. Lower doses of the E2-CDS did not affect PRL concentrations. Plasma GH concentrations were not altered in response to the E2-CDS at any dose or time. Also, anterior pituitary and uterine weights increased in a dose- and time-dependent manner in response to E2-CDS administration. Collectively, these data demonstrate that the E2-CDS effects on gonadotropins suppression are dose and time dependent and this duration of suppression is consistent with the long half-lives of the E2-CDS metabolites in the brain.
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    Steady-State Pharmacokinetics and Pharmacodynamics of Benazeprilat in Spontaneously Hypertensive Rats (SHR) and Wistar–Kyoto (WKY) Rats (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 883-887 
    Details
    ISSN: 1573-904X
    Keywords: benazepril ; benazeprilat ; pharmacokinetics ; pharmacodynamics ; steady state ; i.v. infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of the simultaneous steady-state intravenous infusion of benazeprilat, the active metabolite of benazepril HC1, and angiotensin I (AI) on mean arterial blood pressure were investigated in the conscious, unrestrained spontaneously hypertensive rat (SHR) and its normotensive parent strain, the Wistar–Kyoto (WKY) rat. A competitive inhibition model is applied and the limits of its validity are discussed. Deviations from the model are apparent at high drug infusion rates and may relate to the effect of benazeprilat on the clearance of AI. The strains differ in the amounts of angiotensin converting enzyme (ACE) or responsiveness to angiotensin II (AII), the drug clearances, and either the pharmacology or the distribution of the drug. Since the latter two differences are drug dependent, prediction between strains is rendered difficult. This steady-state approach relates the hypertension in the SHR to the amount of ACE or responsiveness to AII and renal function.
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    URL: http://dx.doi.org/10.1023/A:1015803529013
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    Pilocarpine Disposition and Salivary Flow Responses Following Intravenous Administration to Dogs (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1064-1069 
    Details
    ISSN: 1573-904X
    Keywords: xerostomia ; pilocarpine ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Oral doses of pilocarpine increase salivary flow rates in patients afflicted with xerostomia (dry mouth). This study examined the pharmacokinetics of and a pharmacodynamic response (salivation) to intravenous pilocarpine nitrate administration in dogs. Disposition was linear over a dose range of 225–600 µg/kg; plasma concentrations were 10–120 µg/L. Elimination was rapid and generally biphasic, with a terminal elimination half-life of approximately 1.3 hr. The systemic clearance of pilocarpine was high (2.22 ± 0.49 L/kg/hr) and its steady-state volume of distribution (2.30 ± 0.64 L/kg) was comparable to that of many other basic drugs. All doses of pilocarpine induced measurable submaxillary and parotid salivary flow rates which could be maintained constant over time. Cumulative submaxillary saliva flow was linearly related to total pilocarpine dose. Plasma pilocarpine concentration was linearly related to both steady-state and postinfusion submaxillary salivary flow rates.
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    Corticosteroid Pharmacodynamic Modeling: Osteocalcin Suppression by Prednisolone (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1096-1098 
    Details
    ISSN: 1573-904X
    Keywords: pharmacodynamics ; osteocalcin ; prednisolone ; corticosteroids ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015875016041
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    The Effects of Urine pH Modification on the Pharmacokinetics and Pharmacodynamics of Phenylpropanolamine (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 96-102 
    Details
    ISSN: 1573-904X
    Keywords: phenylpropanolamine ; urinary pH modification ; urine alkalinization ; renal clearance ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To determine whether uninary alkalinization had an effect on the plasma pharmacokinetics and pharmacodynamics of phenylpropanolamine, a double-blind crossover study was conducted in four healthy, normotensive male volunteers. The subjects received 25 mg immediate-release phenylpropanolamine and either placebo or sodium bicarbonate in a balanced randomized order. The bicarbonate treatment consisted of 6 g sodium bicarbonate 30 min prior to the phenylpropanolamine and then 3 g sodium bicarbonate every 4 hr for the next 16 hr. During the control treatment, phenylpropanolamine and a placebo for bicarbonate (lactose) were given on the same schedule. Blood and urine samples were collected over 24 hr and analyzed by HPLC. A supine blood pressure and pulse were obtained before each blood sample. The bicarbonate treatment significantly increased the urine pH throughout the study period and decreased phenylpropanolamine renal clearance by 33.5%. The apparent total-body clearance was also decreased by 31.5% and resulted in higher postabsorptive plasma phenylpropanolamine concentrations in each subject as compared to the control treatment. Both systolic and diastolic blood pressures changed significantly from baseline in both treatments. The bicarbonate treatment was accompanied by significantly higher diastolic blood pressures than in the control treatment, but there was no effect on systolic blood pressures. Generally, when the blood pressure–concentration pairs were plotted chronologically, clockwise hysteresis curves resulted. Heart rates did not change significantly from baseline values for either treatment. In this small group of normotensive healthy male volunteers, urinary alkalinization significantly depressed the renal clearance of phenylpropanolamine, producing higher postabsorptive phenylpropanolamine plasma concentrations and a small but significant increase in the diastolic blood pressure.
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    Altered Pharmacokinetics and Dynamics of Apomorphine in the Malnourished Rat: Modeling of the Composed Relationship Between Concentration and Heart-Rate Response (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 318-324 
    Details
    ISSN: 1573-904X
    Keywords: apomorphine ; pharmacokinetics ; pharmacodynamics ; heart rate ; rat ; malnutrition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The impact of malnutrition on the pharmacokinetics and pharmacodynamics (change in heart rate) of apomorphine was studied in the rat. One group of rats received a low-protein diet (0.5%) ad libitum to produce prekwashiorkor. The control group received commercial food pellets. In the first experiment, the two groups received a 2 mg/kg iv bolus dose of apomorphine to determine any differences in the basic pharmacokinetic parameters. The pharmacodynamic characteristics in each group were studied at different steady-state plasma levels, achieved by iv infusions with continuous measurements of the heart rate. There was an almost twofold decrease in the plasma clearance in the malnourished rats compared with controls. A pronounced change in the pharmacodynamic response was also observed in the malnourished group. In the control group, apomorphine produced bradycardia at low concentrations and tachycardia at high concentrations, while only bradycardia was registered in the malnourished group, with maximum effects at steady-state plasma concentrations of 50 ng/ml and a return to baseline at higher concentrations. The effects in control and malnourished rats were fitted simultaneously to the sum of two Hill equations with a nonlinear regression program, and the fits were compared by means of an F test. The maximum pure tachycardia obtainable differed significantly in the prekwashiorkor group compared to the control group. These results suggest a selective down regulation/desensitization only of the receptors responsible for the tachycardia produced by apomorphine during malnutrition.
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    Age and the Pharmacokinetic-Pharmacodynamic Relationship of Phenobarbital in Rats: “Pseudo”-Longitudinal vs Cross-Sectional Study Design (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1456-1459 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; aging ; phenobarbital ; cross-sectional ; “pseudo”-longitudinal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In a previous study, an apparent age-related increase in brain sensitivity to the anesthetic effect of phenobarbital was observed in BN/BiRij rats. However, since this study was conducted according to a cross-sectional design, the observed change could, in principle, also have been the result of a cohort effect. The purpose of the present investigation was to exclude the role of such a cohort effect by adopting a “pseudo”-longitudinal study design. In this design 45 animals out of one cohort were reserved, and one subgroup was investigated at five ages (7, 14, 21, 29, and 34 months). A decrease in the anesthetic threshold dose of phenobarbital was found during aging, which appeared to be due mainly to an increase in the brain sensitivity. It is concluded that the previously observed increase in brain sensitivity is indeed the result of the aging process rather than a cohort effect.
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    URL: http://dx.doi.org/10.1023/A:1015815014166
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    An in Vitro Pharmacodynamic Model to Simulate Antibiotic Behavior of Acute Otitis Media with Effusion (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 920-924 
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    ISSN: 1573-904X
    Keywords: in vitro ; pharmacodynamics ; pharmacokinetics ; amoxicillin ; otitis media
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The purpose of this investigation was to develop an in vitro pharmacodynamic model (IVPM) that would simultaneously simulate in vivo serum and middle ear amoxicillin pharmacokinetic characteristics of acute (purulent) otitis media and then utilize the IVPM to assess amoxicillin-mediated killing of a type 7F Streptococcus pneu-moniae (MIC = 0.002 mg/L). The IVPM consisted of a sterile central compartment and a membrane-bound “infected” peripheral compartment. Peak peripheral compartment amoxicillin concentrations occurred within 2 hr after its introduction into the central compartment and were approximately 30% of peak central compartment concentrations. Amoxicillin elimination from the central compartment was designed to provide a 1-hr t 1/2. Amoxicillin elimination from the peripheral compartment was slower than from the central compartment, with an average half-life of 2.3 hr. Significant concentration-related differences in maximal bacterial kill rates were not detected over the range of amoxicillin concentrations studied (0.26 to 14.6 mg/L). However, at peak central compartment amoxicillin concentrations of ≤2 mg/L, a lag phase in killing was observed. In general, the in vitro pharmacokinetic data derived from this model compare well with published in vivo data.
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    Pharmacokinetics and Pharmacodynamics of L-703,014, a Potent Fibrinogen Receptor Antagonist, After Intravenous and Oral Administration in the Dog (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 426-431 
    Details
    ISSN: 1573-904X
    Keywords: fibrinogen receptor antagonist ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 ± 1.3% (i.v.) and 80.5 ± 11.9% (p.o.) were recovered in the feces; 20.3 ± 3% (i.v.) and 2.2 ± 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 ± 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 ± 0.05. The mean terminal half-life was 118 ± 36 min, the mean steady-state volume of distribution was 0.61 ± 0.22 L/kg, and the mean plasma clearance was 8 ± 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 µg/ mL collagen in the presence of 1 µM epinephrine as an agonist. The mean C 50 was 44.4 ± 6.0 ng/mL, and the mean Hill coefficient was 1.5 ± 0.3. The mean bioavailability was 4.9 ± 1.4% in dogs administered 2.0 mg/kg (p.o.).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018973323039
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