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  • 101
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 24 (1983), S. 7-14 
    ISSN: 1432-1041
    Keywords: oxprenolol ; coronary heart disease ; normals ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration profile of oxprenolol after intravenous bolus injection, during intravenous infusion and following sustained oral administration was studied in a total of 106 patients with coronary heart disease. Speed of onset of pharmacodynamic activity, as measured by suppression of isoprenaline tachycardia, was discernible within a few seconds of central injection and complete within 5 min in all patients; variability in response was small. Following both i.v. bolus and intravenous infusion, plasma oxprenolol concentrations showed considerable between patient variability The plasma concentration/time profile observed in 16 patients following single intravenous oxprenolol bolus therapy was substantially higher, particularly during the early distribution phase, than observed and predicted volunteer data. Higher plasma oxprenolol concentrations were also attained during the more extended time sampling of the infusion studies; these findings would be compatible with reduced oxprenolol clearance in patients with ischaemic heart disease. During chronic oral therapy there was a many-fold between-subject variability in plasma concentration achieved following a given ingested dose. Correlation of antagonism of exercise tachycardia inhibition with plasma oxprenolol concentration in 15 male volunteers demonstrated near complete blockade of exercise stimulation of chronotropic beta-adrenoceptors at an average plasma oxprenolol concentration of 150 ng/ml. In coronary heart disease, such plasma concentrations can most conveniently be achieved by a 4 mg oxprenolol intravenous bolus with simultaneous infusion of 0.05 mg/kg/h; however, these studies provide sufficient information to allow alternative regimens to be derived should lesser plasma concentrations be considered desirable.
    Type of Medium: Electronic Resource
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  • 102
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 24 (1983), S. 209-215 
    ISSN: 1432-1041
    Keywords: sobrerol ; mucus liquefaction ; pharmacokinetics ; bronchial mucus level ; mass fragmentography ; metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic profile of Sobrerol, a mucolytic drug, has been studied in patients with acute exacerbations of chronic bronchitis and dense sputum. In addition to measurement of serum and urine levels, the concentration in bronchial mucus was also examined, and their correlation was calculated. Mass fragmentographic analysis was used to assay free sobrerol and its principal urinary metabolites hydrated carvone and glucuronidated sobrerol. After the doses and administration routes used, there appeared to be accumulation of sobrerol in bronchial mucus. This is a feature of great interest and value for a drug which has the specific action of liquefying mucus.
    Type of Medium: Electronic Resource
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  • 103
    Electronic Resource
    Electronic Resource
    Springer
    Investigational new drugs 1 (1983), S. 47-58 
    ISSN: 1573-0646
    Keywords: dihydro-5-azacytidine ; DHAC ; pharmacokinetics ; clearance ; foxhound
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An HPLC analytical method was applied to the determination of plasma concentrations of 5,6-dihydro-5-azacytidine (NSC 264880, DHAC) in two foxhounds after a rapid intravenous infusion of 300 mg/kg DHAC. The dose employed is the mouse equivalent LD10 dose which results in mild reversible toxicity in the dog. The decline in DHAC plasma concentrations was greater than three log decades after dosing. The plasma concentration-time data was computer-fitted by NONLIN to a three compartment open model with first-order elimination using the equations for a short intravenous infusion. The half-lives corresponding to the three exponential phases were: t1/2α =5.78 min, t1/2β =1.57 h and t1/2γ =22.0 h in dog 1 and t1/2α =7.41 min, t1/2β =2.25 h and t1/2γ =21.6 h in dog 2. The terminal phase of the plasma concentration time profiles represented a minor contribution (2.2–3.2%) to the total area under the curve. The plasma concentration time data for the first 12 h after dosing was computer fitted to a two compartment open model. The initial and terminal half-lives determined from the two compartment fits were similar to the t1/2α and t1/2β values of the fits to the three compartment open model. Similar total body clearance values were calculated from the areas under the plasma concentration time curves from time zero to infinity for the computer fits to the three and two compartment models, respectively. Thus, for practical purposes, it appears feasible to define adequately the total body clearance of DHAC by analysis of the plasma concentration time data during the time interval in which the plasma concentration is described as a bi-exponential equation. Renal excretion of the parent drug is the principal route of excretion of DHAC from the dog.
    Type of Medium: Electronic Resource
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  • 104
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 499-513 
    ISSN: 1573-8744
    Keywords: methotrexate ; 7-hydroxy-methotrexate ; pharmacokinetics ; nonlinear pharmacokinetics ; dose-dependent pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX), a major metabolite, were investigated in rabbits after intravenous bolus injection and infusion using a specific HPLC assay. The arterial sampling (from the carotid artery) was used in all the studies since peculiar and significant arterial-venous differences in the plasma concentration of MTX and 7-OH-MTX were found following bolus administration of the drug. The disposition kinetics of MTX appeared polyexponential with a small terminal phase having a half-life of 10.2–27.5 hr. Extensive formation of 7-OH-MTX occurred at the two dose levels (15 and 50 mg/kg). Nonlinear disposition of MTX was reflected in several aspects of data analysis. A disproportionate increase in the AUC with dose was observed. An increase in dose not only reduced the mean total body clearance (7.49 vs. 4.26 ml/min/kg) and renal clearance (4.89 vs. 2.76 ml/min/kg), but also prolonged the mean residence time (26.2 vs. 43.3 min). The steady-state volume of distribution (Vss) of MTX was estimated to range from 0.16 to 0.25 L/kg. More than 90% of the dose was excreted as MTX and 7-OH-MTX within 8 hr after dosing. Renal clearances decreased with the increasing plasma levels, suggesting active tubular secretion as one of the excretion mechanisms. A similar pattern for renal clearance of 7-OH-MTX was obtained. Infusion studies of 7-OH-MTX revealed that this metabolite had a longer residence time and a larger Vss as compared with MTX, which were in accordance with its physicochemical properties. Essentially complete doses of 7-OH-MTX could be recovered in the rabbit urine.
    Type of Medium: Electronic Resource
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  • 105
    ISSN: 1573-8744
    Keywords: insulin ; continuous subcutaneous infusion ; plasma immunoreactive insulin ; pharmacokinetics ; preprogrammable infusion pump ; reconstruction of predetermined plasma insulin profiles ; dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A preprogrammable insulin delivery system which can provide the flexibility of varying plasma insulin concentration in a physiological manner has been developed. This system involves a program of continuous subcutaneous infusion of insulin at variable rates to reproduce arbitrarily selected plasma insulin concentration-time profiles. The desired insulin infusion rate profile was calculated from the desired insulin pattern using pharmacokinetic parameters experimentally determined by measurement of immunoreactive plasma insulin following a subcutaneous bolus dose to depancreatized dogs.
    Type of Medium: Electronic Resource
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  • 106
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 289-301 
    ISSN: 1573-8744
    Keywords: parameter estimation ; upper and lower bounds ; pharmacokinetics ; initial estimates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The upper and lower bounds of rate constants for general mammillary three and four compartment systems have been derived. It is further proposed that the midpoints of the bounds can be used as initial estimates for parameter estimation. Numerical examples are given demonstrating the closeness of the calculated midpoints to the “known” rate constants of both the three and four compartment systems.
    Type of Medium: Electronic Resource
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  • 107
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 561-576 
    ISSN: 1573-8744
    Keywords: methylprednisolone ; bioavailability ; pharmacokinetics ; oral and parenteral administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This study was conducted to evaluate the influence of route of administration upon the bioavailability and pharmacokinetics of methylprednisolone sodium succinate. Fourteen healthy adult male volunteers received 40 mg doses of methylprednisolone as the following treatments after an overnight fast in a 4-way crossover design: (a) as a 1 ml i.v. bolus;(b) as a 1 ml i.m. injection;(c) administered as an oral solution;and (d) as 5×8 mg oral tablets. Both the ester and free methylprednisolone were determined in plasma and urine. Study results indicate that the ester is rapidly and extensively converted to free methylprednisolone after all routes. The extent of methylprednisolone absorption was equivalent after i.v. and i.m. administration. Both orally administered treatments resulted in a lower extent of absorption attributed to a first-pass effect. Although a slightly lower extent of absorption was demonstrated following the oral administration of the methylprednisolone sodium succinate solution relative to the methylprednisolone oral tablets, this average difference of 9% would probably be of minimal therapeutic importance.
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  • 108
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 183-187 
    ISSN: 1573-8744
    Keywords: nonlinear regression ; parameter estimation ; invariance ; transformation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract It is shown that when one nonlinear regression model is a reparametrization of a second model, the parameter estimates, and their standard errors, for one model can be obtained directly from those obtained from fitting the other model.
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  • 109
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 389-400 
    ISSN: 1573-8744
    Keywords: time-dependence ; volume of distribution ; curve-fitting ; simulations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The present study was conducted to develop, test, and apply a simple exponential time-dependent volume of distribution function to describe the pharmacokinetics of compounds following instantaneous, zero-order and first order input. Simulations were used to show the applicability and flexibility of the equations. Experimental data from the literature were fitted using the equations developed in the present study. In addition, the results of these fitted curves were compared to the results of the original fitting procedures to compare and contrast the methods. In the present analysis, the change from an initial volume (V1)to the total volume (VT)is perceived as a simple exponential function. Therefore, a single exponential term to describe elimination and a single exponential term to describe the change from V1 to VT were used to describe the entire blood concentration profile. The results from present simulations and fitted data indicate that the transition from V1 to VT is a more continuous process than observed with classical methods and is consistent with results obtained from physiologic flow-limited models. This observation suggests that the present curve-fitting technique may be more akin to physiologic reality, in that it depicts the change from the initial volume of distribution to the total volume of distribution as a continuous exponential function which reflects the establishment of an equilibrium.
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  • 110
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 31-46 
    ISSN: 1573-8744
    Keywords: bumetanide ; probenedd ; pharmacokinetics ; pharmacodynamics ; doseresponse relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of intravenous bumetanide (0.250 mg/kg), alone (treatment I) and after probenecid pretreatment (treatment II), were studied in four mongrel dogs. Lactated Ringer's solution was administered by vein throughout both treatments at a flow rate of 2 ml/min to avoid fluid and electrolyte depletion. Bumetanide and probenecid concentrations were analyzed by HPLC, sodium by flame photometry, and creatinine by colorimetry. Although the probenecid markedly reduced the plasma and renal clearances of bumetanide, as well as the fraction excreted unchanged in the urine, there was no significant difference between treatments I and II in the 4-hr natriuretic and diuretic responses. However, analysis of the dose-response curves between treatments I and II showed that sodium, excretion was better correlated with bumetanide urinary excretion rate than with plasma concentration. The reasons for a poor correlation between treatments during the early time periods are discussed.
    Type of Medium: Electronic Resource
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  • 111
    Electronic Resource
    Electronic Resource
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 47-61 
    ISSN: 1573-8744
    Keywords: d-tubocurarine ; pharmacokinetics ; pharmacodynamics ; multicompartrnent model ; Hill equation ; plasma ; tibialis anterior muscle ; protein binding ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels ≤0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of3H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses ≤0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range ≤0.15 mg/kg.
    Type of Medium: Electronic Resource
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  • 112
    ISSN: 1573-8744
    Keywords: naltrexone ; controlled release ; pharmacokinetics ; gas chromatography ; biodegradable copolymer delivery system ; release rate quantitationin vivo ; Loo-Riegelman method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Naltrexone release rates from a controlled release delivery system have been quantitated over a time period greater than one month in the monkey. The method requires calibration of the pharmacokinetic parameters of each monkey utilizing an intravenous bolus dose and assay of unchanged naltrexone levels in plasma as a function of time after dosing. Also required are periodic plasma levels of unchanged naltrexone obtained subsequent to administration of the delivery system. Release rates are then calculated as well as the total amount released. Application of the methodology to a biodegradable copolymer naltrexone delivery system in three monkeys showed an initial release rate of 3– 8% of the dose per day over the first 3– 5 days followed by a slow, rather constant release rate of 1– 3% per day from day 5 to the time of the last measurable plasma sample (36– 43 days). Comparison of alternative calculation methods using both experimental and simulated plasma naltrexone data verified the accuracy of the release rate calculations. The sum of the calculated total amount of naltrexone released plus the assayed amount remaining in the delivery system after removal from the animal accounted for 91– 94% of the administered dose in the two monkeys in which complete data were obtained.
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  • 113
    Electronic Resource
    Electronic Resource
    Springer
    Acta applicandae mathematicae 1 (1983), S. 105-120 
    ISSN: 1572-9036
    Keywords: Systems ; control ; Biomathematics ; identification in compartmental systems ; compartmental models ; pharmacokinetics ; optimal control of drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We first introduce some main problems in pharmacokinetics and then we propose methods for their resolution. Of course, identification problem is considered. A numerical efficient method is given. It brings back to the resolution of a succession of linear algebraic systems. In the case of non unicity we suggest an approach based on the adjunction of a criterion to minimize. The last part studies the optimal injection of a drug associated to an optimization criterion. An explicit solution can be found for a n-compartments linear system.
    Type of Medium: Electronic Resource
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  • 114
    Electronic Resource
    Electronic Resource
    Springer
    Investigational new drugs 1 (1983), S. 219-224 
    ISSN: 1573-0646
    Keywords: methyl-GAG ; rabbits ; pharmacokinetics ; three compartmental model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a paired ion exchange high pressure liquid Chromatographic assay, pharmacokinetic evaluation of methyl glyoxal bis guanylhydrazone (methyl-GAG) was performed in nine male New Zealand albino rabbits following administration of a single intravenous bolus dose of 50 mg/kg B.W (550 mg/m2 BSA). Blood samples were collected before and at intervals of 5, 10, 15, 30 min and 1, 2, 3, 4, 6, 8, 12, 18, and 24 h after administration of the drug. The analysis of experimental data indicates a three compartment open model with first order elimination from the central compartment described by the equation C pt =A.e−αt +B.e−βt +C.e−γt , where A, B, C, are 107.985, 4.785, and 0.763 μg/ml, respectively, α, β,γ, are 5.466, 0.487, and 0.030 h−1, respectively, and $$T_{\frac{1}{2}\alpha ,\beta ,\gamma } $$ are 7.6, 85.3 min and 23.1 h, respectively. The mean volume of distribution in the central compartment V c was 0.44 liters (l)/kg, volume of distribution Vd area 30.326 l/kg, and the total body clearance 0.9097 l/kg/h. The existence of a long terminal plasma half life of methyl-GAG reported previously in human studies was also confirmed in experimental animals and may explain the cumulative toxicity of this drug.
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