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Biomedical subjects

K Stoeckel

Publications and source records attributed to K Stoeckel.

At least 55 records · Page 3Linked to original sources
PubMed1985

Single-dose ceftriaxone kinetics in the newborn.

Ceftriaxone kinetics were characterized after a single, 2-minute, intravenous infusion of 50 mg/kg to 20 sick infants 1 to 8 days old who weighed 1.78 to 4.36 kg. Plasma binding parameters could be determined by equilibrium dialysis in 16 of the infants, in whom kinetic parameters for free ceftriaxone in plasma were also determined. Compared with corresponding values in adults, the elimination t1/2 was longer in infants (19 and 8.4 hours) because of reduced total systemic clearance (4.48 and 8.51 ml/min/m2). The apparent steady-state volume of distribution was of the same order in infants and adults (5,130 and 5,350 ml/m2). Both renal and nonrenal clearance of free ceftriaxone were reduced in infants, but these decreases were partially offset by an increased free fraction; plasma binding affinity and capacity constants for infants were about half the adult values. The mean fraction of dose excreted unchanged in urine was estimated at 70% in the neonates and 46% in adults. There were no clinically significant correlations between the kinetic parameters and either age since birth or age since conception. The fraction of free ceftriaxone in plasma inversely correlated with age since conception and was lower in female infants, which decreased the systemic clearance and volume of distribution of total drug in the female infants compared with the male infants. Values for the volume of distribution and clearance parameters were not related to body size (weight or body surface area). From our results, a ceftriaxone dosage of 50 to 100 mg/day is recommended during the first week of life for newborn infants who weigh between 1.8 and 4.4 kg. Impaired renal function may require a reduction in dosage.

Adult↗
PubMed1985

Lack of effect of tenoxicam on glibornuride kinetics and response.

The pharmacokinetics of glibornuride (25 mg i.v.) and the accompanying insulin and glucose responses were characterized in eight human subjects in the presence and absence of steady-state tenoxicam (20 mg p.o./day for 2 weeks). Tenoxicam affected neither the pharmacokinetic parameters of glibornuride (systemic clearance, volume of distribution and biological half-life) nor the responses of plasma insulin and blood glucose to glibornuride. The single i.v. dose of glibornuride had no detectable effect on the kinetics of tenoxicam.

Adult↗
PubMed1984

Pharmacokinetics of ceftriaxone in patients with renal and liver insufficiency and correlations with a physiologic nonlinear protein binding model.

In patients with normal hepatic and renal function, between 30 and 60 percent of administered ceftriaxone is eliminated by nonrenal (biliary) mechanisms. Substantial nonrenal elimination reduces the need for dose adjustments in mild and moderate renal impairment. Minor increases in the biologic half-life (12 hours versus normal of 8 hours) of ceftriaxone have been seen in (functionally) anephric patients with normal extrarenal clearance mechanisms. Anephric patients with decreased nonrenal elimination (additional liver damage) showed a greater increase in biologic half-lives (greater than 15 hours). In patients with various degrees of liver insufficiency (alcoholic fatty liver and cirrhosis with and without ascites), only those with ascites showed significant changes in total drug clearance and volume of distribution. However, these changes in patients with ascites were such that they did not demonstrate significantly different biologic half-lives (9.7 hours versus normal of 8 hours). Simulations of observed concentration versus time data support a physiologic disposition model whereby ceftriaxone, like other cephalosporins, distributes only in plasma and in the extravascular-extracellular (interstitial) fluid and ceftriaxone is saturably bound to albumin in both spaces. All observations in normal subjects and patients were in good agreement with the physiologic disposition model predictions. The consequences of the nonlinear binding behavior of ceftriaxone are such that they favor the administration of ceftriaxone in a large single dose rather than in divided doses. No major drug accumulation is expected in patients with renal or hepatic insufficiency, but anephric patients with a decrease of more than 80 percent in nonrenal elimination will require dose adjustments.

Blister↗
PubMed1984

Pharmacokinetics of ceftriaxone in neonates and infants with meningitis.

The pharmacokinetics of ceftriaxone was studied in the plasma, urine, and cerebrospinal fluid of seven neonates and seven infants with meningitis. In addition, plasma and urine data were obtained in five neonates and one infant receiving ceftriaxone for other serious infections. All neonates younger than 14 days received daily doses of 50 mg/kg ceftriaxone; all other patients but two received 100 mg/kg. The average weight-corrected values for total body clearance (ClT), volume of distribution (Vdss), and biologic half-life (t 1/2) were 0.37 ml/min/kg, 0.45 L/kg, and 16.2 hours in neonates younger than 1 week; 0.77 ml/min/kg, 0.48 L/kg, and 9.2 hours in neonates older than 1 week; and 1.03 ml/min/kg, 0.39 L/kg, and 7.1 hours in older infants, respectively. There was a significant difference in ClT and t 1/2 between the neonates younger and both neonates older than 1 week, and infants. The Vdss was not significantly different among the three age groups. The average renal clearance in neonates younger than 1 week (0.28 ml/min/kg was 70%, in neonates older than 1 week (0.54 ml/min/kg) was 77%, and in older infants (0.49 ml/min/kg) was 47% of ClT, indicating that nonrenal elimination was less developed in neonates. The quantitation of CSF diffusion of ceftriaxone was assessed by comparison of the areas under the CSF and plasma concentration-time curve. The mean ceftriaxone penetration into the CSF in neonates and infants with bacterial meningitis was 17%. On the other hand, penetration in patients with aseptic meningitis amounted to only 4%. Mean ceftriaxone concentrations in the CSF in patients with bacterial meningitis were 2.8 mg/L after 24 hours, exceeding by many times the minimum inhibitory concentration of the common meningitis pathogens at this time.

Cefotaxime↗
PubMed1984

Single-dose ceftriaxone kinetics in liver insufficiency.

The disposition profile of ceftriaxone was studied in eight normal subjects and in 15 subjects with various degrees of chronic liver damage (alcoholic fatty liver [FL] and cirrhosis without [C] and with [CA] ascites) who received bolus injections of ceftriaxone, 1 gm iv. Plasma protein binding fell in all. As a result, mean free fraction in plasma rose between 140% (FL) and 320% (CA). An exceptionally large rise (1270%) occurred in one subject with CA when the condition was aggravated by renal impairment. Fourteen of 15 subjects had renal clearance of unbound drug of the same order as that in healthy adults. In chronic liver disease, mean nonrenal clearance of unbound drug fell with severity of liver damage. Kinetic parameters with reference to total drug differed in normal subjects and subjects with CA. Kinetic changes in the latter were such that elimination t 1/2 beta did not differ (9.7 and 8.4 hr). Because of the wide therapeutic range of ceftriaxone, subjects with chronic liver disease would require no dose adjustments, whereas dose reductions are envisaged for subjects with cirrhosis (C,CA) on the basis of increased unbound drug concentrations.

Adult↗
PubMed1984

Single-dose pharmacokinetics of Ro 17-2301 (AMA-1080), a monocyclic beta-lactam, in humans.

Ro 17-2301 (AMA-1080) is a new N-sulfonated monocyclic beta-lactam that is highly active against gram-negative bacteria, especially against Enterobacteriaceae and Haemophilus, Neisseria, and Pseudomonas spp. (Kondo et al., Proc. Int. Congr. Chemother. 13th, Vienna, Austria, p. 56/1-56/5, 1983). The single-dose pharmacokinetics of this compound were studied in six healthy male volunteers who received intravenous infusions of 500, 1,000, and 2,000 mg. A good linear correlation (r2 = 0.99) was found between the dose infused and the resulting area under the plasma concentration-time curve. Maximal plasma concentrations of 36, 78, and 150 micrograms/ml appeared after doses of 500, 1,000, and 2,000 mg, respectively. The mean terminal elimination half-life was 1.8 h (range, 1.4 to 2.3 h), the apparent volume of distribution at steady state was 17 liters, and the total systemic clearance was 150 ml/min. Within 72 h 78 to 89% of the dose was recovered intact from urine. After administration of 14C-labeled Ro 17-2301, 96% of the radioactivity was found in the urine and 3% was found in the feces. The concomitant administration of probenecid did not affect the renal clearance or urinary excretion of this beta-lactam, an indication that the renal elimination of this substance is only by glomerular filtration. Ro 17-2301 was 18% bound to human plasma protein, and this binding was independent of concentration between 25 and 400 micrograms/ml. Based on these data, the pharmacokinetics of this monocyclic beta-lactam should be predictable in the foreseen dose ranges.

Adult↗
PubMed1983

Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding. I. Theoretical considerations.

We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both V beta and the model-independent VSS) were inaccurate/invalid; b) V beta based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms (-fp and V-TSS) were introduced which provide additional insight concerning the disposition of this type of drug. The -fp is the area-weighted average fraction unbound in the plasma and V-TSS is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.

Blood Proteins↗
PubMed1983

Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding. II. Physiological significance.

Guidelines presented previously for the analysis of plasma concentration versus time data for a drug exhibiting concentration-dependent plasma protein binding were successfully applied to the distributional parameters of a new cephalosporin, ceftriaxone. This approach provided several striking observations when the pharmacokinetics of ceftriaxone in a healthy and uremic population were re-examined. First, the parameter -fp converted the apparent dose-dependent distributional terms of ceftriaxone into a function of the concentration-dependent plasma protein binding. Second, a strong correlation between the term VUSS and the reciprocal of -fp was established within each of the two populations. While this -fp term accounted for the variability within the respective populations due to ceftriaxone-albumin binding differences, it did not account for all of the distributional differences between the two populations. The present analysis revealed that the altered physiologic state of uremia (larger plasma volumes and interstitial to intravascular albumin ratios), in addition to differences in plasma protein binding, dictated the distribution of ceftriaxone in healthy and uremic subjects. Furthermore, the binding-disposition model which accounts for the presence of plasma proteins outside the vascular space, was established to be appropriate in describing the distribution of ceftriaxone.

Blood Proteins↗
PubMed1983

Single-dose ceftriaxone kinetics in functionally anephric patients.

The disposition profile of ceftriaxone was studied in 12 functionally anephric patients (creatinine clearance less than 10 ml/min) who received bolus injections of 150, 500, and 1500 mg IV in a noncrossover fashion. As in healthy subjects, the kinetics in uremic patients were nonlinear for total (bound plus unbound) and linear for free (unbound) drug. The plasma protein binding was reduced due to a decreased association constant, resulting in a doubling of the free fraction in plasma. Ten of 12 patients showed nonrenal clearance values of unbound drug (ClFNR) identical to those in healthy adults and only minor increases in their biologic t1/2(beta) compared to normal (12 and 8 hr). These patients would require no dose adjustments in their dosing regimen. Two of the patients exhibited decreased ClFNR values and increased t1/2(alpha) of 20 and 34 hr. Anephric patients with impaired nonrenal elimination would require minor dose adjustments.

Adult↗
PubMed1982

Pharmacokinetics of ceftriaxone following intravenous administration of a 3 g dose.

The pharmacokinetic parameters of total (bound and unbound) and free (unbound) ceftriaxone in six healthy volunteers after intravenous injection of 39 were compared with low-dose data from a previous study. The dose-dependent behaviour of total drug was considerably more pronounced after the 3 gram dose. In contrast, total body clearance (C1FS = 258 ml/Min), renal clearance (C1FR = 170 ml/min) and volume of distribution (VFD (beta) = 168 1) of free (unbound) drug did not differ from the data reported earlier. There was no significant change in biological half-life (t1/2 (beta) = 7.8 h) or in the fraction excreted unchanged in urine (fu = 0.67).

Adult↗
PubMed1982

Single-dose pharmacokinetics of ceftriaxone in infants and young children.

The pharmacokinetics of ceftriaxone were studied in five infants (7 to 15 months old) and five young children (24 to 70 months old). Both groups received a single 50-mg/kg dose in an intravenous infusion over 5 min. No major pharmacokinetic differences were observed between the two populations. The total (bound plus unbound) plasma concentration-versus-time data could be described in each case by a biexponential equation. Changes in renal clearance indicated time- and dose- dependent pharmacokinetic behavior. The fraction excreted unchanged in the urine (fu) and the biological half-life (t 1/2 (beta)) were, however, dose independent. The average values were 47% for fu (0 to 12 h) and 6.5 for T 1/2 (beta). Weight-corrected total systemic clearance was C1TS = 0.71 ml/min per kg; volume of distribution was VD (beta) = 394 mg/kg. The data support intravenous administration of 50 mg of ceftriaxone per kg of body weight every 12 h in assessing its activity against Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis in postneonatal-stage pediatric patients.

Cefotaxime↗
PubMed1981

Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics.

The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose-dependent increase in total systemic clearance (ClTS) from 9.7 ml/min at the 150-mg dose to 13 ml/min at the 1500-mg dose. The dose-dependent changes in ClTS could be explained in terms of the concentration-dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCFO-infinity) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (ClFS) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (ClFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t1/2 was not influenced by dose and averaged 8 hr. This biological t1/2 is by far the longest ever for a cephalosporin in healthy subjects.

Adult↗
PubMed1981

Biological importance of the retrograde axonal transport of nerve growth factor in sensory neurons.

Nerve growth factor is retrogradely transported in sympathetic and sensory neurons throughout life. Although this transport is known to be biologically significant in sympathetic neurons, such a function was not yet known in sensory ganglia. By using the neuropeptide substance P as a biochemical marker, we show that sensory ganglia from newborn and adult rats respond in nerve growth factor and that its retrograde axonal transport is biologically relevant, as indicated by an increase in substance P and in general protein content.

Animals↗
PubMed1981

Pharmacokinetics of Rocephin, a highly active new cephalosporin with an exceptionally long biological half-life.

The total (bound and unbound) plasma concentration time profiles following the three intravenous doses of Rocephin (150, 500 and 1,500 mg) declined in a biphasic manner. A simple compartment analysis was inappropriate since a dose-disproportional increase in the area under the total drug concentration time curve (AUCT,0(-8)) occurred. This resulted in unstable, dose-dependent total systemic clearance (9.7-13.0 ml/min) and volume of distribution (7.0-8.6 litres) values. The dose-dependent pharmacokinetic changes could be completely explained in terms of the concentration-dependent plasma protein binding (fp ranging from 0.04 to 0.17 in the concentration range from 0.5 to 300 micrograms/ml). Hence, the pharmacokinetics of free (unbound) Rocephin was linear and dose-independent. With reference to free (unbound) drug the mean total clearance was 255 ml/min and the mean renal clearance about 160 ml/min. The renal clearance was therewith slightly higher than the average glomerular filtration rate in man (approximately 125 ml/min). Consequently the coadministration of probenecid (1 g) had no effect on the pharmacokinetics of Rocephin. The mean plasma half-life of Rocephin was not influenced by dose and averaged 8 h. It was therewith the longest ever reported one for a cephalosporin in healthy volunteers.

Ceftriaxone↗
PubMed1980

Nonlinear pharmacokinetics of indocyanine green in the rabbit and rat.

The pharmacokinetic behavior of indocyanine green (ICG) in the rabbit can be described by a two-compartment open model, allowing for saturable transport of drug to the peripheral compartment and for its first-order elimination from the peripheral compartment. Use of this model led to the prediction of the accumulation of ICG in the plasma of a rabbit following the administration of repeated i.v. injections. Furthermore, studies conducted in the rat were also consistent with this model. One characteristic of the model is that above certain dose levels, the accumulation of ICG in the liver (i.e., the peripheral compartment) should reach a maximum independent of dose during certain time periods. This prediction was confirmed in a series of studies in the rat. The findings presented in this report provide evidence that a single model may be capable of explaining the variety of pharmacokinetic characteristics which have been reported for ICG, at least in the dose range studied.

Animals↗
PubMed1980

Tocainide kinetics and metabolism: effects of phenobarbital and substrates of glucuronyl transferase.

Tocainide, a lidocaine congener with low hepatic clearance, is eliminated predominantly by formation of a novel glucuronide conjugate. This suggested the possibility of metabolic interactions with enzyme inducers or competitive substrates for glucuronyl transferase. The time course of tocainide blood concentration as well as the urinary excretion-time profiles of drug and principal metabolite (a glucuronide of tocainide carbaminic acid, TOCG) were examined in six subjects before and after 15 days on phenobarbital (100 mg/day). In another study, the effect of salicylamide and clofibrate on the time courses of tocainide and TOCG urinary excretion were examined in four of the same six subjects. After 600 mg tocainide HCl by mouth, the area under the tocainide blood concentration-time curve was 48.2 +/- 11.9 hr micrograms/ml for the control dose and 49.6 +/- 4.2 hr micrograms/ml (mean = SD) after phenobarbital. Percent of dose excreted unchanged in urine (46.0 +/- 4.9 and 43.4 +/- 5.6) and percent of dose excreted as TOCG (30.6 +/0 3.3 and 27.7 +/- 7.2) were not affected by phenobarbital (data presented as control and after phenobarbital). Because salicylamide has been reported to be a potent inhibitor of the glucuronidation of some drugs and because clofibrate yields metabolites that may be competitive inhibitors of tocainide conjugation, the two were given together with tocainide. Average percent of dose recovered in urine as unchanged tocainide in 24 hr was 26.8%, 28.3%, and 29.7% in the control, salicylamide, and clofibrate studies. The urinary excretion of TOCG was also not affected. It is concluded that under the conditions of our investigation, the principal urinary metabolite of tocainide, a glucuronide of tocainide carbaminic acid, is formed by a mechanism not subject to induction by phenobarbital or competitive inhibition by salicylamide or clofibrate.

Adult↗
PubMed1979

Screening methods using sulfamethazine for determining acetylator phenotype.

Analysis of sulfamethazine (SMZ) kinetics in man has revealed complexities including wide intersubject variability. In our study, an attempt was made to assess the potential influence of changes in nonmetabolic parameters (absorption and urinary elimination rate constants) on the markers of acetylation capacity normally used in clinical screening procedures to determine phenotype. Seven normal subjects were classified as slow (SA) or fast acetylators (FA) according to their metabolic rate constant for SMZ (Km), plasma SMZ half-life, and percentage of N-acetyl SMZ in a 6-hr blood sample (PI6), a 5- to 6-hr urine collection (UI5--6), or a 6-hr total urine collection (UI6). Computer simulations were applied to baseline SMZ kinetic data from these subjects, varying nonmetabolic kinetic parameters over experimentally defined ranges singly, or in parallel with 1 or more of the other parameters. The simulations indicate that all the usual phenotyping procedures were sensitive to changes in absorption and urinary elimination rate constants. While these predictions require experimental confirmation, results show that the PI6 method is least sensitive to such changes, suggesting this method may minimize errors in phenotyping screening.

Absorption↗