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K Stoeckel

Publications and source records attributed to K Stoeckel.

At least 37 records · Page 2Linked to original sources
PubMed1990

Pharmacokinetics and biliary concentrations of fleroxacin in cholecystectomized patients.

Patients with biliary tract infections received 800 mg of fleroxacin orally once daily on five consecutive days; cholecystectomy was on day 3. Starting on the day when dose 5 was administered, serial blood and T-drain bile samples were taken for 72 h and urine was collected for 96 h. The mean (+/- the standard deviation) peak concentration in plasma was 8.2 +/- 4.0 mg/liter at 8.3 h. The harmonic mean elimination half-life was 10.5 h, which is comparable to that reported for healthy volunteers. This increase resulted from reduced renal clearance (mean [+/- standard deviation], 38 +/- 22 ml/min), as the volume of distribution in the patients (1.4 +/- 0.7 liter/kg) did not differ from that reported for healthy subjects. Maximum concentrations in T-drain bile were high (median, 22.1 mg/liter) and exceeded those measured in plasma by a factor of 2 to 3; the individual ratios of the area under the curve for bile divided by that for plasma ranged from 1.3 to 9.9. As observed in healthy volunteers, the major pathway for elimination of fleroxacin was via the kidneys. The fraction of dose 5 eliminated in the 0- to 24-h urine was reduced, however, and the fraction of the dose in the urine as the N-demethyl and N-oxide metabolites was elevated. At the dose regimen used in this study, the MICs for most pathogens that cause biliary tract infections were surpassed in plasma and bile for more than 24 h.

Adolescent↗
PubMed1990

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with hepatic cirrhosis.

The pharmacokinetics of orally administered cefetamet pivoxil and intravenously administered cefetamet were studied in 12 healthy subjects and 12 patients with hepatic cirrhosis without ascites. Cirrhosis had no detectable effect on the pharmacokinetics of cefetamet and on the bioavailability of cefetamet pivoxil. After intravenous cefetamet in control versus cirrhotic subjects, respectively, the following mean +/- standard deviation values were observed: total body clearance, 128 +/- 10.2 versus 123 +/- 28.8 ml/min; steady-state volume of distribution, 23.2 +/- 2.2 versus 22.7 +/- 4.6 liters; half-life, 2.42 +/- 0.21 versus 2.35 +/- 0.41 h. Renal and nonrenal clearances of cefetamet were similar in both groups, as were the mean residence times and areas under the plasma concentration-time curve. For oral cefetamet pivoxil, no differences were detected in the mean values of the percentage of dose absorbed: 44.6 +/- 9.1 versus 50.1 +/- 12.9. The rate of appearance of cefetamet in the plasma also was not affected by cirrhosis: similar mean values were found for the mean residence time and the maximum concentration in plasma and its time of occurrence.

Administration, Oral↗
PubMed1990

Effects of timing of food and fluid volume on cefetamet pivoxil absorption in healthy normal volunteers.

Cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 16 male subjects (age, 23.4 +/- 1.7 years; weight, 73.9 +/- 7.0 kg) 1 h before (BE), with (WI), and 1 h after (AF) a standard breakfast. The time to peak concentration of cefetamet in plasma (Tmax) was increased from 3.25 +/- 1.44 h in the BE group to 4.31 +/- 1.54 and 4.13 +/- 1.54 h in the WI and AF groups, respectively (P less than 0.05). The maximum cefetamet concentration in plasma (Cmax) and the area under the plasma cefetamet concentration-time profiles (AUC) in the BE, WI, and AF groups were 5.50 +/- 1.06, 5.47 +/- 1.4, and 6.57 +/- 0.93 micrograms/ml and 38.2 +/- 10.1, 35.7 +/- 11.9, and 42.8 +/- 6.8 micrograms.h/ml, respectively. The Cmax and AUC values were not different between the BE and WI groups (P greater than 0.05). However, differences in these values were found between the WI and AF groups (P less than 0.05). The effect of fluid volume intake on cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 12 male subjects (age, 23.8 +/- 2.3 years; weight, 74.9 +/- 9.0 kg) under fasted and WI conditions. Increasing fluid volume intake from 250 to 450 ml under the fasted condition had no effect on the absorption of the prodrug (Tmax, 2.50 +/- 0.52 versus 2.83 +/- 0.94 h; Cmax, 4.89 +/- 1.04 versus 4.84 +/- 0.89 micrograms/ml; AUC, 29.6 +/- 5.1 versus 30.7 +/- 7.1 micrograms.h/ml; P greater than 0.05. Thus, independent of fluid volume intake, cefetamet pivoxil absorption is enhanced when it is given within 1 h of a meal, and it is recommended that the prodrug should be taken during this period of increased bioavailability.

Absorption↗
PubMed1990

Influence of antacid and ranitidine on the pharmacokinetics of oral cefetamet pivoxil.

The purpose of this investigation was to assess the influence that treatment with antacid and ranitidine had on the pharmacokinetics of oral cefetamet pivoxil in 18 healthy male volunteers. Each subject received, in an open-labeled, randomized, three-way crossover design, a single oral dose of 1,000 mg (two tablets) of cefetamet pivoxil 10 min after a standard breakfast during each of the following treatments: treatment A, control period; treatment B, antacid (80 ml of suspension; Maalox 70) administered on the evening before cefetamet pivoxil dosing (-12.5 h) and again 2 h before and 2 h after a standard breakfast; treatment C, ranitidine (150 mg) administered twice a day for 4 days and again 1 h and 10 min prior to cefetamet pivoxil dosing. Plasma and urine samples were collected over a 24-h period following cefetamet pivoxil administration. Cefetamet was analyzed by high-performance liquid chromatography. Oral bioavailability parameters (area under the concentration-time curve from 0 to 12 h, area under the concentration-time curve from 0 h to infinity, time to maximum concentration of drug in plasma, and maximum concentration of drug in plasma) were obtained by noncompartmental techniques. The results showed that none of these bioavailability parameters was significantly (P greater than 0.05) affected by antacid or rantidine coadministration. A compartmental analysis showed no significant differences. In addition, the terminal elimination half-life and the fraction of cefetamet excreted unchanged in the urine was also not significantly (P greater than 0.05) affected by antacid or ranitidine exposure. Relatively wide intrasubject variability was observed for time to maximum concentration of drug in plasma and terminal elimination half-life in several of the 18 subjects studied. Although these irregularities did not appear to be strongly associated with a particular treatment, they increased in subjects in both the antacid and H2-receptor antagonist treatment groups compared with those in subjects in the control treatment group. We conclude that antacid and ranitidine treatment likely does not alter the bioavailability of oral cefetamet pivoxil.

Administration, Oral↗
PubMed1989

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency.

The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLS), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min per kg to 0.14 +/- 0.04 and 0.04 +/- 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 +/- 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 +/- 0.74 versus 14.8 +/- 6.14 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 0.05). Based on these observations, it is recommended that patients with CLcr of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily. Patients with CLcr between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLcr of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.

Administration, Oral↗
PubMed1989

Pharmacokinetics of intravenous cefetamet (Ro 15-8074) and oral cefetamet pivoxil (Ro 15-8075) in young and elderly subjects.

The purpose of this investigation was to evaluate the effect of advanced age on the pharmacokinetics of cefetamet and its prodrug, cefetamet pivoxil. A secondary objective of this study was to assess the effect of food on the absorption of cefetamet pivoxil in the elderly. Twenty-four healthy subjects (twelve young and twelve elderly) received (in a Latin square design) a single-dose, 515-mg infusion of cefetamet, a single 1,000-mg oral dose of cefetamet pivoxil during fasted conditions, and a single 1,000-mg oral dose of cefetamet pivoxil 10 min after a standardized low-fat breakfast. Serial blood and urine samples were collected over a 36-h period and analyzed by high-performance liquid chromatography. Intravenous and oral pharmacokinetic parameters were obtained by using model-independent techniques. The systemic clearance and renal clearance of cefetamet were significantly lower (P less than 0.05) in elderly subjects compared with in young controls after intravenous administration. No significant difference was observed in the apparent volumes of distribution at steady state between the two groups. Consequently, half-life and mean residence time were prolonged. A trend toward a lower renal clearance/creatinine clearance ratio was observed in our elderly population. Oral clearance of cefetamet was only slightly reduced in our elderly subjects, consistent with an increase in plasma half-life. Otherwise, oral pharmacokinetic parameters were comparable between elderly and young subjects. Additionally, the same effects of food were observed on the absorption characteristics of cefetamet (no change in maximum concentration of drug in plasma and an increase in both time to maximum concentration of drug in plasma and bioavailability) in our elderly subjects as in our young volunteers. Age did not appear to alter the deesterification and bioavailability of cefetamet pivoxil. We conclude that the small reduction in the elimination of cefetamet in the elderly would not require dose adjustment for this population.

Administration, Oral↗
PubMed1989

Pharmacokinetics of cefetamet pivoxil (Ro 15-8075) with ascending oral doses in normal healthy volunteers.

The pharmacokinetics of cefetamet pivoxil during administration of ascending oral doses were studied in 16 male normal healthy volunteers (age, 24.5 +/- 2.1 years; weight, 73.5 +/- 8.5 kg). The subjects were randomly assigned to four oral treatments of 500, 1,000, 1,500, and 2,000 mg of cefetamet pivoxil according to a four-by-four Latin square design. After an overnight fast, the drug was administered 10 min after a standard breakfast. It was found that both the rate and extent of prodrug absorption, measured as cefetamet adsorption, were reduced with increasing doses. The time to maximum concentration of cefetamet in serum was delayed from 4.00 +/- 0.81 to 4.88 +/- 0.96 h (P less than 0.05) when the dose of cefetamet pivoxil was increased from 500 to 2,000 mg. The dose-normalized values of area under the curve from 0 h to infinity for cefetamet and fraction of dose excreted as cefetamet were reduced by averages of 10.3 and 12.5%, respectively, over the dose range studied (P less than 0.05). The changes in rate and extent of prodrug absorption are thought to be the main factors contributing to the nonlinear relationship between maximum concentration in serum and dose. The change in absorption characteristics of cefetamet pivoxil with dose is, however, expected to have few clinical consequences because the magnitudes of these changes are comparable with their respective intragroup variations.

Administration, Oral↗
PubMed1989

Pharmacokinetics of oral cefetamet pivoxil (Ro 15-8075) and intravenous cefetamet (Ro 15-8074) in humans: a review.

Cefetamet pivoxil belongs to the class of orally absorbed pro-drug esters which are hydrolyzed to the active compound (cefetamet) on their first pass through the gut wall and/or the liver. The intravenously administered cefetamet is eliminated predominantly unchanged in the urine by glomerular filtration. Systemic and renal clearance values for cefetamet were 140 and 130 ml/min, respectively. The plasma protein binding is 22%, whereby the only binding protein is albumin. The steady state volume of distribution (0.29 l/kg) corresponds roughly to the extracellular water space which is consistent with other low protein-bound cephalosporins. In general, after intravenous doses, cefetamet follows the kinetic behaviour of a cephalosporin with low protein binding, limited non-renal clearance, and renal clearance that is predominantly due to glomerular filtration, e.g. ceftizoxime, ceftazidime. After oral administration, cefetamet pivoxil shows a significant food effect (F = 41% vs 51%). Hence, cefetamet pivoxil is recommended to be taken after food. The food effect, however, is not of such a magnitude that it will be of clinical consequence when this recommendation is not followed. The food effect is not related to a change in gastric pH because antacids and ranitidine do not affect the absorption of cefetamet pivoxil, although in approximately 20% of the subjects absorption of the drug is delayed. The elimination of cefetamet is directly proportional to renal function. In patients with varying degrees of renal insufficiencies, dosage should be decreased accordingly. Age has no effect on the bioavailability of cefetamet pivoxil. However, the clearance of cefetamet is higher in children and lower in the elderly.

Administration, Oral↗
PubMed1988

Protein binding of ceftriaxone in extravascular fluids.

Ceftriaxone binding in extravascular fluids and diluted plasma was characterized by equilibrium dialysis techniques and the data was subjected to Scatchard analysis. The extent of ceftriaxone binding in extravascular fluids (synovial, lymph, ascites, and pleural exudate) was less than plasma due primarily to lower albumin concentrations. Ceftriaxone capacity constants were highly correlated (r2 = 0.900, p less than 0.001) with measured albumin concentrations (range of 43 g/L for albumin to 4.7 g/L for one of the pleural exudate samples). The binding affinity constant (M-1 x 10(-4] was comparable for plasma (3.67), synovial fluid (4.14), and lymph (3.40), but was lower for ascites (2.37) and pleural fluid (range of 2.77 to 0.31). Plasma samples diluted with plasma water (range of 100 to 3%) exhibited a common affinity constant (mean value 4.03 x 10(4) M-1) and capacity constants which correlated directly with albumin concentration (r2 = 0.998, p less than 0.001). Analysis of these observations suggests that extravascular binding of ceftriaxone can readily be predicted if extravascular albumin concentration and corresponding disease-state plasma protein binding are known.

Ascitic Fluid↗
PubMed1988

Effect of probenecid on the elimination and protein binding of ceftriaxone.

The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d. Probenecid increased the total systemic clearance (CLTS) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t1/2T (beta)) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CLFR) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone. The final value of CLFR was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CLFNR) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CLFS) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg). As a consequence of a decreased affinity constant (KA), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid. The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.

Adult↗
PubMed1988

Randomized treatment of patients with typhoid fever by using ceftriaxone or chloramphenicol.

Sixty-three patients with Salmonella typhi infections were randomly assigned to receive either ceftriaxone iv in single daily doses of 75 mg/kg for children and 3-4 g for adults for seven days or to receive 60 mg of chloramphenicol/kg a day orally or iv in four divided doses until defervescence and then 40 mg/kg a day to complete 14 d. In the ceftriaxone group, one death occurred, and two of seven patients still febrile 11 d after starting treatment were given chloramphenicol. In the chloramphenicol group, one death and one gastrointestinal perforation occurred. The probability of remaining febrile was similar for both groups during the first seven days but was significantly greater for patients receiving ceftriaxone during the 14-d period. Patients in the chloramphenicol group were more likely to be bacteremic on day 3. These results suggest that a seven-day course of once-daily ceftriaxone shows promise as an alternative to 14 d of chloramphenicol for treating typhoid fever.

Adolescent↗
PubMed1988

Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans.

This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.

Administration, Oral↗
PubMed1986

Indocyanine green: pharmacokinetics in the rabbit and relevant studies of its stability and purity.

The plasma concentration-time profile of indocyanine green (1) in the rabbit was determined by spectrophotometric and high-performance liquid chromatographic (HPLC) analysis following doses of 5 or 25 mg/kg. Spectrophotometric analysis yielded plasma concentration estimates that were higher than those obtained by an HPLC method and this difference was particularly large at time points greater than or equal to 30 min postdose. Chromatograms of plasma samples from each rabbit exhibited two peaks, both of which were maximal in the first postdose sample, suggesting an impurity in the commercial preparation. HPLC analysis of five different lots of 1 suggested a variable abundance of this impurity (1.7-4.0%). When stored in a variety of aqueous solutions, 1 degraded to a compound with a retention time identical to that of the impurity. The time for 50% degradation of 1 in deionized, distilled, and sterile water was 19, 92, and 99 h, respectively, and the rate of decay in these solvents exhibited significant interday variability. Dilute acetic acid (approximately 20 mM; pH = 3.2) was found to substantially accelerate this degradation (50% degradation in less than 1 h). Interestingly, this acid-catalyzed rate of conversion of 1 to the degradation product fit about equally well assuming a zero-order or first-order process. In an effort to elucidate the structure of this degradation product (impurity), UV-visible spectra of appropriate column eluates were obtained. The spectra of these compounds differed from that of 1 in only minor details.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Ceftriaxone pharmacokinetics during peritoneal dialysis.

The purpose of this study was to investigate the pharmacokinetics of intraperitoneally (IP) administered ceftriaxone (CRO) in patients maintained on chronic peritoneal dialysis. A single 2 g dose of CRO was administered IP to six adult patients who did not have peritonitis at the time of study. After a 5 hour dwell, the peritoneal fluid was exchanged with CRO-free fluid. Exchanges were carried out every 4 to 8 h, over a 24- to 28-h period. The peak total plasma CRO concentration was 104 micrograms/ml. An average of 74.1% of the IP dose of CRO was absorbed. Plasma protein binding was nonlinear; mean free fraction ranged from 12.8 to 17.9% at low and high concentrations. Dialysate concentrations at the end of subsequent exchanges ranged from means of 19.9 to 2.9 micrograms/ml. Total CRO clearance from plasma was 10.1 ml X kg-1 X h-1 and the mean terminal t 1/2 was 12.7 h. Dialytic clearance averaged 0.69 ml X kg-1 X h-1, only 6.9% of total clearance. A model which incorporates known characteristics of CRO binding and distribution in anuric patients was used to simulate plasma and peritoneal concentrations of CRO during multiple dose IP drug administration.

Adult↗
PubMed1986

Biliary excretion and pharmacokinetics of ceftriaxone after cholecystectomy.

Three groups of patients with biliary tract disease treated by cholecystectomy were given ceftriaxone. In Group 1 single doses of 150 mg and 1500 mg were given on Days 1 and 5 after cholecystectomy. In Group 2 2 g was given daily for 6 days and the cholecystectomy was on Day 2. Patients in Group 3 received 2 g every 12 h for 3 to 5 doses before cholecystectomy. Plasma samples, urine and T-drain bile were collected at various times from Groups 1 and 2 patients. Gallbladder bile and plasma were collected from Group 3 patients at the time of cholecystectomy. The mean (+/- SEM) T-drain bile-to-plasma concentration ratio of ceftriaxone in Groups 1 and 2 was 6.7 +/- 0.92. The mean (+/- SEM) gallbladder bile-to-plasma concentration ratio was 33 +/- 4.2. No clinically significant differences were detected between the kinetics of ceftriaxone in the cholecystectomy patients compared to normal volunteers. The usual dosage of ceftriaxone appeared adequate for prophylaxis or treatment of biliary tract infection by susceptible organisms.

Adult↗
PubMed1986

Pharmacokinetics of carumonam in patients with renal insufficiency.

The pharmacokinetics of carumonam after a single 1,000-mg intravenous infusion (20 min) were evaluated in four groups of subjects who had various degrees of renal impairment: group 1, CLCR greater than 60 ml/min; group 2, CLCR = 30 to 60 ml/min; group 3, CLCR = 10 to 30 ml/min; and group 4, CLCR less than 10 ml/min). The elimination half-life of carumonam increased with decreasing creatinine clearance (CLCR) from 1.7 h in group 1 to 11.3 h in group 4. Peak carumonam concentration (103 micrograms/ml) and steady-state volume of distribution (12.8 liters) did not change with decreasing CLCR. Total body clearance (r = 0.98), renal clearance (r = 0.98), and nonrenal clearance (r = 0.67) of carumonam correlated with decreasing CLCR. Mean nonrenal clearance was 21 ml/min in group 1 and 12 ml/min in group 4. With regard to dosage, patients with a CLCR above 60 ml/min should receive their standard maintenance dose of carumonam without any changes; patients with a CLCR between 30 and 60 ml/min should receive the dose every 12 h; and individuals with a CLCR between 10 and 30 ml/min should be given the dose once a day. Patients with a CLCR of less than 10 ml/min should receive one-half of the dose once a day. Our recommended dosage regimens should produce within the CLCR borderlines of each group average plasma concentrations that are between one and two times that achieved in normal subjects with a t.i.d. dosage regimen.

Adult↗