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Biomedical subjects

J J Schentag

Publications and source records attributed to J J Schentag.

At least 163 records · Page 9Linked to original sources
PubMed1984

Rebound following hemodialysis of cimetidine and its metabolites.

The effect of hemodialysis on the pharmacokinetics of cimetidine and its metabolites was studied after the intravenous administration of a 300-mg dose of cimetidine. Serum concentrations were monitored before, during, and after hemodialysis. Cimetidine pharmacokinetics were similar to those in patients with end-stage renal failure, with a total body clearance of 3.3 +/- 1.0 mL/min/kg and a half-life of 4.1 hours. Dialysis caused an initial decrease in serum concentrations for cimetidine, hydroxymethyl cimetidine, and cimetidine sulfoxide, followed by a rebound in serum concentrations immediately after treatment. Dialysis clearances, as calculated from extraction ratios, were 83 +/- 15, 90 +/- 16, 93 +/- 24, and 126 +/- 23 mL/min for cimetidine, hydroxymethyl, sulfoxide, and creatinine, respectively. After four hours of dialysis, 10% +/- 3.2% of the cimetidine dose was recovered in the dialysate. The sulfoxide and hydroxymethyl metabolites demonstrated relatively constant serum concentrations for up to 24 hours postdosing, and therefore, estimates of their terminal half-lives were not possible. In one patient, accumulation of both metabolites occurred during multiple dosing. Hemodialysis is an ineffective means of decreasing the total body load of cimetidine and its metabolites. Presumably, sequestration of the drug in body tissues decreases the amount of drug present in the blood available for dialysis removal, with rebound occurring due to postdialysis re-equilibriation between blood and extravascular fluids.

Adult↗
PubMed1984

Effect of protein binding on cefmenoxime steady-state kinetics in critical patients.

The effect of protein binding on cefmenoxime steady-state kinetics was studied in 20 critical patients with gram-negative pneumonia. Sixteen patients were given 1 gm cefmenoxime every 6 hr, two received 2 gm every 6 hr, and two received 2 gm every 8 hr. Serum protein binding was measured by equilibrium dialysis. Assays were by HPLC. Serum cefmenoxime concentration-time data were characterized by a model-independent method based on statistical moment theory. Despite varying renal function in patients, mean cefmenoxime serum concentration-time curves for all three dosing regimens were closely aligned, reflecting successful empiric dosage adjustment. Terminal phase t 1/2 ranged from 0.8 to 2.9 hr and was significantly related to creatinine clearance. Cefmenoxime total clearance was significantly related to both lambda z (2.303 times the slope of the terminal portion of the log-concentration-time curve) and creatinine clearance (CCr). Plasma clearance of free cefmenoxime was more strongly correlated with CCr than the clearance of total cefmenoxime. Drug recovery from 24-hr urine collections at steady state was 76.9 +/- 19.8% of the daily dose (mean +/- SD, n = 13). Cefmenoxime protein binding in patients differed markedly from normal values. A regression equation derived from data on 11 cephalosporins appeared to predict total volume of distribution in the steady state (Vdss-Total) from the fraction of unbound drug accurately. Since cefmenoxime has a high therapeutic index, no clinical consequences are expected to result from variation in protein binding. Observed differences in protein binding between patients and normal subjects could have clinical consequences for highly bound acidic drugs that, unlike cefmenoxime, have narrow therapeutic indices.

Aged↗
PubMed1984

Cimetidine kinetics during resuscitation from burn shock.

Severely burned patients suffer from rapidly changing metabolic and hemodynamic abnormalities that could alter drug kinetics. The kinetics of cimetidine, commonly used in the prophylaxis of acute stress erosions, were studied during fluid resuscitation of 11 patients with mean burn sizes of 45% total body surface area. Six patients were studied after the completion of fluid resuscitation. Total clearance, steady-state volume of distribution, and cimetidine t1/2 did not change between the early period after burn and after fluid resuscitation, but before the completion of fluid resuscitation patients had lower renal and greater nonrenal cimetidine clearance than after resuscitation. The increase in nonrenal cimetidine clearance resulted in decreased urinary recovery of unchanged drug, 50.7 +/- 14% during fluid resuscitation and 81.0% +/- 6% after resuscitation.

Adult↗
PubMed1984

Ranitidine disposition and systemic availability in hepatic cirrhosis.

Single-dose ranitidine kinetics were studied in 10 patients with cirrhosis as proved by liver biopsy. All were clinically stable. After an overnight fast, ranitidine was given in a randomized crossover order as a bolus intravenous injection (50 mg) or was taken by mouth (150 mg). Terminal t1/2 was 2.7 +/- 0.4 hr after oral dosing and 2.9 +/- 0.4 hr after intravenous injection. Total plasma clearance was 470 +/- 170 ml/min and the steady-state volume of distribution was 1.2 +/- 0.2 l/kg. There was considerable intersubject variability in the ranitidine serum concentration-time profile after oral dosing. Systemic availability as assessed by AUC analysis was 58% +/- 11%. Not all of the dose could be recovered in the urine as unchanged ranitidine and its known metabolites after intravenous injection. At 0.5 microgram/ml the serum protein binding of ranitidine was 4.6% +/- 1.3%. It is concluded that disposition of ranitidine in these 10 stable subjects with cirrhosis was not significantly altered. The minor changes observed in some were as likely to be the result of secondary perturbations in physiologic status as to effects of cirrhosis on drug metabolism.

Administration, Oral↗
PubMed1984

Cefmenoxime in the treatment of nosocomial pneumonias in critical care patients.

Nephrotoxicity frequently complicates the use of aminoglycosides in severely compromised acute care patients. Therefore, we initiated an open clinical trial to determine if cefmenoxime alone is useful for serious Gram-negative pneumonias in this population. Thirty consecutive patients were studied. Average age was 66 years. Most were malnourished at entry, with serum albumin averaging 2.8 g/dl and prognostic nutritional index values over 70% (normal less than 40%). One-half of the patients had severe COPD and 67.9% were on ventilators. Fifty-seven per cent suffered concomitant cardiac disease, and 78.6% had been previously treated with antibiotics. Pneumonia was proven by new infiltrates on chest X-ray, new fever, elevated WBC count and Gram-negative rods on Gram's stain and in cultures of tracheal aspirate or sputum. Patients were given cefmenoxime 1-2 g every 6 h for an average of 12 days. Cefmenoxime peak (1 h) and trough concentrations were measured by HPLC and averaged 58 and 7 mg/l respectively. Gram-positive organisms, Escherichia coli, Klebsiella spp. and Haemophilus influenzae were usually eradicated. Persistence was noted for Enterobacter, Pseudomonas and Acinetobacter spp. Persistence in patients with good clinical response was considered colonization rather than superinfection. Overall, satisfactory clinical response rate was noted in 78.6%, while four patients responded satisfactorily with recurrence, and two treatments were unsatisfactory. No serious adverse effects were observed. Cefmenoxime is a promising agent for treatment of susceptible pneumonias in critical care patients.

Aged↗
PubMed1984

Integration of pharmacokinetics and pharmacodynamics of methicillin in curative treatment of experimental endocarditis.

The rabbit model for Staphylococcus aureus endocarditis was used to compare cure rate and pharmacokinetic profile of four dosing regimens of methicillin. Equal daily doses (120 mg/kg) in five day treatment periods were given to 40 rabbits. Doses were given by bolus 20 mg/kg every 4 h (q 4 h), 40 mg/kg every 8 h (q 8 h), 60 mg/kg every 12 h (q 12 h) or by continuous infusion. The methicillin pharmacokinetics resulting from each regimen were monitored along with the course of the infection in each rabbit. For each regimen, time above MBC, peak height, area under the curve (AUC) above MIC and MBC were measured. Post antibiotic effect (PAE) duration and log growth time (LGT) values were obtained from the literature. Significantly more rabbits treated by q 4 h and q 8 h (P less than 0.05) survived 14 days after cessation of methicillin treatment than did rabbits treated q 12 h or continuous infusion. The four regimens differed in peak concentration and time above MBC. Despite producing the highest peak concentrations, the q 12 h regimen was the least effective. The duration above MBC was 2.0, 1.5, and 0.6 hours for q 12 h, q 8 h and q 4 h regimens, respectively. Continuous infusion produced methicillin concentration just above MBC over the entire five day treatment period, but was not as effective as q 4 h or q 8 h regimens. The most successful intermittent bolus regimens were those in which the sum of time above MBC, the duration of PAE, and one LGT were approximately equal to the actual dosage interval.

Animals↗
PubMed1984

Pharmacokinetics of ceftazidime in patients with renal insufficiency.

The pharmacokinetics of ceftazidime were studied in 14 adult volunteers with different degrees of renal function. The elimination of ceftazidime was totally dependent on renal excretion. The clearance of ceftazidime ranged from 7.5 to 145.1 ml/min and correlated with both renal ceftazidime clearance and creatinine clearance (ClCR). It is recommended that 0.5 to 2.0 g of ceftazidime be given in extended dosages, with intervals dependent on the renal function of the patient. Patients with a ClCR of greater than 50 ml/min should be given ceftazidime every 8 h, those with a ClCR of 30 to 50 ml/min should be given the drug every 12 h, those with a ClCR of 15 to 30 ml/min should be given the drug once a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a 36- to 48-h regimen.

Adult↗
PubMed1984

Moxalactam penetration into normal heart valve, cardiac vegetations, and myocardium in relation to protein binding and physiological distribution spaces.

Rabbits with catheters implanted in the left ventricle were given a single dose of moxalactam and sacrificed at various times thereafter for measurement of the concentration of this antimicrobial agent in serum, heart muscle, and various heart valves. Penetration into both extravascular sites was rapid; steady state was achieved within 5 min after the dose. Moxalactam showed essentially complete penetration into valve lesions, whereas concentrations in heart muscle were only 20% of those in serum. The physiological distribution of moxalactam in heart muscle was beyond the inulin space, but substantially lower than total body water. This myocardial distribution ratio was not predicted by the serum-free fraction or blood trapped in tissues alone, but was in good agreement with that of extracellular fluid plus blood trapped in tissues. The moxalactam distribution profile was most compatible with that of drugs which are excluded from cells but readily distributed throughout extracellular fluids. This explains its nearly complete penetration into heart valves as well as its incomplete penetration into heart muscle, since the two sites differ in their relative proportions of cells and extracellular fluid spaces.

Animals↗
PubMed1984

The pharmacokinetics and metabolism of cimetidine in neonates.

Cimetidine pharmacokinetics and metabolism were studied in 2 full-term and 1 premature neonates. All infants demonstrated the capacity to eliminate cimetidine via both metabolic and renal routes. The half-life of cimetidine ranged from 3.4 to 2.1 h, and decreased as total body clearance increased. These alterations in pharmacokinetics were felt to represent developmental and maturational differences, primarily in renal function. In contrast to the 60% routinely seen in adults, approximately 90% of the administered dose was recovered in the urine of the full-term infants as cimetidine and its known metabolites. Cimetidine sulfoxide and hydroxymethyl cimetidine were detected in the serum and urine of 2 patients, and the elimination half-life of these metabolites was two- to threefold longer than values seen for cimetidine. During multiple dosing of cimetidine, significant accumulation of cimetidine metabolites may be expected. The reported dose of 15-20 mg/kg/day is adequate in full-term neonates, however, it appears that premature infants and those with renal dysfunction may require lower dosing rates.

Biotransformation↗
PubMed1984

Distribution of cimetidine in postmortem tissues.

The postabsorptive distribution of cimetidine is described. Assays by high pressure liquid chromatography (HPLC) of postmortem samples of cerebrospinal fluid, serum, and solid tissues were used to determine pharmacokinetic parameters as well as mean tissue: serum concentration (T:S) ratios in seven patients with renal and liver dysfunction. Correlations were calculated between the T:S ratio and the volume of distribution, and between the T:S concentration ratio and the time of sampling after death. The highest T:S ratios occurred in the eliminating organs, the liver and kidneys, and the lowest in fat. As the time of autopsy increased after death, the T:S ratios decreased.

Adipose Tissue↗
PubMed1983

Specificity of renal tubular damage criteria for aminoglycoside nephrotoxicity in critically ill patients.

Two populations of critical care patients were studied using indices of renal tubular damage (beta 2-microglobulin, enzymes, casts) and indices of glomerular filtration (creatinine, creatinine clearance). The purpose of these studies had been initially to elucidate the type of renal failure typical of the critically ill patient treated with aminoglycoside gentamicin or tobramycin, then to determine its frequency. The second study population included a control group of patients given the nonnephrotoxic cephalosporin moxalactam, in order to assess the specificity of the renal tubular damage criteria for aminoglycoside nephrotoxicity versus other types of renal injury in critical care patients. Creatinine rise occurred in approximately 30 per cent of each tobramycin-treated group and in only 12 per cent in the moxalactam control patients (P less than 0.05). Thus, the data indicate that aminoglycosides are associated with an approximate doubling of the renal damage in those older, critically ill patients. Renal tubular damage criteria appear specific for the aminoglycoside effect, but a substantial percentage of the renal damage in this population is not associated with detectable alterations in renal tubular status.

Adult↗
PubMed1983

Steady-state moxalactam pharmacokinetics in patients: noncompartmental versus two-compartmental analysis.

Moxalactam pharmacokinetics at steady state was examined in a group of 40 patients with presumed or proven abdominal sepsis. Mean steady-state serum concentrations ranged from 27.0 to 211.0 mcg/ml and correlated inversely with creatinine clearance (r = 0.91, p less than 0.0001). Terminal half-life ranged from 1.27 to 8.27 hr and reflected the varying renal function of the patients. Moxalactam total body clearance (CL) displayed excellent correlation with creatinine clearance as 92% (r2 x 100) of the variance in clearance could be accounted for by renal function (p less than 0.0001). Pharmacokinetic parameters were estimated using noncompartmental analysis based on statistical moment theory. Noncompartmentally determined CL was in agreement with CL determined by nonlinear least squares regression (r = 0.99, p less than 0.0001). Moxalactam total body clearance is best predicted from creatinine clearance corrected for body surface area.

Biological Assay↗
PubMed1983

Failure of cimetidine in Zollinger-Ellison syndrome.

Both the pharmacokinetics and the pharmacodynamics of cimetidine were investigated in three patients with Zollinger-Ellison syndrome, who were unresponsive to conventional dosing regimens. Doses employed in these patients ranged from 2400 to 5400 mg daily. The poor response to oral cimetidine, as measured by acid secretion and gastric pH, was associated with subtherapeutic and unreliable cimetidine serum concentrations. The response to intravenous cimetidine was only a transient suppression of gastric secretion. The failure of cimetidine to control gastric hypersecretion in these patients was attributed to both a diminished oral bioavailability and a decreased pharmacologic response to the drug.

Administration, Oral↗
PubMed1983

Effect of cimetidine on the pharmacokinetics and pharmacodynamics of quinidine.

The influence of cimetidine (1.2 g/day for 7 days) on the disposition and pharmacodynamic effects of a single oral dose of quinidine was studied in 6 normal volunteers. Cimetidine reduced the mean apparent oral clearance of quinidine (+/- standard error of the mean) from 25.5 +/- 2.7 to 16.2 +/- 1.4 liters/h (p less than 0.05). This was reflected in a 55% (range 30 to 109) increase in the mean half-life from 5.8 +/- 0.2 to 9.0 +/- 0.6 hours (p less than 0.05). Peak quinidine plasma concentrations and times to peak were also increased (p less than 0.05). Plasma protein binding and urinary excretion of quinidine were unchanged by cimetidine treatment. Alterations in the pharmacokinetic variables of quinidine were mirrored in simultaneously measured electrocardiographic parameters. Changes in Q-T, rate-corrected Q-T, QRS, and R-R intervals after a single oral dose of quinidine sulfate (400 mg) were significant. Treatment with cimetidine potentiated these pharmacodynamic changes, but failed to achieve significant differences from quinidine alone. Thus, cimetidine impairs the elimination of oral quinidine in normal volunteers. This interaction may lead to quinidine toxicity in patients in whom cimetidine is concomitantly administered.

Adult↗
PubMed1983

Hepatic encephalopathy and altered cimetidine kinetics.

Cimetidine kinetics were followed in 16 cirrhotic patients after a single IV 300-mg dose. The patients were grouped according to a history of portal systemic encephalopathy (PSE). There were no differences among the groups in volume of distribution, biologic t 1/2, or distributional clearance. In cirrhotic patients with no history of PSE, cimetidine kinetics and metabolism were the same as in healthy subjects. Patients with a history of PSE (n = 8) had lower cimetidine total body clearance than cirrhotic patients without a history of PSE and healthy subjects. Cirrhotic patients with a history of PSE also had decreased formation of cimetidine sulfoxide (as judged by differences in the sulfoxide serum concentration-time AUC). Because of the 40% decrease in total clearance, dosage in cirrhotic patients with a history of PSE should be reduced to minimize the risk of CNS side effects associated with cimetidine.

Adult↗
PubMed1983

A randomized clinical trial of moxalactam alone versus tobramycin plus clindamycin in abdominal sepsis.

One hundred patients with intraabdominal infections were assigned randomly in double-blind fashion to receive either the combination of tobramycin plus clindamycin (TM/C) or moxalactam (MOX) alone. Fifty patients comprised each group, but one patient in each group died of infection before 48 hours treatment. In the remaining 98 patients, the average age was 62 years, initial serum albumin was 3.0 mg/dl, serum creatinine was 1.5 mg/dl, and over half of the patients were nutritionally deficient by the prognostic nutritional index criteria. In approximately one-half of the patients, the source of infection was perforated colon or perforated appendix. There were no significant differences in demographic factors between these groups, except that those who were given TM/C were older, while those who were given MOX had a more serious long-term prognosis due to underlying disease. The average length of treatment was 11 days, and the average hospitalization time was 24 days. Clinical response to therapy was identical, since 74% of the TM/C patients and 76% of the MOX patients had satisfactory responses. Bacteria persisted at the site of infection in 63% of the TM/C patients and in 65% of the MOX patients, with the most common isolate being Staphylococcus epidermidis. Pseudomonas infections were the most difficult to cure in both groups. The two regimens differed only in side effects; TM/C was a more frequent (p less than 0.05) cause of nephrotoxicity, and elevated prothrombin time/partial thromboplastin time (PT/PTT) was more frequently (p less than 0.05) observed in MOX. All PT/PTT elevations responded to injections of vitamin K, and no serious bleeding occurred. Choice between these regimens depends on the risk of renal versus hematologic side effects, rather than efficacy.

Abdomen↗
PubMed1983

Antibiotic penetration in abdominal infection: a case of tobramycin failure responsive to moxalactam.

A 50-year-old male developed an Enterobacter cloacae abdominal infection as the result of gangrene of a gastric remnant after gastrectomy. Aggressive antibiotic treatment with tobramycin and clindamycin was instituted, but despite documented in vitro bacterial sensitivity and high serum tobramycin levels, the patient's clinical condition worsened. Enterobacter cloacae continued to grow in the abdominal drainage cultures. As a last resort, moxalactam therapy was started. Within 36 hours, dramatic clinical improvement was seen and Enterobacter disappeared from the abdominal fluid cultures. Antibiotic assays showed that abdominal fluid contained approximately 50 percent of the simultaneous serum moxalactam concentration, while tobramycin was present in abdominal fluid at less than 15 percent of the serum concentration. In spite of bacterial sensitivity to both drugs, it is likely that moxalactam produced better results than did tobramycin, because of better tissue penetration characteristics.

Abdomen↗