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Biomedical subjects

J J Schentag

Publications and source records attributed to J J Schentag.

At least 145 records · Page 8Linked to original sources
PubMed1987

Repeated oral doses of activated charcoal and the clearance of tobramycin, a non-absorbable drug.

Factors which determine the ability of activated charcoal to increase systemic drug clearance include adsorption characteristics, the extent of back diffusion, and biliary excretion into the gut. Orally absorbed drugs diffuse back into the gut, but it is not known whether non-absorbed agents also diffuse back. Tobramycin was studied with a highly activated charcoal to determine whether this occurs. Five volunteers received a single IV dose of tobramycin on two occasions. Using a randomized, crossover design, subjects received 10 g of activated charcoal (as SuperCharR suspension) 2 hr prior, and at 0, 2, 6, and 8 hr after tobramycin administration during one of the study days. In vitro, tobramycin adsorbed to charcoal at pH 5.6, but not at pH 2.6. A 20:1 charcoal:tobramycin ratio resulted in 34.9% of tobramycin adsorbed to activated charcoal. Blood (0-12 hr) and urine (0-24 hr) were collected and tobramycin concentrations determined. Urinary tobramycin recovery, renal and total drug clearance, half-life, and volume of distribution were calculated. There were no differences in these parameters between the two groups. We conclude that activated charcoal has no effect on tobramycin distribution or elimination in normal volunteers, and that back diffusion does not occur with this drug.

Administration, Oral↗
PubMed1987

Potential impact of quantitative susceptibility tests on the design of aminoglycoside dosing regimens.

Therapeutic drug monitoring of aminoglycosides currently applies pharmacokinetic principles to maintain peak concentrations between 4 and 10 micrograms/ml and troughs less than 2 micrograms/ml. These predetermined concentrations are based on statistical rates of cure and incidences of adverse effects. At present, recommended serum concentration ranges for aminoglycosides (as with other antibiotics) do not specifically target the susceptibility of the individual organism, but compensate only for altered clearance due to diseases. The design of antibiotic regimens based on both pharmacokinetics and pharmacodynamics is called dual individualization. Logically, the pharmacodynamic parameters, the minimum inhibitory concentration (MIC) of the organism and the postantibiotic effect (PAE), should also play a significant role in design of the dosing regimen. Simulations were performed to examine the consequences of designing aminoglycoside regimens considering both disease effects on excretion and bacterial susceptibility (MIC and PAE). The application of dual individualization concepts to aminoglycosides argues for a wider range of dosage requirements than observed with regimens that maintain desired peaks and troughs. If these concepts are accepted, some patients will clearly require more aminoglycoside than is currently used, and others can be managed with substantially less. The aminoglycoside therapeutic window, as it is now conceived, could be markedly different in the future.

Aminoglycosides↗
PubMed1986

Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs.

The single-dose pharmacokinetics and bioavailability of three ketoconazole formulations were evaluated using HPLC in five healthy human volunteers and six male mongrel dogs. The human volunteers received 400 mg po of ketoconazole as tablet (Ktab) and solution (Ksol) formulations. The dogs received 400 mg po of Ktab and Ksol, and 376 mg iv of an intravenous dose (Kiv). In humans the AUC value for Ksol (62.21 +/- 21.2 microgram X h/ml; mean +/- SD) was significantly greater than for Ktab (50.0 +/- 15.2 micrograms X h/ml; p less than 0.05). Peak serum concentrations (Cmax), time to peak serum concentrations (tmax), t1/2, and the terminal elimination rate constant (kel) did not differ between Ktab and Ksol. This suggests that the administration of Ksol may be a useful alternative to dosage increases in situations where low bioavailability of ketoconazole in tablet form is suspected. The mean systemic clearance (CLs) of Kiv in dogs was 2.74 +/- 1.10 mL/min/kg, the volume of distribution at steady state (Vdss) was 0.72 +/- 0.28 L/kg, and the half-life was 2.7 +/- 1.6 h. Considerable variability was seen in the AUC of ketoconazole, particularly with the oral preparations. The absolute bioavailability of Ktab was 0.50 +/- 0.38, which did not differ statistically from that of Ksol, 0.56 +/- 0.23. The Ksol showed less variability in AUC, Cmax, and F values than did Ktab, and two dogs with low bioavailability with Ktab (0.04 and 0.07) had substantially greater bioavailability with Ksol (F = 0.96 and 0.57, respectively). Evaluation of Kiv in dogs confirms decreased bioavailability from orally administered tablet formulations of ketoconazole.

Administration, Oral↗
PubMed1986

Pharmacokinetics and nephrotoxicity of continuous intravenous infusion of gentamicin in low birth weight infants.

We evaluated the pharmacokinetics and renal effects of continuous intravenous infusion of gentamicin compared with multiple-dose therapy given in equivalent daily amounts. Nine infants (mean gestational age 34.7 weeks, mean birth weight 2107 gm) were given intermittent injections of gentamicin and 10 infants (mean gestational age 34.8 weeks, mean birth weight 2078 gm) received gentamicin by continuous infusion. Comparison of gentamicin pharmacokinetic data revealed a larger volume of distribution and AUC, prolonged terminal t1/2, and slower total body clearance of the drug in those infants receiving gentamicin by continuous infusion. During and after therapy the fractional excretion of sodium was significantly increased in the continuous infusion group. After treatment the creatinine clearance and excretion of beta 2-microglobulin were significantly lower in the continuous therapy group. Our results indicate that infants receiving gentamicin by constant infusion are at higher risk of nephrotoxicity. The extent of this nephrotoxic hazard remains to be determined.

Creatinine↗
PubMed1985

Treatment with aztreonam or tobramycin in critical care patients with nosocomial gram-negative pneumonia.

During the course of one year, 47 critical care patients with gram-negative bacillary pneumonia at Millard Fillmore Hospital were randomly assigned to aztreonam or tobramycin therapy (two to one). Of these, 40 were fully evaluable for microbiologic and clinical response. All evaluable patients had gram-negative organisms in tracheal aspirate culture specimens and confirmed susceptibility of the organism to both study drugs. There was no difference between the two groups with respect to the percentage of patients who received concurrent antibiotics for gram-positive organisms. More than 60 percent of the patients received mechanical ventilation. Essentially, all had new lung infiltrates as shown by chest radiography, leukocytosis, recent onset of fever, and increased volume of purulent secretions. Half had multilobar pulmonary infiltrates. Their mean age was 73 years, with none under age 50. Most had chronic obstructive pulmonary disease, congestive heart failure, or both. By the prognostic nutritional index criteria, over 70 percent were nutritionally deficient at entry. The majority of infections were caused by Pseudomonas, Enterobacter, Klebsiella, and Escherichia coli. Aztreonam eradicated 92 percent of the causative gram-negative organisms, compared with 57 percent for tobramycin (p less than 0.05). Aztreonam produced a favorable clinical response (cure or improvement) in 93 percent of patients, compared with 50 percent for tobramycin (p less than 0.05). There were no differences in the minor adverse effects observed in the two treatment groups. Overall, aztreonam was superior to tobramycin for treatment of pneumonia due to susceptible gram-negative bacteria in these critical care patients.

Aged↗
PubMed1985

A rapid, universal TI-59 model-independent pharmacokinetic analysis program based on statistical moment theory.

A model-independent program for pharmacokinetic analyses based on statistical moment theory is presented and demonstrated. The program uses an inexpensive and portable TI-59; a PC-100A printer adds convenience but is optional. The program may be used in analysis of blood, serum, or plasma concentration vs. time curves originating from iv, im, po, sl, or sc administration. Drug input can be zero or first order; both single-dose and multiple-dose steady-state conditions can be evaluated. A comparison between results generated using moment analysis and traditional two-compartment nonlinear regression showed excellent agreement.

Computers↗
PubMed1985

Estimation of the steady-state volume of distribution for digoxin: a comparison of model-independent methods with a two-compartment model in healthy volunteers.

Digoxin serum concentration vs. time data have been described in the literature by a linear two-compartment model. When calculating the steady-state volume of distribution for digoxin after oral dosing, a computer fitting program is often used because of the complex first-order absorption, two-compartment model employed. Since computer programs are not always available, we computed and compared the steady-state volume of distribution/bioavailability for digoxin using both a model-independent (area) and compartmental approach. Six healthy subjects participated in the study; each received digoxin 0.2 mg in capsule form daily for ten days. The mean steady-state volume of distribution/bioavailability calculated by noncompartmental analysis was 785 L and the mean for compartmental analysis was 784 L. The small difference between methods suggests that area analysis offers a simpler alternative to computerized compartmental fitting to determine this parameter for digoxin.

Adult↗
PubMed1985

Liquid-chromatographic determination of ciprofloxacin in serum and urine.

We describe the liquid-chromatographic determination of ciprofloxacin in patients' serum and urine. Serum samples were prepared by precipitating protein with perchloric acid. Urine samples were diluted 100-fold with mobile phase. The mobile phase, consisting of pH 3 phosphate buffer/acetonitrile/methanol (81/5/14, by vol), was pumped through a mu Bondapak C18 reversed-phase column at 1.5 mL/min. Fluorescence of the effluent was monitored, at wavelengths for excitation and emission of 270 and 440 nm, respectively. Standard curves were linearly related to concentration from 0.08 to 10 mg/L for serum, 1 to 20 mg/L for urine. The procedure was evaluated in a clinical setting to determine its usefulness in studying the pharmacokinetics of ciprofloxacin in patients with concurrent diseases and receiving multiple drug therapies.

Chromatography, Liquid↗
PubMed1985

Clinical risk factors for prolonged PT/PTT in abdominal sepsis patients treated with moxalactam or tobramycin plus clindamycin.

Factors associated with prolongation of the prothrombin time were analyzed in 94 patients with intra-abdominal sepsis. Patients were randomized prospectively to receive either the combination of tobramycin and clindamycin (TM/C) or moxalactam (MOX). This paper presents a retrospective review designed to compare the frequency of prolonged clotting times and to analyze predisposing factors. Prothrombin time (PT) prolongation occurred more frequently in patients given moxalactam (19 of 47 patients) than in patients given the combination of tobramycin and clindamycin (9 of 47 patients) (p less than 0.05). Prolongation of the partial thromboplastin time (PTT) occurred in all patients with a prolonged PT. Liver disease, upper gastrointestinal surgery, and use of cimetidine were more frequent in those patients with abnormal PT/PTT values (p less than 0.05). Two moxalactam-treated patients with subsequent PT/PTT prolongation had individual clotting factors assayed before moxalactam treatment and at the time of detection of the abnormal PT. The activity of clotting factors II, VII, VIII, IX, X, and XII was reduced during MOX therapy. Treatment with vitamin K reversed the abnormality. In view of underlying abnormalities and rapid response to parenteral vitamin K, the mechanism is probably an acute vitamin K deficiency superimposed upon chronic vitamin K deficiency. In patients with intra-abdominal infection, those treated with MOX are more likely to develop abnormal PT than those treated with TM/C. Since abnormal PT/PTT was common even in TM/C patients, supplemental vitamin K should be considered for all seriously ill, older patients with abdominal infections.

Abdomen↗
PubMed1984

Cefmenoxime efficacy, safety, and pharmacokinetics in critical care patients with nosocomial pneumonia.

Nephrotoxicity frequently complicates the use of aminoglycosides in severely compromised acute care patients. Therefore, an open clinical trial was initiated to determine if cefmenoxime alone is useful in serious nosocomial pneumonias. Thirty consecutive patients were entered in the trial, and 28 patients with an average age of 66 years were evaluable. Most were malnourished at entry, with serum albumin averaging 2.8 g/dl and prognostic nutritional index values over 70 percent (normal less than 40 percent). One-half the patients had severe chronic obstructive pulmonary disease and 68 percent required ventilators. Fifty-seven percent had concomitant cardiac disease, and 79 percent had previously been treated with antibiotics. Pneumonia was proven to be present by new infiltrate on chest x-ray, new fever, elevated white blood cell count, and gram-negative rods on gram stain and in cultures of tracheal aspirates or sputum. Patients were given cefmenoxime 1 to 2 g every six hours an average of 12 days. Cefmenoxime peak (one hour) and trough concentrations were measured by high pressure liquid chromatography and averaged 58 and 7 micrograms ml, respectively. Pharmacokinetic data in 18 patients were determined from serum profiles. Gram-positive organisms, Escherichia coli, Klebsiella, and Hemophilus influenzae were usually eradicated. Persistence was noted for some Enterobacter, Pseudomonas, Serratia, and Acinetobacter. Persistence in patients with good clinical response was considered colonization rather than superinfection. Overall, a satisfactory clinical response rate was noted in 78.6 percent of evaluable patients, whereas four patients responded satisfactorily with recurrence and two treatments had an unsatisfactory response. No serious adverse effects were observed. Cefmenoxime is a promising agent in the treatment of susceptible pneumonias in critical care patients.

Aged↗
PubMed1984

Role for dual individualization with cefmenoxime.

Cefmenoxime concentration/effect relationships were retrospectively explored for gram-negative bacteria isolated from 14 critical care patients treated for nosocomial pneumonia. The effects of cefmenoxime concentrations on in vitro growth kinetics of 21 isolated pathogens were studied using the Abbott MS-2 Research System, from which a dynamic response concentration was derived. Serum pharmacokinetic profiles were obtained in each patient. These data were used to calculate the in vivo total area under the curve over dynamic response concentration and the time that cefmenoxime concentrations exceeded the dynamic response concentration for each bacteria. The same determinations were made in 18 patients prospectively treated, except that dosage was optimized on the basis of previous mathematical relations to achieve bacterial eradication in four days. This method of dosage optimization is termed dual individualization. Serial cultures of infected tissues were evaluated to determine the number of days to the eradication of bacteria, and the pharmacokinetic and pharmacodynamic variables were used to describe the bacteriologic response of the original pathogen isolated in pretreatment culture. Bacterial eradication rates could be described from cefmenoxime pharmacokinetics in the patient and from the relation between concentration and bacterial inhibition. Patients who were prospectively treated using these retrospectively derived relationships had a predictable day of bacterial eradication. This, in turn, was associated with a shorter duration of treatment (p less than 0.05). The success of prospective dual individualization is encouraging and suggests that more precise optimization of antibiotic dosage can yield a predictable rate of bacterial eradication from the infection site.

Aged↗
PubMed1984

C-reactive protein as an indicator of infection relapse in patients with abdominal sepsis.

C-reactive protein (CRP) concentrations were monitored serially in 97 patients with abdominal sepsis to determine if differences in infection type or site would produce diagnostic or prognostic CRP level elevations. After surgery and abdominal infection, the average (+/- SD) CRP peak values were 21.2 +/- 9.0 mg/dL. The CRP values rose markedly with infection, rose further with surgery, and subsided to less than 10 mg/dL with cure. Persistent levels of more than 10 mg/dL indicated abscess formation or continued infection. The average normal value at complete tissue healing after resolution of infection was 1.2 mg/dL, which was not different from that for healthy volunteers. Analysis suggested that CRP concentrations were not predictive of the type, site, or severity of abdominal infection; however, since persistent elevations were frequently associated with new or unresolved bacterial infection, serial determinations may be helpful in monitoring the course of disease and response to treatment.

Abdomen↗
PubMed1984

Pharmacokinetics of capacity-limited tissue distribution of methicillin in rabbits.

Single-dose and steady-state studies were carried out in rabbits to characterize the pharmacokinetics of methicillin elimination and tissue distribution. Serum methicillin concentrations after single doses exhibited a biexponential decline with a mean terminal half-life of 27 +/- 5 min. Steady-state volume of distribution (Vdss) decreased twofold as doses increased from 5 to 125 mg/kg, while total clearance was consistent over this dosage range. During steady-state infusions of 8.7-87.2 mg/kg/h, the serum and extravascular fluid concentrations increased in proportion to dose, while clearance remained constant. Methicillin tissue concentrations did not increase in proportion to dose and serum concentration, and the Vdss measured from tissue recovery decreased as dosage and serum concentrations increased. Central compartment volume and serum protein binding did not change. The cause of the dose-dependent change in Vdss was a capacity-limited uptake of methicillin into essentially all nonexcretory tissues. This process was described by a partial physiological pharmacokinetic model based on the actual weights or volumes of the rabbit tissues. Distribution into extracellular fluids was assumed to be complete, while entry into cellular, nonexcretory tissue became capacity limited as the Km (17.2 micrograms/mL) was exceeded. The result was a decline in Vdss with increasing serum concentrations to a limiting value which approached the volume of the central space (Vc) and was similar to the extracellular water volume of the rabbit (0.17 L/kg). In the dosage range where total clearance was independent of serum concentration, the distribution of methicillin was concentration dependent and could be predicted by equations derived from the Michaelis-Menten equation.

Animals↗
PubMed1984

The bioavailability and pharmacokinetics of cimetidine and its metabolites in juvenile cystic fibrosis patients: age related differences as compared to adults.

The pharmacokinetics and metabolism of cimetidine were studied in five cystic fibrosis patients (mean age 12.6 years) after oral and intravenous administration. As compared to healthy adult volunteers, cystic fibrosis children had an elevated cimetidine total body clearance (474 vs 300 ml/min/m2) as well as renal clearance (293 vs 232 ml/min/m2) whether normalized for body weight or surface area differences. Cimetidine elimination was elevated in juvenile cystic fibrosis patients as compared to adult volunteers, however, it did not differ significantly from that previously seen in age matched children. There were no appreciable differences in cimetidine metabolism after either route of administration. Differences between adults and cystic fibrosis children were attributed to development and age related differences between the two groups. The recommended pediatric dose of 15 to 20 mg/kg, although four-fold greater than that used in adults, produces serum concentrations similar to those seen in adults, and is adequate for most juvenile cystic fibrosis patients.

Administration, Oral↗