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Biomedical subjects

J J Schentag

Publications and source records attributed to J J Schentag.

At least 199 records · Page 11Linked to original sources
PubMed1981

Predicted tissue accumulation of netilmicin in patients.

The two-compartment pharmacokinetics of netilmicin were investigated in 11 patients with stable renal function who were being treated for gram-negative infections. The initial dosage of netilmicin ranged from 2.5 to 5.0 mg/kg per day, with subsequent changes made on the basis of serum concentrations. Venous blood samples were obtained every 2 to 4 days during therapy and daily for an average of 10 days after the final dose. Serum concentrations were measured by both microbiological assay and radioimmunoassay. Peak and trough netilmicin concentrations were significantly greater (P less than 0.01) at the end of therapy than at the first dose, even though renal function was stable throughout treatment in all patients. After the final dose, serum concentrations declined in a biphasic manner, with a first-phase half-life of 5.4 h and a terminal half-life of 198 h. The total body clearance averaged 31 ml/min. An average of 99 mg of netilmicin (approximately 5% of the total dose) was predicted to be in the tissue compartment at the end of therapy. A comparison of these pharmacokinetic parameters with those obtained in a previously reported but similar study with gentamicin showed no significant differences between the two aminoglycosides with respect to peak and trough concentrations (initially or at the end of therapy), volumes of distribution, total body clearance, or amount of drug in the tissue compartment at the end of therapy. The terminal half-life of netilmicin was significantly greater than that of gentamicin, whereas the rate constant of netilmicin for tissue influx (k12) was significantly less.

Adult↗
PubMed1981

Cimetidine in systemic mastocytosis.

54-year-old caucasian women with systemic mastocytosis manifested by gastrointestinal and dermatological symptoms that were treated with cyproheptadine, Lomotil (diphenoxylate-atropine), and cimetidine was studied. The patient consented to discontinue the H2-receptor antagonist, and to have the following values measured: serum and urine concentrations of cimetidine: complete blood count (CBC) with differential, serum chemistry, and urinalysis; and systemic mastocytosis symptomatology. The patient experienced prompt recurrence of gastrointestinal and dermatological symptoms after stopping the cimetidine; the drug was restarted in three days and the symptoms subsided. The preceding laboratory and symptomatological values were recorded for 11 days after the reinstitution of cimetidine therapy. Histamine, gastrin, CBC, serum chemistry, and urinalysis remained normal, with and without cimetidine. Exacerbations of her symptoms were worst when no drug was detected in the serum. Therefore, it appears that cimetidine has a role in treating the symptoms of systemic mastocytosis.

Adult↗
PubMed1981

Alteration of theophylline clearance and half-life by cimetidine in normal volunteers.

Interaction between cimetidine and theophylline was studied in six male volunteers, who were randomly divided into two groups to eliminate temporal effects. The effect of cimetidine on theophylline elimination was immediate and progressed as cimetidine treatment was continued. Cimetidine prolonged theophylline half-life compared to that in control periods an average of 36.2% (range, 0 to 103%) on the first day of cimetidine exposure (p less than 0.05). Theophylline clearance was decreased an average of 18.5% (range, 4.9% to 36%), whereas theophylline volume of distribution was unchanged by cimetidine. After 8 days of cimetidine treatment at the usually recommended dosage, theophylline half-life further increased to 64.3% (range, 9% to 128%) of control values, whereas clearance declined an average of 30% (range, 5% to 50%) (p less than 0.01). Theophylline volume of distribution remained unchanged. Although cimetidine-theophylline interaction needs confirmation in a patient population, we advise caution when these agents are coadministered. Some adjustment in theophylline dosage may be needed in treated patients who are also given cimetidine, and these patients who are also given cimetidine, and these patients should be studied closely with theophylline serum concentration measurements and careful clinical assessments.

Adult↗
PubMed1981

Creatinine clearance predictions in acutely ill patients.

In acutely ill patients, predicted creatinine clearance (Clcr) values [obtained using the Siersbaek-Nielsen nomogram (SNN) and ideal body weight (IBW)] were compared with actual Clcr based on measured urine creatinine concentrations. Timed urine collections were obtained from 118 patients (423 collections from 68 men, 400 collections from 50 women) before, during, and after aminoglycoside therapy. Patients were in intensive care units for management of acute exacerbations of sepsis, pneumonia, or abscess; most had other complicating conditions and were chronically ill. Urine was collected for 8 to 24 hours (70% for 24 hours) from Foley-catheterized patients. Patients were divided into low (less than 15 mg/kg/day), normal (15-25 mg/kg/day), and elevated (greater than 25 mg/kg/day) urinary creatinine excretion groups. Actual body weight (ABW) was used in some patient subgroups to explore differences between using IBW and ABW. SNN most accurately predicted Clcr in the 20% of the urine collections characterized by normal urinary creatinine excretion (Ucr). Most study patients excreted significantly less creatinine than the age-matched population tested in developing the SNN. In acutely ill patients with low Ucr, SNN overpredicted Clcr by 10-20 ml/min. SNN also overpredicted Clcr values in obese patients, but use of IBW rather than ABW improved the correlation between measured and predicted values in this subgroup. The SNN nomogram is applicable to critically ill patients if adjustments are made in predicted values. The characteristics of patients with low Ucr and the mechanism responsible for the decreased Ucr deserve further study.

Acute Disease↗
PubMed1981

Liquid-chromatographic determination of cimetidine, its known metabolites, and creatinine in serum and urine.

We describe a liquid-chromatographic procedure for determination of cimetidine, its hydroxymethyl-, sulfoxide-, and guanyl urea metabolites, and creatinine in patients serum and urine. SKF 92374 is used as the internal standard. Protein in 0.5 mL of serum or diluted urine is precipitated with 2 mL of acetonitrile, the organic and aqueous phases are separated by adding 0.3-0.5 g of anhydrous K2HPO4. The organic phase is evaporated, and 0.5 mL of 50 mmol/L HCl is added. This solution is washed with 3 mL of water-saturated isoamyl alcohol, the aqueous phase is extracted with 3 mL of methylene chloride and enough K2HPO4 to saturate the solution. The methylene chloride is evaporated, the residue reconstituted with 100 microL of mobile phase, and a 25-microL aliquot injected onto the chromatographic column (Dupont Sil). The mobile phase is acetonitrile/methanol/water/ammonium hydroxide (1000/50/50/2, by vol). The column effluent is monitored at 228 nm. Lower limits of detection ranged from 0.05 mg/L for cimetidine to 0.2 mg/L for guanyl urea. We determined cimetidine and its principal metabolites in the serum of a patient receiving cimetidine for the treatment of Zollinger-Ellison syndrome, and have assessed use of the assay in a clinical setting.

Chromatography, High Pressure Liquid↗
PubMed1980

Two-compartment gentamicin pharmacokinetics in premature neonates: a comparison to adults with decreased glomerular filtration rates.

Eleven premature neonates received gentamicin sulfate for treatment of suspected gram-negative sepsis with accompanying respiratory distress syndrome. Serum gentamicin concentrations were measured during and after treatment to monitor therapy and to determine the two-compartment distribution and elimination characteristics of the drug. The measured pharmacolinetic parameters were compared to those of 14 adult patients with similar glomerular filtration rates. Neonates, like adults and children, had a prolonged persistence of gentamicin in the serum after treatment was stopped. Although there were marked differences between neonates and adults in administered dose, clearance, and distribution volume when the data were expressed on the basis of body weight, these differences were no longer apparent when the data were expressed relative to body surface area. Differences in gentamicin disposition cannot explain the apparent lack of aminoglycoside nephrotoxicity among premature neonates.

Adult↗
PubMed1980

Patterns of urinary beta 2-microglobulin excretion by patients treated with aminoglycosides.

Aminoglycoside antibiotics are relatively mild nephrotoxins, but their action is site-specific to the proximal tubule. Therefore, use of these drugs presents a unique opportunity to study the temporal relation between the damage to the cells lining the renal proximal tubule and the subsequent rise in the serum creatinine concentration. Our study of 52 aminoglycoside-treated patients included measurements of daily serum creatinine, daily 24-hour urinary beta 2-microglobulin (beta 2M) excretion, and determination of aminoglycoside tissue accumulation. An elevation in beta 2M excretion above the baseline value occurred in 37 of 52 (71%), whereas the serum creatinine concentration rose in only 17 of 52 (33%) of patients. Even fewer patients (10 of 52) demonstrated all three criteria for aminoglycoside nephrotoxicity. These 10 patients had elevated tissue accumulation, evidence of renal tubular damage, and a rise in serum creatinine concentration. The increased beta 2M excretion greater than 50 mg/day preceded the serum creatinine rise by 2 to 7 days. An abnormal baseline beta 2M was not a risk factor for a subsequent rise in creatinine concentration or vice versa. Although each test is primarily site specific, widespread and severe renal proximal tubular damage, regardless of cause, will eventually lead to an elevation of serum creatinine. Thus, serial monitoring of proximal tubular function with urinary beta 2M excretion has potential value in the assessment of insults to this site, but cannot be expected to explain all changes in serum creatinine.

Aged↗
PubMed1980

Removal of cimetidine by peritoneal dialysis, hemodialysis, and charcoal hemoperfusion.

Dialysis clearance of cimetidine in patients receiving peritoneal dialysis, hemodialysis, and hemoperfusion was compared in stable and seriously ill patients. Two methods of determining dialysis clearance were employed, one of which was the method employed for cimetidine previously in the literature. Cimetidine clearance was lowest for peritoneal dialysis (5 ml/min), intermediate for hemodialysis (28 ml/min), and greatest for hemoperfusion (85 ml/min). Using both methods to calculate dialysis clearance, we found that cimetidine clearance during dialysis has been overestimated. In addition, pharmacokinetic analysis revealed that peritoneal and hemodialysis apparently removed cimetidine from the central compartment only, whereas hemoperfusion apparently removed drug from the peripheral compartment as well. A possible mechanism to explain this difference is based on the observation that hemodynamic changes occur during hemodialysis that may not be seen during hemoperfusion. No dosage adjustment need be made when patients receiving cimetidine undergo any form of dialysis; hemoperfusion may be of some benefit in removing drug from the central as well as tissue compartments in an acute overdose situation.

Aged↗
PubMed1980

High-pressure liquid chromatography analysis and single-dose disposition of tobramycin in human volunteers.

A sensitive and specific fluorometric high-pressure liquid chromatography technique was developed to measure both tobramycin and an internal standard (gentamicin C2). The assay utilizes direct extraction of the o-phthalaldehyde derivatives from serum and urine. Coefficients of variation were 7.9% (serum) and 6.0% (urine) at a tobramycin concentration of 1.0 microgram/ml. The lower limit of assay sensitivity was 0.2 microgram/ml. Results obtained from high-pressure liquid chromatography were in excellent agreement with those from radioimmunoassay for both serum (r = 0.97) and urine (r = 0.91). No other aminoglycoside antibiotics and no other antibiotics that were tested caused interfering peaks. Tobramycin (1 mg/kg intravenous bolus) was administered to three healthy volunteers. Tobramycin concentrations were detectable for 10 h in serum and for 240 h in urine after a 1-mg/kg intravenous dose. A two-compartment pharmacokinetic model was required to describe the tobramycin disposition. Urinary recovery of tobramycin over a 10-day period accounted for 95.8, 94.3, and 83.1% of the administered dose. High-pressure liquid chromatography methodology is sufficiently sensitive to determine single-dose, two-compartment tobramycin pharmacokinetics from urinary excretion data, thus verifying the prolonged excretion of tobramycin after a single dose. The analytical methodology and pharmacokinetic techniques described may be useful in studying other aminoglycosides.

Anti-Bacterial Agents↗
PubMed1980

Animal model distinguishing in vitro from in vivo carbenicillin-aminoglycoside interactions.

Aminoglycosides and carbenicillin are frequently co-administered to patients with serious gram-negative infections. Aminoglycosides are inactivated by carbenicillin in vitro, and a loss of antibacterial activity of both antibiotics results. Although these interactions are presumed to occur in vivo, previous studies have not used assay methodology that can distinguish inactivation occurring prior to and during microbiological assay from inactivation in vivo. To address this problem, we gave seven bilaterally nephrectomized mongrel dogs doses designed to achieve simultaneous therapeutic serum concentrations of aminoglycosides and carbenicillin. Serum samples were tested by radioimmunoassay on three occasions: immediately, to determine in vivo interactions, and at 24 h and 1 week to assess the time course of in vitro inactivation. In comparison with immediate radioimmunoassay, gentamicin and tobramycin concentrations decreased by 39 and 53%, respectively, when assayed at 24 h (P < 0.05) and by 75 and 82% when assayed at 7 days (P < 0.001). In contrast, amikacin concentrations were reduced by only 9 and 30% at 24 h and 7 days. Tobramycin concentrations were also determined by immediate microbiological assay and were found to be similar to those in samples stored for 24 h before radioimmunoassay. Immediate radioimmunoassay demonstrated that carbenicillin reduced in vivo serum half-lives of gentamicin and tobramycin by 40% (P < 0.05). The half-life of amikacin in vivo was not significantly altered. In the presence of carbenicillin, amikacin was the most stable aminoglycoside both in vivo and in vitro, and it is the aminoglycoside of choice in patients with renal failure who require this combination.

Aminoglycosides↗
PubMed1980

Dose and serum concentration relationships in cimetidine-associated mental confusion.

A patient with severe liver disease and mildly obnormal but stable renal function was given cimetidine on two occasions for gastrointestinal hemorrhage. In each course, dosing was initiated at half the recommended dosage of 600 mg daily, and mental status deteriorated shortly after dosing began. A further dosage decrease to 300 mg daily allowed continuation of cimetidine therapy in absence of mental status alterations. In this patient, mental status changes occurred at lower serum concentrations than we have previously reported. This discrepancy was explained by analysis of cimetidine CSF concentrations, as this patient had abnormally high cimetidine blood to CSF permeability. Although the cause of increased CSF concentrations is unclear, cimetidine-associated mental confusion was dose related and completely reversible upon a decrease in dosage. Patients who develop cimetidine-associated mental status changes and who cannot have treatment stopped may be safely treated by individualizing the dosing rate.

Blood-Brain Barrier↗
PubMed1980

Cimetidine-associated mental confusion: further studies in 36 severely ill patients.

Fifteen cases of cimetidine-associated mental confusion have recently appeared. To further study this syndrome, we monitored cimetidine serum concentrations in 36 patients and correlated these with changes in mental status. Thirty patients did not change on cimetidine and 6 experienced moderate to severe mental status changes. These 6 patients had both renal and liver dysfunction (p less than 0.05), as well as cimetidine trough concentrations above 1.25 micrograms/ml (p less than 0.05), in close association with mental status changes. The changes in mental status became progressively more severe as trough concentrations rose. Five patients underwent lumbar punctures. The cerebrospinal fluid to serum ratio of 0.24:1 indicates that cimetidine passes the blood-brain barrier, and this raises the possibility that mental status changes are due to blockade of central nervous system histamine H2 receptors. Our studies identify a subgroup at high risk for both elevated troughs and mental confusion. These patients with severe compromise of both renal and hepatic excretory systems must be closely observed and given reduced cimetidine doses if side effects are to be avoided.

Adult↗