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Biomedical subjects

H J Mann

Publications and source records attributed to H J Mann.

At least 37 records · Page 2Linked to original sources
PubMed1987

Aminoglycoside redistribution phenomenon after hemodialysis: netilmicin and tobramycin.

The serum concentration time profile of netilmicin and tobramycin before, during, and after hemodialysis was assessed in 5 noninfected adult chronic hemodialysis patients. The pharmacokinetic profile was biexponential for both agents in the pre-hemodialysis period. The total body clearance of netilmicin was significantly greater than that of tobramycin (5.32 +/- 0.75 ml/min vs 3.66 +/- 1.00 ml/min; p less than 0.05). The hemodialysis clearances of netilmicin and tobramycin were similar (60.8 +/- 16.6 ml/min and 54.7 +/- 18.8 ml/min, respectively). Netilmicin and tobramycin serum concentrations increased significantly 10 minutes after cessation of hemodialysis and maximally rebounded to 38.3 +/- 16.2% and 18.3 +/- 3.0% at 1.7 +/- 0.3 hours and 1.9 +/- 0.7 hours, respectively. This phenomenon may be a primary contributor to the marked variability observed in the clinical pharmacokinetics of these agents in hemodialysis patients. These data suggest that clinical serum concentrations should not be drawn until two hours after hemodialysis.

Adult↗
PubMed1987

Altered aminoglycoside pharmacokinetics in critically ill patients with sepsis.

The pharmacokinetic disposition of aminoglycosides in critically ill patients with sepsis was studied. In an open-label study of the disposition of gentamicin and tobramycin, individualized pharmacokinetic values of 100 critically ill patients in the surgical intensive-care unit were compared with those of a concurrently monitored group of 100 surgery patients who were not critically ill. The a priori computer-predicted dosage requirements of the critically ill patients were also compared with the dosages derived from their individualized pharmacokinetic values, and intrapatient variation in the critically ill patients was studied. Serum concentration-time data were analyzed using a one-compartment model and the DataMed Clinical Support Services system to provide individualized dosage requirements. Initial dosing guidelines were also generated for the critically ill patients using the a priori model of the DataMed Clinical Support Services program and patient demographic information. The critically ill patients were significantly older, had higher serum creatinine concentrations (SCr), and had lower elimination rate constants (k) and total body clearances (CL) than the surgery patients who were not critically ill. The volume of distribution (V) was not significantly different. The a priori computer predictions for the critically ill patients were significantly lower than the individualized values for V, CL, dose, and amount of drug per 24 hours. The dosing regimen from the a priori model was the same as the individualized regimen in only 2/100 patients. In the 76 critically ill patients who had a second pharmacokinetic analysis performed, there was a significant decrease in k and CL from the first analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Decreased hepatic clearance of clindamycin in critically ill patients with sepsis.

Clindamycin pharmacokinetics was compared in critically ill patients with sepsis and healthy volunteers, and the relationship between pharmacokinetic values and physiological measurements obtained from the critically ill patients was characterized. Pharmacokinetic evaluations were performed on 10 patients with sepsis who were receiving clindamycin phosphate 900 mg i.v. every eight hours and on 6 previously studied healthy men receiving the same dosage regimen. Physiological variables measured included age, weight, cardiac index, systemic vascular resistance, central venous pressure, liver-function tests, alpha 1-acid glycoprotein concentration, and APACHE II score. Clindamycin was administered to the critically ill patients via a central venous catheter over 30 minutes; the healthy volunteers received their infusions via a peripheral venous catheter over 30 minutes. Blood samples were obtained at five minutes before and at various intervals after drug administration. Serum clindamycin concentrations were determined by a gas-liquid chromatographic method. Serum concentration data were analyzed using noncompartmental methods based on statistical moment theory, and the a priori level of significance was 0.05. The critically ill patients had significantly increased values for area under the curve (AUC), area under the moment curve (AUMC), mean residence time (MRT), and average concentration at steady state (Css), while total body clearance (TBC) was less than half that in the healthy volunteers. TBC in three of the critically ill patients was not different from that in the healthy volunteers. The apparent volume of distribution at steady state (Vss) was not significantly different between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Acute renal failure.

Acute renal failure (ARF) is common among critically ill patients and renal dysfunction is often associated with the multisystem organ failure syndrome. The mortality of ARF remains high but animal data indicate that prevention and early treatment may decrease the morbidity and mortality. This review defines ARF based on urine volume, laboratory parameters, and clinical presentation. The pathophysiology of prerenal, postrenal, and intrinsic ART are differentiated and diagnostic criteria provided. Preventive therapy, supportive care, and proposed treatments are outlined. Studies examining the prevention and treatment of ARF in animal models and trials in humans are evaluated. Mannitol 0.5-1 g/kg, furosemide 0.5-1 mg/kg initially, and dopamine 1-5 micrograms/kg/min are effective in preventing or decreasing the severity of ARF in animal models. In humans these drugs are effective at maintaining urine output in various clinical situations and converting oliguria to nonoliguria in some patients; however, increased survival has not been adequately proven as of yet. Dialysis and experimental therapy are briefly discussed.

Acute Kidney Injury↗
PubMed1986

Cefamandole distribution in serum, adipose tissue, and wound drainage in morbidly obese patients.

Distribution and elimination of cefamandole 2 g iv were studied in 11 morbidly obese patients during a gastric bypass operation and again on the first postoperative day. Serum, subcutaneous adipose tissue, wound drainage, and urine were analyzed by high performance liquid chromatography for cefamandole and pharmacokinetic parameters from the intraoperative period were compared to those obtained postoperatively. Total body clearance was significantly greater (p less than 0.001) postoperatively (297 ml/min) than intraoperatively (254 ml/min). Volume changes were unpredictable but the elimination rate constant tended to increase postoperatively. Renal clearance and percentage of urinary recovery were significantly increased (p less than 0.01) postoperatively. The patients had a mean (+/- SD) volume of the central compartment of 10.3 (+/- 2.3) L, volume at steady state of 18.3 (+/- 3.9) L, and elimination rate constant of 1.67 (+/- 0.63) h-1. Tissue concentrations of cefamandole were highest during the first hour after drug administration and were less than 1 microgram/g after 3.5 hours. Mean wound drainage concentrations ranged between 10 and 12 micrograms/ml during a dosing interval and dropped to 7 micrograms/ml 12 hours after the last dose. Intraoperative dosing of cefamandole is required to maintain subcutaneous adipose tissue concentrations greater than 1 microgram/g during procedures longer than three hours in morbidly obese patients. A postoperative dose of cefamandole 2 g iv q6h will provide sustained and therapeutic concentrations in the wound drainage of morbidly obese patients.

Adipose Tissue↗
PubMed1983

The use of a cosyntropin stimulation test to predict adrenal suppression in renal transplant patients being withdrawn from prednisone.

Eighteen renal transplant patients were studied to identify predictors of steroid-induced adrenal suppression. A cosyntropin adrenal stimulation test was administered to each patient and the response was correlated with the past transplant course and their subsequent prognosis. Eight (44%) of the 18 patients studied had a suppressed cosyntropin stimulation test. The suppressed adrenal response could not be predicted accurately by any one factor, although a history of a total prednisone dose greater than 25 g or a duration of steroid therapy of more than 12 months occurred more often among the suppressed patients. Four of the five deaths occurred among the suppressed patients. These deaths occurred despite maintenance of steroid administration. The cosyntropin stimulation test can be easily performed to identify renal transplant patients at risk of steroid-induced adrenal suppression when rapid steroid tapering is desired. An unsuppressed response gives assurance that steroid withdrawal is safe.

Adolescent↗
PubMed1983

Cimetidine-associated thrombocytopenia.

A case of thrombocytopenia associated with cimetidine administration in a 65-year-old white female with recurrent adenocarcinoma is reported. Her platelet count fell from 273 000/mm3 to 35 000/mm3 after cimetidine therapy was started. Upon discontinuation of cimetidine, the platelet count increased to 164 000/mm3. Later in her hospital course, the patient again received cimetidine and her platelet count fell to 37 000/mm3. The patient was never leukopenic during her hospitalization. This is the only reported case of thrombocytopenia in the absence of leukopenia that is documented by a rechallenge with cimetidine.

Aged↗
PubMed1983

Effect of pH on disintegration and dissolution of ketoconazole tablets.

The effect of pH on the in vitro disintegration, dissolution, and solubility of ketoconazole tablets was studied. One 200-mg ketoconazole tablet was added to each of five different buffer solutions having pH values of 2 to 6;900 ml of each solution containing the ketoconazole was placed in a stationary basket dissolution device and stirred at 500 rpm at 37 degrees C for 60 minutes. Single 1-ml samples of each solution were obtained at 1,3, and 5 minutes after addition of the drug, and then every 5 minutes for the duration of the sampling period. This same procedure was repeated using two 200-mg tablets in the buffer solution at pH 3. The effect of pH on ketoconazole solubility was studied by gradually increasing the pH of a ketoconazole solution at pH 3 to pH 10. Samples of this solution were analyzed periodically after allowing a short period for equilibration of pH. All samples were assayed spectrophotometrically against blanks, and concentrations were determined by comparison with a standard curve. Disintegration of ketoconazole tablets occurred within 5 minutes in each buffer solution and was unaffected by pH. At pH 2 and 3, dissolution of ketoconazole was greater than 85% complete after five minutes, and all ketoconazole had dissolved after 30 minutes. As pH increased, the rate and extent of dissolution slowed; only 10% of ketoconazole was dissolved after 60 minutes at pH 6. Ketoconazole precipitated rapidly from solution as the pH of the dissolution medium exceeded 5.5. There was no difference in the rate or extent of dissolution of ketoconazole for the two doses studied at pH 3. In the buffer solutions tested, dissolution but not disintegration of ketoconazole tablets is pH-dependent. Dissolution characteristics of 200- and 400-mg doses of ketoconazole are similar at pH 3.

Hydrogen-Ion Concentration↗
PubMed1979

Tobramycin pharmacokinetics in morbidly obese patients.

Tobramycin kinetics were examined in 9 morbidly obese women following a single intravenous (120 mg) bolus. After the injection, serum elimination conformed to a 2-compartment open model with alpha and beta t1/2s of 0.285 and 2.1 hr. The volume of distribution (Varea) was determined to be 0.44 1/kg ideal body weight (IBW) and 0.20 1/kg total body weight (TBW). To normalize Varea to 0.26 1/kg, 58% of the patients' adipose weight (TBW -- IBW) must also be taken into account.

Anti-Bacterial Agents↗
PubMedDate not supplied

Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis.

The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age-matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5-mg/kg dose to compute half-life (t 1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady-state peak concentrations of 8.0 micrograms/ml with a dosing interval of every six hours. For tobramycin the mean (+/- SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) l/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) l/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Extracorporeal application of a gel-entrapment, bioartificial liver: demonstration of drug metabolism and other biochemical functions.

Metabolic activity of a gel-entrapment, hollow fiber, bioartificial liver was evaluated in vitro and during extracorporeal hemoperfusion in an anhepatic rabbit model. The bioartificial liver contained either 100 million rat hepatocytes (n = 12), fibroblasts (n = 3), or no cells (n = 7) during hemoperfusion of anhepatic rabbits. Eight other anhepatic rabbits were studied without hemoperfusion as anhepatic controls, and three sham rabbits served as normal controls. Albumin production rates (mean +/- SEM) were similar during in vitro (17.0 +/- 2.8 micrograms/h) and extracorporeal (18.0 +/- 4.0 micrograms/h) application of the hepatocyte bioartificial liver. Exogenous glucose requirements were reduced (p < 0.01) and euglycemia was prolonged (p < 0.001) in anhepatic rabbits treated with the hepatocyte bioartificial liver. The maximum rate of glucose production by the hepatocyte bioartificial liver ranged from 50-80 micrograms/h. Plasma concentrations of aromatic amino acids, proline, alanine, and ammonia were normalized in anhepatic rabbits during hepatocyte hemoperfusion. Gel-entrapped hepatocytes in the bioartifical liver performed sulfation and glucuronidation of 4-methylumbelliferone. P450 activity was demonstrated during both in vitro and extracorporeal application of the BAL device by the formation of 3-hydroxy-lidocaine, the major metabolite of lidocaine biotransformation by gel-entrapped rat hepatocytes. In summary, a gel-entrapment, bioartificial liver performed multiple hepatocyte-specific functions without adverse side effects during extracorporeal application in an anhepatic, small animal model. With its potential for short term support of acute liver failure, scale-up of the current bioartificial liver device is indicated for further investigations in large animal, preclinical trials.

Albumins↗
PubMedDate not supplied

Intrinsic sympathomimetic activity: physiological reality or marketing phenomenon.

Intrinsic sympathomimetic activity (ISA) describes the partial beta-adrenergic agonist responses elicited by a series of beta-adrenergic antagonists. The dual effect on the beta-adrenergic receptor appears to be related to structural specificity of the drugs allowing competitive binding to the receptor (antagonist activity) and partial interaction at the receptor's activation site (agonist activity). The clinical effects of a beta-adrenergic antagonist with ISA depend on the relative balance of the drug's inherent antagonist and agonist activity and on the degree of underlying sympathetic tone in the patient. Theoretically, the agonist activity may be beneficial in the patient in whom beta-adrenergic antagonists are indicated, but who has concomitant bradycardia and/or mild to moderate congestive heart failure or compromised pulmonary function, or in the patient being withdrawn from beta-adrenergic antagonist therapy. There is positive evidence from clinical trials that in select patient populations a few of these benefits of ISA are afforded without compromise to beta-adrenergic antagonist activity. However, predisposing factors such as acute illness and individual idiosyncrasies may interfere with the manifestations of the agonist effects. Further, maximal response to full beta-adrenergic agonists will be diminished by concurrent therapy with beta-adrenergic antagonists regardless of ISA presence. In summary, ISA does have a physiological basis and increased experience in larger patient populations will help to place it in proper clinical perspective.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Pharmacokinetic analysis verifies P450 function during in vitro and in vivo application of a bioartificial liver.

Lidocaine is a sensitive substrate for evaluating liver P450 function. In this study, metabolism of lidocaine by xenogeneic hepatocytes in a hollow fiber, bioartificial liver was measured under in vitro conditions (n = 6) and in an anhepatic rabbit model. Animals in the treatment group (n = 6) received hemoperfusion by a bioartificial liver that contained 100 million rat hepatocytes. Other anhepatic rabbits received no hemoperfusion (n = 3) or a bioartificial liver with no cells (n = 3). Lidocaine clearance was 7.0 +/- 0.6 ml/min, and the half-life of lidocaine was 5.6 +/- 0.8 hr under in vitro conditions. Conversion of lidocaine to 3-hydroxy-lidocaine was confirmed in vitro and accounted for 46% of lidocaine elimination in the hepatocyte bioartificial liver. During in vivo application of the bioartificial liver, pharmacokinetic parameters of lidocaine metabolism, including drug half-life and metabolite formation, were significantly improved in anhepatic rabbits. 3-Hydroxy-lidocaine profiles verified the activity of a P450 isozyme expressed preferentially by rat hepatocytes in the bioartificial liver. We conclude that hepatic P450 activity was provided by xenogeneic hepatocytes during in vitro and in vivo applications of a bioartificial liver.

Animals↗