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Biomedical subjects

T P Gibson

Publications and source records attributed to T P Gibson.

At least 19 recordsLinked to original sources
PubMed1996

Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl.

Chronic pain remains a problem because it is often misdiagnosed and undertreated. Adverse effects and safety concerns associated with many analgesics have limited the use of these agents and contributed to the undertreatment of pain. With regard to the pharmacologic agents most commonly used to manage pain, centrally acting analgesics (e.g., morphine, codeine) are associated with respiratory depression, tolerance, and dependence, and most nonsteroidal anti-inflammatory drugs (NSAIDs) produce adverse gastrointestinal effects. New to the United States, tramadol HCl, which has been prescribed for almost 2 decades in Europe, is a single-entity, centrally acting analgesic that is effective for the management of moderate to moderately severe pain. Although the mechanism of action of this analgesic is not completely understood, animal models suggest that at least two complementary modes of action appear applicable: (1) binding of parent compound and mono-O-desmethyltramadol (M1 metabolite) to the mu-opioid receptor and (2) weak inhibition of norepinephrine and serotonin reuptake. Clinical experience suggests that tramadol appears to have a low potential for abuse or addiction. Results from clinical trials conducted in the United States as well as European postmarketing surveillance studies indicate that tramadol is an effective analgesic that may have a particularly important role in the management of chronic painful conditions.

Analgesics, Opioid↗
PubMed1992

Continuous quality improvement at work in radiology.

The performance of a system depends on how its parts fit together. A radiology department is such a system. When doctors complain to administrators about the time it takes to get test results, the system isn't performing well. Use of the continuous quality improvement (CQI) process helps analyze the system, identify problems and fix them. At Sentara Norfolk General Hospital one year ago, an average 72.5 hours elapsed between the time a radiological examination was completed and a written report delivered. Today, that time is 11.3 hours, and still improving. This article describes Sentara Health System's CQI process and how it worked for radiology.

Hospital Bed Capacity, 500 and over↗
PubMed1987

Biotransformation of sulindac in end-stage renal disease.

In normal humans sulindac, a prodrug, undergoes two major biotransformations: irreversible oxidation to the inactive sulfone metabolite and reversible reduction to the pharmacologically active sulfide metabolite. To assess any effect of end-stage renal failure on sulindac biotransformation, six patients were given 200 mg sulindac orally. Plasma was sampled over 24 hours. Protein binding of sulindac and metabolites was determined by equilibrium dialysis. Results were compared with historic controls. AUC(0-12) for sulindac and the sulfone were similar to controls. AUC(0-12) for the sulfide was significantly reduced to 4.85 micrograms X hr/ml from 13.1 micrograms X hr/ml (P less than 0.02). Protein binding of all three compounds was significantly reduced by renal failure. When corrected for protein binding, the AUC(0-12) for sulindac and the sulfone was twice that of controls whereas that of the sulfide was 42 ng X hr/ml compared with 83 ng X hr/ml in normal individuals (P less than 0.001). This suggests that end-stage renal failure impairs the reduction of sulindac to the active sulfide whereas oxidation to the sulfone is intact.

Administration, Oral↗
PubMed1986

Renal disease and drug metabolism: an overview.

Renal disease will perturb the disposition of drugs that primarily depend upon renal excretory function for elimination. While changes in drug half-life (T1/2) are often cited as evidence of altered drug disposition, it must be remembered that T1/2 is a dependent variable whose magnitude varies directly with volume of distribution (Vd) and indirectly with total body clearance (ClT). ClT is the one term that succinctly describes drug elimination. ClT is defined as the sum of the renal (ClR) and nonrenal (ClNR), or metabolic, clearances of a drug. Renal failure has been shown to alter the hepatic microsomal mixed-function oxidase system of drug metabolizing enzymes. Therefore, in end-stage renal failure, the potential exists for the modification of the disposition of drugs whose elimination is primarily hepatic. The kidneys themselves contain many of the enzymes important in hepatic drug metabolism. Drugs such as morphine, paracetamol, and p-aminobenzoic acid are metabolized in the kidney and experimental renal disease has been shown to reduce drug metabolism in the diseased kidney compared with the contralateral normal kidney. Renal disease, then, has the potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidneys. It can no longer be assumed that the pharmacokinetics of drugs that are disposed mainly by metabolism will be unaltered in renal failure.

Animals↗
PubMed1985

Imipenem/cilastatin: pharmacokinetic profile in renal insufficiency.

The pharmacokinetics of 250 mg each of intravenous imipenem and cilastatin in combination and 250 mg of cilastatin alone were studied in subjects with varying degrees of renal clearance. Renal disease did not change the volume of distribution of either drug. When the glomerular filtration rate was greater than 100 ml per minute, 48.6 percent of imipenem and 57.1 percent of cilastatin were recovered unchanged in the urine. Consequently, as the glomerular filtration rate declined, the half-life of imipenem increased from 1.02 hours in normal subjects to 3.69 hours in those undergoing dialysis. For cilastatin, the comparable values were 0.86 and 17.08 hours, respectively. The kinetics of cilastatin were unaffected by imipenem. The greater effect of renal disease on the half-life of cilastatin was due to a concomitant 87 percent reduction in nonrenal clearance. Both drugs were removed by hemodialysis. Dialysis reduced the half-life of imipenem from 4.80 to 2.45 hours and that of cilastatin from 16.63 to 3.86 hours. Therefore, dose adjustments will be required in patients with markedly reduced renal function and supplemental dosing will be required after hemodialysis.

Cilastatin↗
PubMed1985

Deconvolution applied to the kinetics of extracorporal drug removal. Haemodialysis of cefsulodin.

A novel approach to the evaluation of the kinetics of drug removal by an extracorporal device (ECD), e.g., haemodialysis, haemofiltration, and haemoperfusion, is presented. The rate and extent of extracorporal drug removal (ECR) are determined by deconvolution. The proposed method is model independent in the sense that no specific models of corporal or extracorporal disposition are required. The estimation of various derived functions and parameters useful for describing ECR such as clearance and fractional drug removal are facilitated by the technique. The kinetics of cefsulodin elimination by haemodialysis in 3 patients were evaluated using the deconvolution approach. The results indicated that cefsulodin was dialyzable with approximately 50% of the drug in the body removed by haemodialysis over 3-4 h.

Cefsulodin↗
PubMed1985

Pitfalls in, and new methods for, the radioimmunoassay for digoxin in urine.

Examining techniques for radioimmunoassay of digoxin in urine, we found that the apparent concentration of digoxin is affected by endogenous substances, independent of the concentration of digoxin itself. We describe a modification of the Becton Dickinson solid-phase RIA that makes it more nearly accurate and more easily performed, and obviates the endogenous interference. Digoxin concentrations from 5.0 to at least 1000 micrograms/L can be measured.

Digoxin↗
PubMed1985

Effect of spironolactone on the renal clearance of digoxin in dogs.

The acute effect of i.v. spironolactone dissolved in ethanol on renal digoxin clearance was studied in 10 dogs. All dogs received i.v. digoxin (0.02 micrograms/kg/min) and 0.9% saline (30 ml/kg of bolus and 0.1 ml/kg/min for maintenance) throughout the study. After 2 hr of equilibration, four 15-min urine collections were made. The dogs then received, over 1 hr, a loading infusion of 4 mg/kg of spironolactone in ethanol (group 1, N = 6) or ethanol alone (group 2, N = 4). Thereafter the infusion was maintained at one-tenth the initial rate for eight 15-min periods. Three additional control dogs received ethanol plus spironolactone without digoxin. Digoxin radioimmunoassay of plasma and urine from these control animals did not reveal any significant cross-reactivity between spironolactone and the antibody of the digoxin radioimmunoassay. The digoxin clearance (CDIG) and ratio of CDIG to inulin clearance (CDIG/CIN) increased insignificantly with ethanol alone, but were respectively reduced by 21 and 28% with spironolactone (P less than .05). The reductions of CDIG and CDIG/CIN were observed immediately after the spironolactone loading infusion and were associated with a sudden rise in plasma digoxin. The changes in digoxin handling with spironolactone appeared to be temporally dissociated from the antimineralocorticoid activity of spironolactone. We conclude that spironolactone inhibits renal CDIG by a mechanism that may be independent of its antimineralocorticoid activity.

Aldosterone↗
PubMed1984

Effect of acute changes in serum digoxin concentration on renal digoxin clearance.

The effect of acute alterations of serum digoxin concentration (S DIG) on the renal clearance of digoxin (C DIG) was studied in six normal subjects undergoing water diuresis. Digoxin in a 5% dextrose and water solution was infused at a rate of 0.01 microgram/kg/min (low dose). One hour after the infusion began, three 20-min urine samples for clearance determination were taken. The digoxin infusion rate was then increased to 0.05 microgram/kg/min (high dose) and three additional urine samples were taken an hour later. With low doses of digoxin, the S DIG was (means +/- SD) 0.63 +/- 0.08 ng/ml, C DIG was 252.3 +/- 65.1 ml/min, inulin clearance (C IN) was 96.8 +/- 15.7 ml/min, the ratio C DIG/C IN was 2.59 +/- 0.38, and renal blood flow (C PAH) was 516 +/- 90 ml/min. With the high-dose infusion, S DIG rose to 3.23 +/- 0.44 ng/ml; C IN, C DIG, C DIG/C IN, and C PAH remained stable. C DIG correlated strongly with both C IN and C PAH. We conclude that in normal subjects undergoing water diuresis, C DIG/C IN is not altered by acutely increasing S DIG, digoxin is extensively secreted by the nephron, and C DIG is linearly related to renal plasma flow.

Adult↗
PubMed1983

Principles of drug dose adjustment during hemodialysis.

Drug removal during dialysis is influenced by physical properties of the drug, its pharmacokinetics, and by the choice of artificial kidney. The amount of drug removed during dialysis can be estimated in several ways. If changes in drug concentration produced by dialysis are used, one must be certain that postdialysis drug reequilibration is complete.

Humans↗
PubMed1983

Kinetic analysis of D-xylose absorption in normal subjects and in patients with chronic renal failure.

D-Xylose kinetics were studied in 12 normal subjects and in nine patients with chronic renal failure requiring dialysis (five hemodialysis and four peritoneal dialysis). None of the study subjects had demonstrable gastrointestinal disease. Doses of D-xylose were given intravenously (10 gm) and orally (25 gm) on different nondialysis days in order to determine the distribution and elimination kinetics and the absolute bioavailability of this compound. Our findings were as follows. (1) The nonrenal clearance of D-xylose is markedly reduced in chronic renal failure patients (43.3 vs. 90.9 ml/min, p less than 0.002). (2) D-Xylose is less completely absorbed in patients with chronic renal failure than in normal subjects (48.6% vs. 69.4%, p less than 0.01). (3) The absorption rate of D-xylose is slower in these patients than in normal subjects (0.555 hr-1 vs. 1.03 hr-1, p less than 0.05). (4) The absorption rate is positively correlated with the extent of D-xylose absorption (r = 0.49, p = 0.03). (5) Although peak D-xylose concentrations measured 1 hr after oral administration are well correlated with the extent of D-xylose absorption in normal subjects and in functionally anephric patients (r = 0.59, p less than 0.01), formal kinetic study is required to determine D-xylose bioavailability precisely because of the large variability in peak serum D-xylose concentrations and in the time required to reach these peak concentrations.

Adult↗
PubMed1982

Pharmacokinetics of bretylium in dogs and the effect of hemoperfusion on elimination.

The pharmacokinetics of bretylium in dogs and the efficacy of hemoperfusion with a resin column in its removal from the body following intravenous administration of bretylium tosylate were investigated. Five mongrel dogs weighing 18-26 kg were given a bolus dose of 15 mg/kg. Serial blood samples were taken for 24 hr. Hemoperfusion, through a resin column, was then initiated and continued for 4 hr under pentobarbital anesthesia. During hemoperfusion, arterial and venous blood samples were collected several times; venous blood samples were then withdrawn for an additional 8 hr. Urine was collected from each dog in three portions for up to 48-54 hr. Pharmacokinetics of bretylium in dogs could be characterized by a two-compartment open model with a distribution half-life of 7 min and biological half-life of 15.9 +/- 1.9 hr. Plasma levels declined rapidly from approximately 20 microgram/ml at 6 min to less than 2 microgram/ml within 1 hr. The ratio of intercompartmental rate constants, k12/k21, was 16.7, and the volume of the central compartment and apparent volume of distribution were 0.245 and 5.22 liter/kg, respectively, indicating a wide distribution of bretylium into the tissues. Plasma dialysis clearance averaged 29.7 ml/min, which is 30% of the total body clearance (98.8 ml/ min). These data suggest that resin hemoperfusion may not be useful in the treatment of bretylium intoxication.

Animals↗
PubMed1982

Cefsulodin kinetics in renal impairment.

Cefsulodin kinetics were determined after a 500-mg dose to normal subjects and patients with varying degrees of renal insufficiency, including those requiring hemodialysis. Elimination kinetics were described by a two-compartment model. Steady-state volume of distribution was 0.26 l/kg regardless of renal function. When glomerular filtration rate (GFR) was more than 80 ml/min, elimination half-life (t1/2) was 1.9 hr, total body clearance (ClT) was 2.01 ml/kg/min, and renal clearance (ClR) was 1.09 ml/kg/ in. When GFR ranged from 79 to 53 ml/min, t1/2 was 2.9 hr, ClT was 1.17 ml/kg/min, and ClR was 0.65 ml/kg/min. In subjects with moderate renal failure in whom GFR was 32 to 22 ml/min, t1/2 was 5.7 hr, Clt was 0.66 ml/kg/min, and ClR was 0.26 ml/kg/min. In anuric patients t1/2 was 13.0 hr. and ClT was 0.19 ml/kg/min or 9.5% of ClT in normal subjects. There was a linear relationship between ClT and GFR such that ClT = 0.19 + 0.017 GFR (r = 0.95). During hemodialysis the average plasma flow was 122 ml/min, dialyzer plasma clearance was 50.9 ml/min, plasma drug concentration was reduced by 60%, and t1/2 fell to 2.1 hr. After dialysis the elimination rate appeared to return to that in nondialysis studies. Therefore, renal failure reduces the ClT of cefsulodin. In hemodialysis patients the maintenance dose of cefsulodin should be reduced to 10% of normal and 60% of the dose should be given after hemodialysis.

Adult↗
PubMed1982

Pharmacokinetics of high molecular weight hydroxyethyl starch in dogs.

The elimination of high molecular weight hydroxyethyl starch (HMW-HES) was determined in dogs. . Eight dogs were divided into two groups; one of which was bled 25 ml/kg. Both groups were given 25 ml/kg of 6% HMW-HES solution over a 30 min period. There was no significant difference in plasma concentration vs time profiles between the two groups. The biological half-life estimated between days 7-28, averaged 7.5 and 8.4 days in control and bled dogs, respectively. The renal clearance of HMW-HES diminished considerably in both groups during the 7 day period. Despite large interanimal variations in renal clearance, there was not a significant difference between groups.

Animals↗