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Biomedical subjects

R L Slaughter

Publications and source records attributed to R L Slaughter.

At least 55 records · Page 3Linked to original sources
PubMed1985

Circulating concentrations of di(2-ethylhexyl) phthalate and its de-esterified phthalic acid products following plasticizer exposure in patients receiving hemodialysis.

The degree of exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) was assessed in 11 patients undergoing maintenance hemodialysis for the treatment of renal failure. The amount of DEHP leached from the dialyzer during a 4-hr dialysis session was estimated by monitoring the DEHP blood concentration gradient across the dialyzer. Circulating concentrations of the biologically active products of DEHP de-esterification, viz., mono(2-ethylhexyl) phthalate (MEHP) and phthalic acid, were also determined during the dialysis session. On the average, an estimated 105 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 23.8 to 360 mg. The rate of extraction of DEHP from the dialyzer was correlated with serum lipid content as expressed by the sum of serum cholesterol and triglyceride concentrations (r = +0.65, p less than 0.05). Time-averaged circulating concentrations of MEHP during dialysis (1.33 +/- 0.58 micrograms/ml) were similar to those of DEHP (1.91 +/- 2.11 micrograms/ml). Blood concentrations of phthalic acid (5.22 +/- 3.94 micrograms/ml) were higher than those of the esters. The length of time patients had been receiving regular dialysis treatment was not a determinant of circulating concentrations of DEHP or MEHP. In contrast, time-averaged circulating concentrations of phthalic acid correlated strongly with the duration (in years) of dialysis treatment (r = +0.92, p less than 0.001). The results indicated substantial exposure to DEHP during hemodialysis and that the de-esterified products of DEHP are present in significant concentrations in the systemic circulation. Further study is needed to assess the contribution of these metabolites to the biological actions of DEHP in man.

Adult↗
PubMed1985

Hepatic drug clearance following traumatic injury.

Trauma is a complex disease state associated with physiologic changes that have the potential to alter hepatic drug clearance mechanisms. These responses include alterations in hepatic blood flow, reduction in hepatic microsomal activity, reduction in hepatic excretion processes, and changes in protein binding. Hepatic blood flow is influenced by sympathomimetic activity. Both animal and human studies demonstrate an initial reduction and subsequent increase in hepatic blood flow, which coincides with an observed increase and subsequent return to normal in serum catecholamine concentrations. Unfortunately, there are no human studies that address the importance these findings may have to the clearance processes of high intrinsic clearance compounds. Animal studies of trauma indicate that hepatic microsomal activity is depressed during the post-traumatic period. Reduction in the hepatic clearance of antipyrine, a model low intrinsic compound, has also been demonstrated in animal models of trauma. In addition to these effects, hepatic excretion of substances such as indocyanine green and bilirubin have been demonstrated to be impaired in both traumatized animals and humans. Finally, substantial increases in the serum concentration of the binding protein alpha 1-acid glycoprotein occur in trauma patients. This has been reported to be associated with subsequent decreases in the free fraction of lidocaine and quinidine. In addition to changing serum drug concentration/response relationships, the pharmacokinetic behavior of drugs bound to alpha 1-acid glycoprotein should also change. Preliminary observations in our laboratory in a dog model of surgically-induced trauma have shown a reduction in the total clearance of lidocaine and reduction in free lidocaine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1984

High-performance liquid chromatographic procedure for the determination of di-(2-ethylhexyl)phthalate in human blood specimens. Problems of variable-extraction yield and the use of standard addition for calibration.

A high-performance liquid chromatographic procedure was developed for the determination of di-(2-ethylhexyl)phthalate (DEHP) concentrations in human whole blood samples. The solvent extraction of DEHP was found to be highly variable between samples obtained from different subjects (coefficient of variation of 30.4%). The recovery of DEHP following extraction with ethyl acetate was negatively correlated with serum lipid content, as expressed by the sum of serum cholesterol and triglyceride concentrations (r = -0.864). The technique of standard addition of DEHP allowed a single-point calibration of DEHP extractability in individual blood samples, and provided an accurate estimation of DEHP concentration (coefficient of variation of approximately 6% in replicate samples). The potential for intersample variability in the solvent extraction of other highly lipid-soluble compounds should be considered.

Chromatography, High Pressure Liquid↗
PubMed1984

Factors affecting quinidine protein binding in humans.

The free (unbound) concentration of drug in plasma is often an important determinant of pharmacological and toxicological effects. Unfortunately, studies examining the factors influencing the free fraction of quinidine in plasma have yielded inconsistent results. It is probable that differences in the type of blood collection tubes utilized and the analytical procedure employed biased some of these estimates of quinidine binding. The present study was executed in a manner free of factors now known to introduce artifacts into estimates of the free fraction of quinidine. In healthy volunteers, the free fraction of quinidine (1.0 microgram/mL) was 0.129 +/- 0.019 (mean +/- SD) and was constant throughout the therapeutic range. A high-affinity, low-capacity binding site (K = 1.17 X 10(5) M-1; nP = 3.49 X 10(-5) M) and a low-affinity, high-capacity binding site (K = 1.33 X 10(3) M-1; nP = 3.14 X 10(-3) M) were identified. The characteristics of quinidine binding in a 4.5-g/dL solution of human serum albumin (K = 3.05 X 10(3) M-1; nP = 1.36 X 10(-3) M) suggested that the low-affinity, high-capacity binding site was on this quinidine free fraction increased from 0.114 to 0.231. A lidocaine concentration of 250 micrograms/mL caused a similar increase. Patients suffering traumatic injury had a significant increase in alpha 1-acid glycoprotein concentration (197 mg/dL) and a decreased quinidine free fraction (0.075 +/- 0.019). Patients with hyperlipidemia had free fractions similar to those observed in healthy individuals (0.118 +/- 0.019).(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1984

Effects of hemodialysis on the pharmacokinetics of amoxicillin/clavulanic acid combination.

The effects that renal disease and hemodialysis have on the pharmacokinetics of amoxicillin/clavulanic acid combination were studied in a patient receiving this combination for the treatment of a Nocardia asteroides infection. Hemodialysis increased the clearance of both substances as evidenced by lower serum concentrations during the on-dialysis day, i.e., 2.3 +/- 0.8 vs. 5.9 +/- 1.2 micrograms/ml for clavulanic acid and 8.0 +/- 1.8 vs. 12.4 +/- 0.9 micrograms/ml for amoxicillin. Clavulanic acid appeared to be influenced to a greater extent as compared to amoxicillin because of its higher extraction ratio (0.74 vs. 0.44) as well as a higher observed ratio of amoxicillin to clavulanic acid during the on-dialysis day (3.59 +/- 1.27 vs. 2.28 +/- 0.65; p less than 0.05). Comparison of the area under the serum concentration-time (AUC) during the off-dialysis day with published AUC values suggested accumulation of amoxicillin/clavulanic acid. These data indicate that dosage adjustments for amoxicillin/clavulanic acid may be required in patients with chronic renal failure who are on hemodialysis. Further studies in this patient population are needed before specific dosing guidelines can be provided.

Amoxicillin↗
PubMed1983

Displacement of lidocaine from serum alpha 1-acid glycoprotein binding sites by basic drugs.

Since little is known of the number and types of binding sites on alpha 1-acid glycoprotein (AAG) and because drug-drug protein binding interactions often fail to fit a simple model, a study of the effect of 9 known AAG binding drugs on lidocaine free fraction (LFF) was performed. Serum was obtained from 10 healthy males, pooled and various concentrations (from 0.15 to 1000 micrograms/ml) of amitriptyline, bupivacaine, chlorpromazine, disopyramide, imipramine, meperidine, nortriptyline, propranolol and quinidine were added. LFF was determined by equilibrium dialysis at an initial lidocaine concentration of 2.0 micrograms/ml. LFF increased from 0.30 +/- 0.019 (mean +/- SD) in the absence of displacing agents to maximum values ranging from 0.59 (nortriptyline) to 0.73 (bupivacaine). Plots of LFF vs. the logarithm of displacing drug concentration yielded simple sigmoidal curves in all cases. LFF was increased 50% by an initial bupivacaine concentration of 6.0 micrograms/ml with all other drugs requiring more than 10 micrograms/ml to increase LFF to that extent. Lidocaine binding in a 4.5 g/dl albumin solution was unaffected by concentrations of quinidine, meperidine, nortriptyline and bupivacaine up to 200 micrograms/ml. Addition of AAG to serum reduced LFF as expected. A plot of the reciprocal of bound drug concentration vs. the reciprocal of free drug concentration in the presence and absence of quinidine suggested a competitive binding interaction. These data indicate that the binding interactions between lidocaine and the various displacing compounds are not significantly complicated by cooperative effects and that, with the possible exception of bupivacaine, displacement of lidocaine by any of these drugs is likely to be of clinical significance.

Binding Sites↗
PubMed1983

Theophylline clearance in obese patients in relation to smoking and congestive heart failure.

The effect of obesity on the total body clearance (Cltot) of theophylline was evaluated in nonsmokers and smokers with and without congestive heart failure (CHF). The obese patients were compared with similar nonobese subjects with regard to age, sex, and disease state. The total patient population numbered 150 adults. Cltot of theophylline, based on total body weight (TBW), averaged 0.60 +/- 0.20 ml/min/kg in obese nonsmokers and did not differ from the nonobese, nonsmoking group. In obese nonsmoking patients with CHF, Cltot based on TBW was 0.40 +/- 0.14 ml/min/kg, which was similar to Cltot values in nonsmoking CHF patients who were not obese. A trend toward a reduction in Cltot, based on TBW, as TBW increased, in nonsmoking patients with and without CHF, was observed. In contrast to the Cltot in nonsmokers, the Cltot of theophylline in obese smokers with and without CHF was similar to the Cltot values in nonobese populations only when based on ideal body weight. However, when compared with nonsmoking, nonobese patients, no differences were observed when Cltot was corrected for TBW. These findings suggest that theophylline maintenance dose can be based on TBW in obese patients who are smokers and nonsmokers (with and without CHF), using the average Cltot obtained for the nonsmoking patients with and without CHF.

Adult↗
PubMed1982

Alpha1-acid glycoprotein concentration and protein binding in trauma.

Alpha 1-Acid glycoprotein (AAG) concentrations were measured every 2 to 3 days in eight trauma patients and seven healthy subjects for approximately 3 wk. Mean AAG concentrations in the trauma patients rose from 100 mg/dl to a peak value of 243 mg/dl at 10 to 14 days. AAG levels averaged more than 200 mg/dl at 15 to 21 days. Mean AAG concentration in healthy subjects was 70 mg/dl with little inter- or intraindividual variability. Lidocaine was added to all serum samples from four of the patients and to selected samples from all of the healthy subjects and protein binding was determined. The binding ratio (bound concentration/free concentration) correlated strongly with AAG concentration in the trauma patients (r = 0.92), in the healthy subjects (r = 0.84), and in both groups combined (r = 0.96). AAG concentration and binding ratio for each of the four patients individually also correlated (P less than 0.05 in all cases). The change in free fraction associated with this increase in AAG was approximately doubled in each patient. Similar findings with drugs commonly used in trauma patients would be expected to alter serum concentration-response relationships significantly.

Adolescent↗
PubMed1982

Hemodialysis clearance of theophylline.

The serum hemodialysis clearance of theophylline was determined in 4 patients compared to systemic serum clearance off dialysis in 3 patients. The serum extraction ratio values obtained were compared to those of urea. Hemodialysis clearance of theophylline averaged 84.3 +/- 11.6 ml/min (mean +/- SD), and extraction ratios obtained were found to be a fairly consistent fraction of the urea extraction ratio (0.72 +/- 0.08). Hemodialysis clearance increased total body clearance (ClTB) off dialysis by 130%, 387%, and 176% in the patients who had their theophylline serum clearance estimated off dialysis. Difference in reported hemodialysis clearance are probably related to the type of dialyser used. Studies utilizing hollow fiber systems (the present study) consistently yielded higher theophylline dialysis clearance values than those using coil systems (84.3% to 88.1 ml/min versus 32 to 39.4 ml/min). Patients receiving theophylline on hemodialysis should be closely monitored for bronchospasm during and after the hemodialysis procedure. Measurement of serum concentrations should be employed to facilitate dosage increases during hemodialysis.

Aged↗
PubMed1982

Lidocaine clinical pharmacokinetics.

A review of the clinical pharmacokinetics of lidocaine is presented. Available evidence suggests that antiarrhythmic effects are reasonably well correlated wih plasma concentration. Adverse effects also covary with plasma concentration, but available evidence suggests that the correlation is not strong. A simple, multiple-bolus loading schedule appears to be superior to techniques using loading infusions; most of the multiple-bolus protocols mandate that only enough drug be given to attain the desired pharmacologic effect. In contrast, the loading infusion protocols almost invariably require the administration of a fixed dose, regardless of what fraction of the dose has been given when arrhythmia suppression is achieved. Since multiple-bolus and constant-rate infusion techniques have been shown to reduce substantially the incidence of primary ventricular fibrillation, they should be considered appropriate prophylactic and treatment regimens for acute myocardial infarction patients.

Humans↗
PubMed1981

Factors influencing serum protein binding of lidocaine in humans.

Several factors that may affect protein binding of lidocaine in human serum were studied in normal volunteers. Evidence was obtained for the presence of two classes of lidocaine binding sites with strikingly different affinity constants (k) and capacities (nP); k1 equals 1.3 x 10(5)M(-1), n1P1 equals 1.7 x 10(-5)M, and k2 equals 6.4 x 10(1)M(-1), n2P2 equals 6.9 x 10(-3)M. The low affinity binding sites are probably on serum albumin, whereas the high affinity site may be located on alpha 1 acid glycoprotein. At a lidocaine serum concentration of approximately 1.4 microgram/ml, it was observed that acidosis (pH 7.4 leads to 7.2) caused lidocaine-free fraction to increase from 0.29 to 0.36 (p less than 0.01) and that the addition of the lidocaine metabolites 3-hydroxylidocaine, 4-hydroxylidocaine, monoethylglycinexylidide, and glycinexylidide had no effect on the binding of lidocaine. Bupivacaine, disopyramide, and quinidine (in concentrations that are observed clinically) caused a significant increase (p less than 0.01) in the free fraction of lidocaine in serum (23%, 21%, and 34%, respectively. Interestingly, N-depropyl disopyramide, dihydroquinidine, procainamide, N-acetyl procainamide, and propranolol had no effect on lidocaine binding.

Acecainide↗