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Biomedical subjects

B J Kline

Publications and source records attributed to B J Kline.

18 recordsLinked to original sources

Phenytoin removal during plasma exchange.

Plasma exchange is currently being used to treat a variety of disorders including immune complex and hematologic disorders. It has been shown that the removal of plasma removes drugs bound to plasma proteins. This case documents the removal of phenytoin during plasma exchange therapy. Total and free phenytoin serum concentrations were obtained before and after each exchange. Aliquots were obtained from each pass, and total phenytoin concentrations were determined. The total phenytoin serum concentration increased during the first exchange, while the total concentration decreased as a result of the second exchange. It was determined that approximately 27.7 mg and 30.4 mg of phenytoin were removed by the first and second plasma exchanges, respectively.

Adolescent

Influence of tube type, storage time, and temperature on the total and free concentration of valproic acid.

The influence of storage conditions on the total and free concentration of valproic acid (VPA) was studied in six normal male subjects who ingested 750 mg of VPA (3 X 250 mg Depakene capsules; Abbott Laboratories). Blood samples were collected in various types of Vacutainer tubes (red top, no additives; green top, sodium heparin; blue top, sodium citrate; and purple top, EDTA) 2 h post administration of VPA. Either these samples were centrifuged immediately or stored for various periods of time at room temperature or refrigerated, or the supernate was frozen prior to analysis. Free VPA samples were obtained utilizing the Amicon ultrafiltration system. All VPA samples were analyzed by gas-liquid chromatography. Total VPA concentrations obtained from plasma collected with sodium citrate were lower (p less than 0.05) than either serum or plasma collected with other anticoagulants. There were no differences (p greater than 0.05) in total or free VPA concentrations between samples collected in serum or in plasma collected with heparin or EDTA. Storing samples for 96 h at room temperature did not alter the total VPA concentrations but was found to increase the free fraction of VPA (p less than 0.05). The refrigeration or freezing of the supernate from the blood samples for 7 days did not alter (p greater than 0.05) the total or the free fraction of VPA. The results of this study demonstrate that total and/or free VPA may be collected from either serum or plasma, provided sodium citrate is not used to collect plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Specimen Collection

Effect of cimetidine on quinidine clearance.

Cimetidine has been reported to inhibit the hepatic metabolism of numerous drugs. Theoretically cimetidine could inhibit the metabolism of quinidine. This study was undertaken to determine the effect of cimetidine on quinidine plasma concentrations. Nine healthy volunteers were entered into the matched-pairs study. Baseline quinidine pharmacokinetic parameters were determined after a single oral 400-mg dose. Study parameters were determined after 3 days of cimetidine 300 mg p.o. q.i.d., when 400 mg quinidine was again administered. Cimetidine increased the area under the time-concentration curve (14.5%, p less than 0.01), decreased the total body clearance (24.9%, p less than 0.05), and prolonged the half-life (22.6%, p less than 0.05) of quinidine in this study. There was no change in peak quinidine concentrations or time to peak. These data document an interaction between cimetidine and quinidine. The clinical importance of this interaction should be greatest in patients with impaired liver function, patients with preexisting near-toxic plasma concentrations of quinidine, and the elderly. Patients placed on cimetidine and quinidine should be monitored closely for signs and symptoms of quinidine toxicity.

Adult

Cefmenoxime pharmacokinetics in patients with renal insufficiency.

The pharmacokinetics of cefmenoxime were determined after a 30-min intravenous infusion of 15 mg/kg of total body weight to 33 adult subjects with normal renal function (CLCR, greater than 80 ml/min per 1.73 m2, group I), mild renal insufficiency (CLCR, 40 to 79 ml/min per 1.73 m2, group II), moderate renal insufficiency (CLCR, 10 to 39 ml/min per 1.73 m2, group III), or severe renal impairment, (CLCR, less than 10 ml/min per 1.73 m2, group IV) or to patients between hemodialysis (CLCR, less than 10 ml/min per 1.73 m2, group V). Concentrations of cefmenoxime in serum and urine were determined by high-pressure liquid chromatography, and serum concentrations were fit to a two-compartment model. There was no significant relationship between creatinine clearance and either peak serum concentrations or volume of distribution at steady state. Patients in group I excreted 81% of the dose into the urine within 24 h; recovery decreased with worsening renal function. The mean terminal half-lives in groups I to V were 1.06, 1.50, 3.55, 4.60, and 11.4 h, respectively. There were good linear relationships between creatinine clearance, and the elimination rate and total body clearance of cefmenoxime. Dosage recommendations for subjects with renal insufficiency are proposed.

Cefmenoxime

Gentamicin and tobramycin penetration into burn eschar. Pharmacokinetics and microbiological effects.

This study was designed to determine whether intravenously administered gentamicin sulfate and tobramycin sulfate penetrate into the eschar of patients with severe burns. In addition, each antibiotic's pharmacokinetics in serum and the effect on eschar microbiology were determined. Twenty patients with suspected burn wound sepsis received either gentamicin or tobramycin. The microbiology of the baseline eschar was determined and repeated on days 2, 4, and 7. All patients had measurable aminoglycoside tissue concentrations, and elimination from serum was not unusually rapid. Thirteen patients had baseline eschar cultures positive for Pseudomonas aeruginosa or Serratia marcescens; eight patients were initially bacteremic. Pseudomonas aeruginosa strains were sensitive to both antibiotics and usually declined in concentration with time or were eliminated; the more drug-resistant isolates of S marcescens persisted or caused super-infection and bacteremia. Aminoglycoside antibiotics penetrate into burn eschar and appear to have a substantial effect on eschar microbiology.

Adolescent

Peritoneal absorption of moxalactam.

We evaluated the rate and extent of the systemic absorption of moxalactam given intraperitoneally to patients with peritonitis and end-stage renal disease who were being maintained on continuous ambulatory peritoneal dialysis. Moxalactam was administered at a concentration of 200 mg per 2-liter dialysate for the first dose, followed by 60 mg per 2-liter exchange for 23 1-h exchanges. Moxalactam concentrations in serum (mean +/- standard deviation) were 2.5 +/- 0.9 mg/liter after the first hourly dialysis, increasing to 10.3 +/- 4.8 mg/liter after 24 h of drug administration. Moxalactam levels in serum at 1 h were above the minimal inhibitory concentrations for most gram-negative organisms except Pseudomonas aeruginosa. No adverse effects of the drug were observed.

Absorption

The determination of azapropazone and its 6-hydroxy metabolite in plasma and urine by HPLC.

A high-performance liquid chromatography (HPLC) procedure has been developed for the determination of azapropazone and its 6-hydroxy metabolite in plasma and urine. The procedure is simple and rapid since extraction of the drug and its metabolite is not required. Plasma proteins are precipitated with methanol, and the supernate is injected onto a reverse-phase HPLC column. With photometric detection at 254 nm, the procedure can determine as little as 0.4 micrograms/ml azapropazone in plasma or urine and 1.5-3 micrograms/ml of the metabolite in urine, depending upon the level of interference. The procedure has been used successfully in single-dose pharmacokinetic and bioavailability studies of azapropazone dosage forms.

Apazone

Rifampin blood and tissue levels in patients undergoing cardiac valve surgery.

Single 600-mg capsules of rifampin were given orally to 26 patients as prophylaxis during cardiac valve replacement. Antibiotic concentrations were measured in blood (serum or plasma) and tissue (excised cardiac valve). The serum or plasma levels of rifampin in 18 patients who ingested this drug 2 h before they received preoperative opiates and anticholinergics intramuscularly were not significantly different from the levels in four normal volunteers who received the drug. These levels were 15.9 +/- 6.5 micrograms/ml (mean +/- standard deviation) 2 h after drug administration, 7.1 +/- 4.3 micrograms/ml 8 h after drug administration and 2 h after a mean of 1.4 h on cardiopulmonary bypass, and 1.6 +/- 1.6 micrograms/ml 24 h after drug ingestion. The valve tissue level was 3.8 +/- 2.7 micrograms/g (mean +/- standard deviation; n = 10). This value was 65% of the simultaneous serum and plasma levels and 31% of the peak serum and plasma levels. Eight patients who were given rifampin at the same time that they received other preoperative medications had significantly lower blood levels than the 18 patients who received rifampin 2 h earlier (P less than 0.001). No rifampin was detected in valves from seven of these patients. Decreased rifampin absorption due to simultaneous administration with opiates and anticholinergics was the probable reason for the low plasma and serum levels observed. These data suggest that, if properly dosed, rifampin administered orally gives high blood and valve tissue levels, which are affected minimally by cardiopulmonary bypass in patients undergoing cardiac valve surgery.

Female

Determination of mean valproic acid serum level by assay of a single pooled sample.

Determinations of single serum drug concentrations are useful in monitoring drug therapy. A mean serum level would supply more information but is expensive and laborious because of the multiple blood samples and assays, calculation of area under the curve (AUC) by the trapezoidal rule, and division of the AUC by the time interval during which the samples were drawn. A method was devised that pools aliquots from individual serum samples taken during the testing period to form on composite sample. A single assay of this sample provides the mean serum level of the testing period. The method was successfully tested with amaranth and then applied to valproic acid serum levels. AUC and mean serum levels were determined by the standard procedure of assays of multiple samples and the trapezoidal rule. Mean serum level was also determined by the pooled sample technique. The correlation coefficient for the comparison of the mean serum levels determined by the two techniques is 0.907 (p less than 0.001). There was no difference between the estimates of the mean serum levels by Student's paired t test (t = 0.693, p greater than 0.2). The good correlation and lack of difference between the conventional method and the pooled sample method indicates that the method is valid.

Blood Specimen Collection

Cefazolin and moxalactam pharmacokinetics after simultaneous intravenous infusion.

A high-performance liquid chromatographic method for the measurement of moxalactam concentrations in serum was modified to permit the simultaneous measurement of both moxalactam and cefazolin. We then studied whether the simultaneous administration of both moxalactam and cefazolin to normal subjects would produce profiles of serum concentration versus time which were the same as those obtained after the administration of each drug individually. Six healthy adults received a 30-min infusion of cefazolin (10 mg/kg), followed in 2 days by the same dose of moxalactam. After 2 days, both antibiotics were administered together. A two-compartment model was found to adequately characterize the data, and the serum concentration curve for each drug when given alone was statistically identical to that obtained after simultaneous administration. Cefazolin was found to produce a significantly greater peak serum concentration (105 +/- 14 versus 81 +/- 21 microgram/ml) and a significantly greater area under the curve (218 +/- 42 versus 157 +/- 19 . microgram h/ml). The terminal half-life of moxalactam was not significantly longer than for cefazolin (2.2 +/- 0.6 versus 2.0 +/- 0.6 h, respectively). The method of simultaneous administration may have distinct advantages over conventional methods for studies of comparative tissue penetration.

Adult

In vitro inactivation of gentamicin, tobramycin, and netilmicin by carbenicillin, azlocillin, or mezlocillin.

The in vitro inactivation of gentamicin, tobramycin, and netilmicin, when combined with carbenicillin, azlocillin, and mezlocillin, was studied. Plasma samples containing the aminoglycosides at a concentration of 5-8 micrograms/ml in combination with the penicillins in concentrations of 500, 250, and 50 micrograms/ml were incubated at room temperature and 37 degrees C for 0.3, 1, 3, 6, and 9 days. The aminoglycoside concentration was determined by radioimmunoassay or enzyme immunoassay. The extent of inactivation was dependent on penicillin concentration, contact time, and temperature. Penicillin concentrations of 500 micrograms/ml caused the greatest loss of aminoglycoside, while little loss occurred at the 50-micrograms/ml penicillin level. Carbenicillin, in concentrations of 250 and 500 micrograms/ml, inactivated all three aminoglycosides to a greater extent than either azlocillin or mezlocillin. The initial rate of decline in aminoglycoside concentration was greater at 37 degrees C than at room temperature. The new acylureidopenicillins, azlocillin and mezlocillin, inactivate the aminoglycosides studied, in a similar manner to that previously described for carbenicillin.

Anti-Bacterial Agents

Effects of food on valproic acid absorption.

The effect of food on valproic acid absorption was investigated in a randomized, cross-over study with eight subjects. Two 250-mg soft-gelatin capsules of valproic acid were administered to the participants under fasting and nonfasting conditions. The time of peak serum concentration, height of the peak concentration, and total area under the curve were determined and compared by the Student's t test for paired data. The time to attain a peak serum concentration was significantly delayed (p less than 0.005) from the 1.6 hours during fasting conditions to four hours after a standard meal. A statistically insignificant trend toward lower peak serum concentrations (54.6 micrograms/ml versus 49.4 micrograms/ml) was found under the nonfasting conditions. This trend becomes significant if the data of one subject who exercised before taking the drug are eliminated. The area under the curve was not different between the two conditions. The administration of the drug with food did not significantly alter the volume of distribution, half-life, or elimination constant. No clinically important interaction resulted from the administration of valproic acid with food. If a patient experiences gastrointestinal side effects with valproic acid, the patient may be advised to take the drug with food.

Adult

Bufotenine esters.

Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been reported to be behaviorally inactive or only very weakly active in man and animals; this may be a consequence of its low partition coefficient and resultant inability to penetrate the blood--brain barrier. The acetyl, propionyl, butyryl, isobutyryl, and pivalyl esters of bufotenine were prepared for future pharmacological evaluation. Unexpectedly, it was found that these esters all possess a relatively high affinity for the serotonin receptors of the isolated rat stomach fundus preparation. A semiquantitative chromatographic measurement of ester hydrolysis suggests that extensive hydrolysis of the esters to bufotenine does not occur under the conditions of the affinity assay.

Animals

Simplified GLC assay for lidocaine in plasma.

A simple, rapid GLC method for the determination of lidocaine in plasma is described. After addition of mepivacaine as an internal standard, the plasma sample is deproteinated and centrifuged. The supernate is alkalinized, and the lidocaine and internal standard are extracted into a microvolume of carbon disulfide. By using GLC with a flame-ionization detector, linear concentration-response curves were obtained in the 1-6 microgram/ml range. The method can easily determine plasma concentrations at the 250-ng/ml level when a 1-ml plasma sample is analyzed.

Chromatography, Gas

Penetration of moxalactam and cefazolin into bone following simultaneous bolus or infusion.

The penetration of cefazolin and moxalactam into bone was studied in 20 adults scheduled for total hip arthroplasty. Patients randomly received both moxalactam and cefazolin (10 mg/kg of each) by either a rapid bolus or a 30-minute infusion. Serum and bone-extract concentrations were measured by HPLC. Serum concentrations of cefazolin were significantly greater than those of moxalactam at 15 minutes, 30 minutes, and at the time of bone removal for both rates of injection. Bone concentrations of cefazolin were significantly greater than those of moxalactam for both the bolus study (7.7 +/- 4.8 micrograms/g versus 5.4 +/- 3.4 micrograms/g) and the infusion study (5.6 +/- 3.4 micrograms/g versus 4.3 +/- 2.6 micrograms/g, respectively). There was no significant difference in the bone levels for the two drugs when penetration was expressed as a function of the simultaneous serum concentration (18% for each drug), and there were no significant differences in bone concentrations between the two rates of administration.

Adult

Effect of food on ethambutol absorption.

The effect of food on the absorption of ethambutol hydrochloride tablets was investigated. Following an overnight fast, 11 normal volunteers ingested ethambutol hydrochloride tablets (15 mg/kg dosage) once while fasting and once immediately following a standardized breakfast. The sequence of administration was assigned randomly. Food and fasting trials were at least seven days apart. In both trials, blood samples were drawn at 1, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. Ethambutol concentrations in plasma were determined by a gas-chromatography method. Completeness of absorption was assessed by calculation of the area under the 24-hour plasma concentration curve (AUC) for each subject after each mode of administration using a trapezoidal approximation. Within-subject difference in AUC between food and fasting conditions was evaluated using the Student's t test for paired data. There was no significant difference between the mean AUC-fasting and the mean AUC-food (p greater than 0.05). Food does not appear to influence the extent of ethambutol absorption.

Ethambutol