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Biomedical subjects

A B Straughn

Publications and source records attributed to A B Straughn.

At least 19 recordsLinked to original sources
PubMed1992

The bioinequivalence of carbamazepine tablets with a history of clinical failures.

The bioavailability of three lots of a generic 200-mg carbamazepine tablet, which had been withdrawn from the market, was compared to the bioavailability of one lot of the innovator product in 24 healthy volunteers. Fifty-three lots of the generic product had been recalled by the manufacturer because of concerns over reports of clinical failures for several of the lots. The three generic lots tested in this study exhibited a wide range of bioavailability, as well as large differences in the in vitro dissolution rates. The mean maximum carbamazepine plasma concentrations for two of the generic lots were only 61-74% that of the innovator product, while the third lot was 142% of the innovator. The mean areas under the plasma concentration-time curve for the three generic lots ranged from 60 to 113% that of the innovator product. The results clearly indicate a significant difference in the rate and extent of absorption of the generic products compared to the innovator, as well as among the generic lots. A good relationship was found between the in vivo parameters and the in vitro dissolution results for the four dosage forms.

Adult↗
PubMed1992

Postmenopausal steroid replacement with micronized dehydroepiandrosterone: preliminary oral bioavailability and dose proportionality studies.

OBJECTIVES: Because dehydroepiandrosterone may protect against neoplasia, osteoporosis, and cardiac disease, we investigated the bioavailability of oral micronized dehydroepiandrosterone, anticipating its adjunctive use in postmenopausal steroid replacement. STUDY DESIGN: Eight postmenopausal women randomly received either a placebo or 150 or 300 mg of oral micronized dehydroepiandrosterone in a lipid matrix. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and estradiol were measured periodically over the 12 hours after each dose. All treatments, all doses, and mean serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone were compared with analysis of variance for repeated measures and Newman-Keuls a posteriori test of statistical significance. RESULTS: Mean peak steroid concentrations after 150 mg (300 mg) doses were dehydroepiandrosterone 1617 (2639) ng/dl, 7 (11.5)-fold above placebo; dehydroepiandrosterone S 1185 (1688) micrograms/dl, 14 (20)-fold above placebo; and testosterone 183 (311) ng/dl, 4 (7)-fold above placebo. Estradiol concentrations remained less than 20 pg/ml, but androgen concentrations rose by 1 hour and remained elevated through the twelfth hour. Peak androgen concentrations and areas under the curves exhibited proportionality with both doses. A testosterone radioimmunoassay with celite chromatography revealed a 300% overestimation for testosterone in the direct-assay method used in this study. Thus after appropriate readjustment maximum testosterone concentrations were observed consistently within physiologic premenopausal ranges after the 150 mg dose. CONCLUSIONS: Micronized dehydroepiandrosterone may provide a steroidal postmenopausal replacement that is adjunctive to estrogens and worthy of further investigation.

Administration, Oral↗
PubMed1991

Circadian rhythms in theophylline disposition: simulations and observations in the dog.

A constant-rate iv infusion of aminophylline approaching steady state in four dogs was used to investigate a circadian rhythm in theophylline disposition. A significant circadian rhythm (p less than 0.05, group cosinor analysis) was observed for serum theophylline concentrations and for the urinary excretion rates of theophylline and 3-methylxanthine. The phase relationship of the observed circadian rhythms in urinary pH to circadian changes in serum theophylline concentrations were supportive of a circadian rhythm in renal clearance of theophylline. Computer simulations indicated that circadian changes in serum theophylline concentration and urinary excretion of theophylline and its metabolites could be accounted for by a circadian rhythm in theophylline renal clearance and metabolism to 3-methylxanthine. A circadian rhythm in theophylline volume of distribution could not be totally dismissed as potentially having some effect on disposition. The timing of food intake is hypothesized to play a role in synchronizing the observed rhythm in serum theophylline concentrations.

Animals↗
PubMed1991

The effect of raising gastric pH with ranitidine on the absorption and elimination of theophylline from a sustained-release theophylline tablet.

Prior to evaluating the effect of ranitidine on theophylline absorption from a sustained-release theophylline tablet, the effect of ranitidine on the time course of gastric pH in 12 healthy subjects was evaluated with an encapsulated radio-telemetry device (Heidelberg capsule). Gastric pH was measured hourly from 7 AM to 1 PM prior to beginning ranitidine treatment at 2 PM (150 mg every 4 hr for eight doses). The next day, pH was again measured hourly from 7 AM to 7 PM. Subjects fasted overnight and remained fasted until lunch at 11 AM. Prior to ranitidine treatment, the mean morning gastric pH remained between 1.5 and 2.2. After lunch, the pH increased to 2.2-2.3. During ranitidine treatment the mean morning gastric pH measurements were 5.5 to 5.8, decreasing after lunch to 3.1 by 4 PM and increasing to 3.9 at 7 PM. One week later the subjects participated in a three-way crossover theophylline bioavailability study receiving at weekly intervals, single doses at 7 AM of (a) 5 x 100-mg immediate-release tablets, (b) 2 x 300-mg sustained-release theophylline tablets, and (c) 2 x 300-mg sustained-release theophylline tablets after ranitidine pretreatment of 150 mg every 4 hr beginning at 2 PM the previous day. The increase in gastric pH with ranitidine had no effect (P greater than 0.05) on the rate and extent of absorption or on the elimination rate of theophylline.

Adult↗
PubMed1989

Gas chromatographic-mass spectrometric analysis of plasma nifedipine.

A gas chromatographic-mass spectrometric assay is described for the determination of plasma nifedipine using nitrendipine as an internal standard. Chromatographic separation was performed on a dimethylsilicone capillary column, and detection was by selected ion monitoring of electron impact-generated base peak ions. The lower limit of quantifiable detection of nifedipine was 2 ng/ml. The method was applied to plasma samples obtained from a human subject who had been dosed with a 10-mg nifedipine capsule every 8 h for eight doses.

Gas Chromatography-Mass Spectrometry↗
PubMed1989

Gas chromatographic-mass spectrometric analysis of plasma oxybutynin using a deuterated internal standard.

A gas chromatographic-mass spectrometric method is described for the quantitative analysis of plasma oxybutynin. Deuterated oxybutynin served as the internal standard and its synthesis is described. Chromatographic separation on a methylsilicone capillary column avoided the thermal decomposition observed using a packed column. Electron-impact ionization and selected-ion monitoring of the alpha-cleavage fragments of drug and internal standard permitted quantitation of oxybutynin down to 0.25 ng/ml of plasma. At the 2 ng/ml level the accuracy and precision are 4 and 10%, respectively, and improved at higher drug concentrations. Application of the method to the pharmacokinetics of oral oxybutynin in man demonstrated rapid absorption and elimination of the drug.

Chemical Phenomena↗
PubMed1988

Circadian rhythm in theophylline disposition during a constant-rate intravenous infusion of aminophylline in the dog.

The disposition of theophylline in three dogs was determined during a 48-h constant-rate intravenous infusion of aminophylline. A systematic fluctuation in serum theophylline concentrations was observed over a 24-h period, which appeared to be characteristic of a circadian rhythm. Neither assay variability nor fluctuations in the infusion pump rate could account for the observed variations in the serum concentrations. It was concluded that the changes in the theophylline concentrations were the result of a circadian rhythm in theophylline disposition.

Aminophylline↗
PubMed1986

Dialyzability and pharmacokinetics of indomethacin in adult patients with end-stage renal disease.

Indomethacin, a nonsteroidal antiinflammatory drug, has been shown to be effective for the treatment of pericarditis in chronic hemodialysis patients. Data regarding the dialyzability of indomethacin in these patients, however, is lacking. The aim of this study, therefore, was to evaluate (1) the dialyzability, and (2) the absorption and elimination kinetics of indomethacin, using six stable anephric adult patients who were maintained on chronic hemodialysis and were receiving indomethacin for the management of their uremic pericarditis. The results from this study demonstrate that indomethacin is dialyzable, but not to an appreciable extent. The mean predialysis and postdialysis indomethacin plasma levels were 3.4 and 1.6 micrograms/ml, respectively. The mean total amount of indomethacin removed by five hours of hemodialysis was 19.6 percent of the single dose of indomethacin 100 mg po. However, mean Cpmax, tmax, t1/2, and AUC0-infinity during and in the absence of hemodialysis were 5.4 and 5.4 micrograms/ml (not statistically significant [NS]), 1.9 and 2.0 h (NS), 6.1 and 5.3 h (NS), and 30.9 and 35.7 micrograms h ml-1 (NS), respectively. Based on these findings, it can be concluded that although indomethacin is dialyzable, no dosage adjustment is required in patients receiving indomethacin for the management of their uremic pericarditis when undergoing maintenance hemodialysis.

Adult↗
PubMed1985

Bioavailability of dyphylline and dyphylline-guaifenesin tablets in humans.

A six-way-crossover bioavailability study was conducted with twelve healthy male volunteers to evaluate the relative bioavailability of three tablet formulations containing dyphylline and three tablet formulations containing dyphylline-guaifenesin. Each subject was administered two tablets of each product with greater than or equal to 3 d separating each dose. Blood samples were obtained just prior to each dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 10.0 h following each dose. An HPLC method was used to assay dyphylline in the serum. The mean tmax ranged from 0.6 to 1.0 h for the six products. The mean values for Cmax differed by 29%, and the AUC values differed by less than 8%. It was noted that the dyphylline-guaifenesin products exhibited a lower bioavailability than the products which only contained dyphylline. It was concluded that the three combination products were bioequivalent, as were the three dyphylline products.

Adult↗
PubMed1985

Comparison of high pressure liquid chromatography and fluorescence polarization immunoassay methods in a theophylline pharmacokinetic study.

High pressure liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) were compared in a theophylline pharmacokinetic study. Eight healthy subjects received single 600-mg oral doses of two different sustained-release theophylline formulations. Fourteen blood samples were collected over 57 h after each dose, and the serum was analyzed for theophylline using both HPLC and FPIA methods. In comparing the two formulations using HPLC, there was no statistical difference in the area under the curve (AUC), terminal rate constant (k), or time of peak. However, there was a 13% difference in peak theophylline concentration (p less than 0.05). The same statistical conclusions were made for all parameters when using FPIA. When comparing the kinetic parameters determined with each assay, the AUC was 12% greater and the k was 17% smaller with FPIA (p less than 0.05). Orthogonal regression of all serum theophylline concentrations showed that FPIA = 1.04 HPLC + 0.20; r = 0.987, p less than 0.001. Stratification of serum theophylline concentrations into different ranges showed that FPIA overestimated the HPLC results in each range, but the percentage of overestimation was greater at lower concentrations (p less than 0.05). The use of FPIA seems appropriate in comparative studies of theophylline pharmacokinetics; however, the calculated kinetic parameters may differ slightly from those obtained with HPLC.

Adult↗
PubMed1985

Determination of free disopyramide plasma concentrations using ultrafiltration and enzyme multiplied immunoassay.

Disopyramide is an antiarrhythmic drug that exhibits nonlinear binding to plasma proteins. As a result, the total body clearance increases with increasing total drug plasma concentration. A rapid and sensitive method for the determination of free (unbound) disopyramide plasma concentrations is described. The procedure employs an ultrafiltration system (Centrifree), which can be used for basic drugs, along with an enzyme multiplied immunoassay system (EMIT) for the measurement of free disopyramide concentrations in plasma water filtrate. The EMIT method was adapted to permit measurement of disopyramide in plasma over a concentration range of 0.02-1.2 micrograms/ml. Plasma storage at -20 degrees C, filtration volume, or the presence of buffer and mono-N-dealkylated metabolite in plasma did not affect the binding determinations. There was no loss of drug during the filtration process. A good correspondence was found between the EMIT assay and a high performance liquid chromatography method, when applied to plasma samples obtained from a human subject who had ingested disopyramide. Furthermore, the extent of protein binding determined by the ultrafiltration system and by equilibrium dialysis were in good agreement. The binding of disopyramide in fortified human plasma decreased from 64 to 52% over a total drug concentration range of 1-5 micrograms/ml.

Blood Proteins↗
PubMed1984

Absorption of phenobarbital from tablets and elixir.

A three-way crossover study was conducted with 24 healthy male volunteers to determine the relative bioavailability of four different 100-mg phenobarbital tablets compared with a reference elixir. Each subject received two of the tablets and the elixir at 30-d intervals. Blood samples were collected daily for 19 d after each dose. Plasma phenobarbital concentrations achieved with the five dosage forms differed by less than 20% within 2-3 h after dosing. The extent of absorption for all dosage forms, as determined from area under the plasma concentration-time profiles, were within 10% of each other. The peak plasma concentration was the greatest and the time to peak concentration was the shortest for the elixir. One of the tablets exhibited a time to peak concentration of 8.6 h, which was significantly longer than any of the other dosage forms. The time to peak concentration correlated with the percent of drug dissolved in 60 min, as determined in 0.1 M HCl, using the USP XX paddle method at 50 rpm.

Adult↗
PubMed1984

Effect of rifampin on theophylline disposition.

The concentrations of theophylline from single 400-mg oral doses were evaluated both before and after 7 days of oral rifampin administration (600 mg/day) in six healthy, nonsmoking adults. The mean oral clearance of theophylline was significantly increased from 54.9 +/- 21.2 to 68.9 +/- 26.5 ml/h/kg. The elimination rate constant was significantly increased in five of the six subjects, with a mean increase of approximately 25%. Although intersubject variability was large, these data indicate the potential need to increase theophylline doses in some patients receiving rifampin.

Administration, Oral↗
PubMed1984

Bioequivalence, dose-proportionality, and pharmacokinetics of naltrexone after oral administration.

Healthy male volunteers (N = 24) participated in a four-way crossover study to compare the rate and extent of absorption of naltrexone after administration of 50 mg tablets as 50, 100, and 200 mg doses and a 10 mg/ml reference syrup. A high-performance liquid chromatographic method was employed to measure naltrexone and 6-beta-naltrexol in plasma and urine. Compared to the syrup, the 50 mg tablets were absorbed more slowly but equally well. There was excellent linearity between the administered dose and the area under the plasma concentration-time profile, as well as total urinary recovery of both drug and metabolite. The mean half-lives for naltrexone and beta-naltrexol were approximately 4 and 12 hours, respectively. The fraction of drug reaching the systemic circulation was estimated to be 5% of the administered dose because of extensive first-pass metabolism. Less than 1% of the dose was excreted in the urine as naltrexone after 48 hours, while 25% was recovered as unconjugated beta-naltrexol. The renal clearance of naltrexone and beta-naltrexol was approximately 127 ml/min and 283 ml/min, respectively. The total systemic clearance for naltrexone was approximately 94 L/hr.

Administration, Oral↗
PubMed1983

Bioavailability of propylthiouracil in humans.

Single lots of five commercially available 50-mg propyl-thiouracil formulations were evaluated in vitro and in vivo. Each product met the USP XIX specifications for drug content, content uniformity, and disintegration time. However, major differences were noted among products in their rate and extent of dissolution. Statistically significant differences (p less than 0.05) were observed in vivo among the drug formulations at all but one of the sampling times, as determined from crossover blood level studies in 12 healthy male volunteers. The differences among the areas under the plasma level-time curves for the various products were not statistically significant. No statistically significant correlations were found between the in vitro and in vivo parameters studied.

Biological Availability↗
PubMed1982

Chloramphenicol clearance in infants.

Chloramphenicol clearance was evaluated over one dosing interval in 10 infants after at least 24 hours of therapy to evaluate dosage guidelines using a specific chemical assay. Serum samples were obtained prior to and at 1, 2, 4, and 6 hours after the start of a 20-minute infusion of 24 mg/kg chloramphenicol as the sodium succinate. The chemical assay used is technically simple and is specific for unesterified chloramphenicol. Peak serum concentrations ranged from 20.9 to 94.0 microgram/ml and occurred from 1 to 4 hours after infusion. Clearances ranged from 0.058 to 0.236 l./kg . hr and paralleled previously reported results using different assay methodology. The 4-hour serum chloramphenicol concentrations were significantly lower (P less than 0.05) in infants on phenobarbital. The currently recommended dose of chloramphenicol for severe infections, 100 mg/kg per day, is excessive in some infants. Widely divergent clearance rates prohibit uniform dosage guidelines so that serum level monitoring with an assay specific for chloramphenicol is essential.

Chloramphenicol↗
PubMed1982

Noneffect of rifampin on theophylline disposition in rabbits.

The pharmacokinetic disposition of theophylline after a single 10mg/kg intravenous dose of aminophylline was evaluated in six rabbits. Three then received rifampin (50mg/kg) a day for 14 days and the disposition of theophylline was re-evaluated in all six rabbits after another 10mg/kg aminophylline dose. The mean theophylline half life before rifampin treatment of 5.11 +/- 0.71 hrs was not different (p greater than 0.10) from the half life of 4.54 +/- 0.71 hrs after treatment with rifampin. In the non-rifampin treated rabbits, the initial mean theophylline half life of 4.78 +/- 1.05 was not different p greater than 0.80) from the half life of 4.94 +/- 1.92 hrs after fourteen days. No significant alterations in clearance or area under the curve were noted for either group. Power analysis indicated that three rabbits were sufficient to detect at least a 25% change in the parameters as being significant (p less than 0.05).

Animals↗