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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
PubMed1999

Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele.

Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of many drugs. Several alleles for the CYP2C9 gene have been reported. Individuals homozygous for the Leu359 variant (CYP2C9*3) have been shown to have significantly lower drug clearances compared with Ile359 (CYP2C9*1) homozygous individuals. A male Caucasian who participated in six bioavailability studies in our laboratory over a period of several years showed extremely low clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP2D6 substrate). His oral clearance of phenytoin was 21% of the mean of the other 11 individuals participating in the study, and his oral clearance of glipizide, a second generation sulfonylurea structurally similar to tolbutamide, was only 188% of the mean of the other 10 individuals. However, his oral clearance of nifedipine and chlorpheniramine did not differ from individuals in other studies performed at our laboratories. An additional blood sample was obtained from this individual to determine if he possessed any of the known CYP2C9 or CYP2C19 allelic variants that would account for his poor clearance of the CYP2C9 substrates (phenytoin and glipizide) compared with the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates. The results of the genotype testing showed that this individual was homozygous for the CYP2C9*3 allele and did not possess any of the known defective CYP2C19 alleles. This study establishes that the Leu359 mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.

Adult↗
PubMed1998

The relative bioavailability and in vivo-in vitro correlations for four marketed carbamazepine tablets.

PURPOSE: To determine if three marketed generic carbamazepine tablets were bioequivalent to the innovator formulation, as well as to each other. In addition, to examine in vivo-in vitro relationships among the four formulations. METHODS: Each formulation was given as a single dose to 18 healthy male and female subjects using a crossover design. Blood samples were collected for 169 hr. Carbamazepine was assayed by HPLC with UV detection. RESULTS: In vivo fraction absorbed plots indicated that the three generic formulations were absorbed more rapidly than the innovator product, and the mean time of maximum plasma concentration was 6-7 hr sooner for the generic formulations. The mean maximum plasma concentration ranged from 17-19 percent higher for the generic products compared to the innovator, and the 90% confidence limits for Cmax data ranged from 11 1% to 126%. The mean AUC(0-infinity) for the generic products ranged from 101-104% compared to the innovator, and the confidence limits for AUC ranged from 97-108%. CONCLUSIONS: The generic products were all more rapidly absorbed than the innovator, but simulations of steady-state concentrations indicated that it would be unlikely that these differences would have any significant clinical effect. An excellent association was seen between the Cmax and the percent of drug dissolved in vitro. The correlation was used to accurately predict the Cmax of four other 200 mg tablets evaluated in an earlier study.

Adult↗
PubMed1998

Lack of in vivo/in vitro correlations for 50 mg and 250 mg primidone tablets.

PURPOSE: To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. METHODS: Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. RESULTS: Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0-infinity) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0-infinity) among the four 250 mg tablets were less than 7%. CONCLUSIONS: Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.

Adult↗
PubMed1996

Delivery of dehydroepiandrosterone to premenopausal women: effects of micronization and nonoral administration.

OBJECTIVES: This single-dose study compares three dehydroepiandrosterone delivery methods (oral crystalline steroid, micronized steroid, and vaginal administration) to ascertain whether physiologic levels of circulating dehydroepiandrosterone and dehydroepiandrosterone sulfate can be obtained while increases in testosterone are minimized. STUDY DESIGN: Two randomized, double-blind, placebo-controlled single-dose comparisons were made. For oral micronized versus crystalline dehydroepiandrosterone 300 mg doses of micronized or crystalline dehydroepiandrosterone were administered, followed by 6 hours of blood sampling (n=7). Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels were measured; areas under the curve and mean peak values were analyzed by Student-Newman-Keuls tests. For oral versus vaginal micronized dehydroepiandrosterone 150 mg oral or vaginal doses of micronized dehydroepiandrosterone were administered, followed by blood sampling over 12 hours (n=5). Data analysis was as described. RESULTS: Oral micronized and unmicronized dehydroepiandrosterone resulted in increases in serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. Micronization increased the area-under-the-curve ratios for dehydroepiandrosterone sulfate/dehydroepiandrosterone and dehydroepiandrosterone sulfate/testosterone. Vaginal administration provided equivalent serum dehydroepiandrosterone; however, it failed to increase dehydroepiandrosterone sulfate or testosterone over placebo. CONCLUSION: Micronization of oral dehydroepiandrosterone diminishes bioconversion to testosterone. Vaginal dehydroepiandrosterone delivers equivalent dehydroepiandrosterone but substantially diminishes dehydroepiandrosterone bioconversion.

Administration, Intravaginal↗
PubMed1995

Replacement of dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women.

OBJECTIVE: To demonstrate bioavailability of 3 weeks of oral micronized DHEA and to delineate changes induced on insulin sensitivity, morphometric indexes, and lipoprotein profiles. DESIGN: Oral micronized DHEa (50 mg/d) was administered in 3-week treatments to 11 postmenopausal women in a prospective, placebo-controlled, randomized, blinded, crossover trial with an interarm washout. After dose (23 hour) serum DHEA, DHEAS, T, and cortisol levels were measured, as were fasting lipoproteins, oral glucose tolerance tests (OGTT), T-lymphocyte insulin binding and degradation, and urine collagen cross-links. Morphometric changes were determined by hydrostatic weighing. RESULTS: Dehydroepiandrosterone sulfate, DHEA, T, and free T increased up to two times premenopausal levels with treatment. Fasting triglycerides declined; no change in collagen cross-links or morphometric indexes was noted. Oral glucose tolerance test parameters did not change, but both T-lymphocyte insulin binding and degradation increased with DHEA. CONCLUSION: Fifty milligrams per day of oral DHEA gives suprahysiologic androgen levels; 25 mg/d may be more appropriate. Dehydroepiandrosterone enhanced tissue insulin sensitivity and lowered serum triglycerides. Rationale is provided for postmenopausal replacement therapy with this androgen.

Aged↗
PubMed1994

Comparative steady-state bioavailability of Theo-24 and Theo-Dur in healthy men.

This study was designed to compare the steady-state theophylline serum concentrations produced by 800 mg daily doses of Theo-24 and Theo-Dur in normal, healthy men administered according to each product's recommended dosing instructions. Sixteen subjects with theophylline clearances ranging from 0.39 to 0.95 mL/min/kg (average, 0.60 mL/min/kg) and theophylline elimination half-lives ranging from 5.1 to 10.5 hours (average 7.9 hours) completed the study. They were all nonsmokers, who ranged in age from 18 to 44 years and were within 10% of normal weight for their height and build. Theo-24 demonstrated a high extent of absorption (89%, range 54% to 115%) relative to Theo-Dur. Both formulations demonstrated similar times to maximum theophylline concentration (11.3 hours for Theo-24 and 11.5 hours for Theo-Dur), similar peak to trough concentration ratios relative to the trough concentration (74% for Theo-24, 62% for Theo-Dur) and similar periods of time within 5 to 15 mg/L (25.2 to 75.7 mumol/L; 21.4 hours for Theo-24, 19.4 hours for Theo-Dur). No "dose dumping" was demonstrated. The results indicate that Theo-24 dosed at least one hour prior to a high-fat breakfast produces serum theophylline concentrations in a range similar to Theo-Dur administered every 12 hours.

Adolescent↗
PubMed1993

Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women.

OBJECTIVE: This study tests the hypothesis that dehydroepiandrosterone or its metabolic products are immunomodulatory in postmenopausal women with relative adrenal androgen deficiency. STUDY DESIGN: A prospective, randomized, double-blind, crossover study of 11 subjects with 3-week treatment arms separated by a 2-week washout period was performed. Immunologic evaluation at the beginning and end of the treatment arms consisted of flow cytometry to delineate T-cell populations, in vitro T-cell mitogenic response and cytokine production, and natural killer cell cytotoxicity. Statistical analysis was based on a split-plot design with analysis of variance with repeated measures. RESULTS: Dehydroepiandrosterone supplementation decreased CD4+ (helper) T cells and increased CD8+/CD56+ (natural killer) cells. Although T-cell mitogenic and interleukin-6 responses were inhibited, natural killer cell cytotoxicity increased dramatically. CONCLUSIONS: These data provide the first in vivo evidence in human for an immunomodulatory effect of dehydroepiandrosterone. The salutary immune changes could account for clinical and experimental evidence of antioncogenic effects of this steroid. This study provides a strong rationale for further clinical studies on dehydroepiandrosterone supplementation in adrenal androgen-deficient states.

Aged↗
PubMed1993

The effect of gastric pH on the absorption of controlled-release theophylline dosage forms in humans.

The bioavailability of three marketed controlled-release dosage forms and a reference solution of theophylline was studied in eight subjects with normal gastric fluid acidity and seven subjects who were achlorhydric. Gastric pH was monitored with a Heidelberg capsule. One of the controlled-release dosage forms dissolved more rapidly in vitro when exposed to acid conditions, one dissolved more rapidly in pH 7.5 media, and the third dissolved at a rate independent of pH. Using a crossover design, each subject received each dosage form twice. Blood was sampled for up to 47 hr after each dose, and serum was assayed for theophylline by HPLC. The product which dissolved more rapidly under acid conditions in vitro exhibited a 3 hr longer Tmax in the achlorhydrics compared to the normal subjects. The product which dissolved more rapidly in the pH 7.5 media exhibited a relatively higher AUC(0-infinity) in the achlorhydric subjects than in normal subjects after the AUC data were normalized for clearance differences between the two subject groups. The in vivo bioavailability of these dosage forms could be related to the in vitro dissolution characteristics for some parameters. However, with the exception of the mean Tmax values, the mean bioavailability parameters differed by less than 20% between the two subjects groups.

Absorption↗
PubMed1993

Biopharmaceutical factors in seizure control and drug toxicity.

Problems related to bioequivalence and bioavailability for four antiepileptic drugs (AEDs) are reviewed. Bioequivalence and bioavailability of AEDs can be affected by many factors, including physicochemical characteristics of the agent, the dosage form, and physiological condition of the patient. In 1988, breakthrough seizures prompted an FDA investigation of one company's generic carbamazepine tablets. Results indicated that the manufacturer had changed its source of carbamazepine, which led to a wide range of dissolution characteristics for different lots of tablets. In two separate studies, clonazepam was shown to be more rapidly absorbed in patients with a normal gastric pH than in those with a higher-than-normal gastric pH. With phenytoin, which exhibits nonlinear pharmacokinetics, differences in the rate and extent of absorption can adversely affect the bioavailability of this agent. Finally, the bioequivalence of generic primidone was contested in an adolescent girl who appeared to experience more frequent seizures with a generic product than with a trade formulation. The effectiveness of a drug depends on complex interactions involving the drug, the drug product formulation, and the patient. Minimizing variability in the absorption process is particularly important with AEDs, because of their narrow therapeutic range.

Anticonvulsants↗
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↗