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Biomedical subjects

S R Cox

Publications and source records attributed to S R Cox.

29 records · Page 2Linked to original sources
PubMed1987

Excretion of flurbiprofen into breast milk.

The extent of flurbiprofen's excretion into mature (postcolostrum) breast milk was evaluated in 10 healthy, nursing mothers after administration of a single 100-mg tablet. Samples of milk and blood were subsequently obtained over a 48-hour period and assayed for flurbiprofen by high-performance liquid chromatography. The average peak plasma flurbiprofen concentration, 15 micrograms/ml, occurred at 1.5 hours, and the harmonic mean half-life of the drug was 5.8 hours. The average peak milk concentration of flurbiprofen was 0.09 microgram/ml, and the maximum recovery of the dose in breast milk was only 0.07%.

Adolescent↗
PubMed1987

Relationships between thromboxane production, platelet aggregability, and serum concentrations of ibuprofen or flurbiprofen.

Arachidonate-induced ex vivo platelet aggregations were performed before and after subjects received various doses of either ibuprofen or flurbiprofen. Both ibuprofen and flurbiprofen reduced the initial rate of thromboxane B2 (TxB2) production, but about 10% of control TxB2 production was refractory to either drug. Aggregation was observed after TxB2 concentrations exceeded a threshold of about 40 ng/ml. Once the threshold was achieved, aggregation and TxB2 production occurred independently of either drug. Ibuprofen and flurbiprofen concentrations of about 3 and 0.2 micrograms/ml, respectively, inhibited aggregation during the 5-minute testing period. A pharmacodynamic model was developed that predicts TxB2 production, aggregation lag times, and percent aggregation as a function of the time course of drug concentrations in serum.

Adult↗
PubMed1986

Effects of cimetidine or ranitidine on the pharmacokinetics of flurbiprofen.

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the nonsteroidal anti-inflammatory agent flurbiprofen was studied. Nine healthy volunteers participated in the study. The subjects were divided into three groups, and each group alternated therapy with each of the following treatments: flurbiprofen 200 mg (two 100-mg tablets), flurbiprofen 200 mg plus ranitidine 150 mg two times daily for seven days before and for two days after receiving flurbiprofen, and flurbiprofen 200 mg plus cimetidine 300 mg four times a day for seven days before and for two days after receiving flurbiprofen. Blood samples were collected at time zero and at various intervals during a 48-hour period. Serum flurbiprofen concentrations were determined by high-performance liquid chromatography. No significant differences in elimination rate constant, peak concentration, time to peak concentration, volume of distribution, or elimination half-life were noted among treatments. The difference in area under the curve (AUC) in subjects treated with flurbiprofen alone and in those treated with flurbiprofen plus cimetidine was significant. Two subjects experienced gastric upset; one case was apparently caused by cimetidine, and the other was likely caused by flurbiprofen. Although a significant increase in AUC was observed in subjects receiving flurbiprofen plus cimetidine, the interaction is probably not clinically important.

Adult↗
PubMed1985

Liquid chromatographic assay for fluoxymesterone in human serum with application to a preliminary bioavailability study.

Fluoxymesterone was extracted from serum with a liquid-liquid extraction procedure. Serum containing both drug and internal standard, 6 alpha-methylprednisolone, was extracted with methylene chloride. The extract was washed with 0.1 M NaOH and water, evaporated, and reconstituted with mobile phase. Chromatography was performed on a Zorbax Sil column, preceded by a guard column, with a mobile phase composed of 50% water-saturated butyl chloride:tetrahydrofuran:methanol:phosphoric acid (880:100:15:0.5). Fluoxymesterone and methylprednisolone were detected by UV absorption at 236 nm. Overall recovery was 80%. Calibration curves were linear for fluoxymesterone concentrations from 5 to 100 ng/mL. The assay is accurate and precise (RSD values less than or equal to 7%); endogenous steroids did not interfere with the assay. Assay suitability was assessed in a bioavailability study in which six subjects each received two treatments of 10-mg fluoxymesterone tablets in a Latin-square crossover study. The two treatments were a tablet administered either buccally or orally. Cmax values ranged from 40 to 150 ng/mL with tmax values of 1-2 h. The harmonic mean half-life of fluoxymesterone was 2.0 h. Less than 8% of the AUC was extrapolated. Mean Cmax and AUC values from the oral treatment were 80 and 76%, respectively, of the mean values from the buccal treatment.

Adult↗
PubMed1985

Ibuprofen stereoisomer hepatic clearance and distribution in normal and fatty in situ perfused rat liver.

Ibuprofen is a 2-arylpropionic acid anti-inflammatory agent that undergoes stereoselective chiral inversion (R to S configuration) as well as oxidative metabolism in humans and rats. The present study was undertaken to define more clearly the role of the liver in ibuprofen stereoisomer clearance in both normal and disease states. Liver perfusion experiments were conducted with normal and fatty rat liver; chronic fatty liver was induced by nutritional deficiency and was used as a model of hepatotoxin-induced fatty liver in humans. Total (R)-ibuprofen clearance (ClRtot), chiral inversion-related clearance (ClRinv), (S)-ibuprofen clearance (ClS) and hepatic distribution coefficients for each stereoisomer (KR and KS) were calculated with a model that corrected for perfusate reservoir sampling. In both normal and fatty liver, ClRinv accounted for 60% of ClRtot, but ClRtot was 30% lower in fatty liver than in normal liver (P less than .001). ClS was 40% of ClRtot in normal liver and was not significantly different from the noninversion clearance of (R)-ibuprofen. ClS was unchanged between normal and fatty liver and KS was greater than KR in normal liver (P = .01) but not in fatty liver. The results indicate that the fatty liver condition stereoselectively affects (R)-ibuprofen clearance and eliminates preferential (S)-isomer hepatic distribution. Based on model simulations, these effects are predicted to have minimal impact on total ibuprofen plasma levels or area-under-curve measurements following a dose of rac-ibuprofen unless ClRtot is reduced by more than 50%.

Animals↗
PubMedDate not supplied

Bioavailability studies with ciglitazone in beagles. I. Effect of a meal on the bioavailability of three ciglitazone dosage forms.

Three separate Latin square crossover studies were conducted in beagles to examine the effect of a meal on the bioavailability of a ciglitazone tablet, suspension, and solution. In these studies, drug was administered to fasted animals with either 50 ml water or with 180 g Purina Dog Chow and 20 g butter. The data indicated that the meal significantly increased the AUC by about 40 per cent for both the tablet and the suspension but had no significant effect on the solution treatment. Comparisons across studies indicated low bioavailability in fasted animals from either the tablet or suspension relative to the solution. When drug was co-administered with a meal, however, bioavailability appeared to be independent of dosage form.

Animals↗
PubMedDate not supplied

Bioavailability studies with ciglitazone in beagles. II. Effect of propantheline bromide and metoclopramide HCL on bioavailability of a tablet.

Bioavailability studies in fasted dogs with ciglitazone (CGZ), an oral hypoglycemic agent, suggested that an absorption window could contribute to the poor oral availability of CGZ. If so, propantheline bromide (PPB) could increase the residence time of CGZ at absorption sites and increase its bioavailability. Using this rationale, a Latin square study was conducted with CGZ in fasted dogs (n = 10) using treatments of a single 125 mg tablet with and without 1.2 mg kg-1 i.m. PPB. PPB was given in a single dose 1 h prior to administration of CGZ. Plasma concentrations of CGZ were assayed by HPLC. PPB significantly increased the AUC of CGZ by a ratio of 1.2:1 (p less than 0.01). PPB also increased Tmax from 2-8 h (p less than 0.001), and appeared to produce first order absorption of CGZ. In a separate CGZ study using fasted dogs (n = 10), a single 125 mg tablet was administered with and without i.v. metoclopramide HC1 (MCP). A 10 mg dose of MCP was given 15 min prior to dosing with CGZ and repeated 1 h after dosing. MCP increases GI motility and was expected to decrease residence time of CGZ. MCP had no effect on Tmax, but significantly decreased AUC by 8 per cent (p = 0.05). MCP also reduced Cmax by 16 per cent (p = 0.06). Taken as a whole, these data suggest that the effect of meals to increase bioavailability of CGZ could be mediated at least in part, through an increase in GI residence time.

Animals↗
PubMedDate not supplied

Mechanism for the interaction between triazolam and cimetidine.

Four normal volunteers each received three intraduodenal infusions of 0.5 mg triazolam solutions. Three treatments were: a pH 2.3 solution in which 47 per cent of the dose had hydrolysed to form a triazolo-benzophenone (TB); a pH 6.0 solution containing negligible TB; the pH 6.0 solution administered during cimetidine treatment (1200 mg day-1). TB was stable in serum and only very low TB serum concentrations were observed from the pH 2.3 treatment. No difference was observed in any triazolam pharmacokinetic parameter between the pH 6.0 and the pH 2.3 treatments. Cimetidine increased the triazolam AUC infinity and Cmax by 54 and 35 per cent, respectively. These results indicate that TB undergoes extensive presystemic conversion to triazolam and the triazolam-cimetidine interaction occurs primarily through a reduction in triazolam clearance.

Adult↗
PubMedDate not supplied

Comparative human study of ibuprofen enantiomer plasma concentrations produced by two commercially available ibuprofen tablets.

Twelve healthy male subjects participated in a two-way Latin square crossover study in which the treatments were a single 400 mg generic ibuprofen tablet (Tablet A) or a single 400 mg MOTRIN Tablet (Tablet B). Blood samples were drawn at various times through 12 h after dosing and plasma samples were assayed for ibuprofen enantiomers with a stereospecific capillary gas chromatographic procedure. Concentration-time data for both enantiomers were in agreement and indicated that drug was absorbed much more quickly from Tablet B than from the Tablet A; enantiomer Tmax values were less than 1.3 h from Tablet B but longer than 4 h from the Tablet A (p less than 0.001). Also, maximum enantiomer plasma concentrations from the Tablet B were about 50 per cent of the peak concentrations observed from Tablet A (p less than 0.001). The total extent of drug absorption appeared to be the same in both products. These data clearly indicate that the two tablets are not bioequivalent with respect to either ibuprofen enantiomer.

Adult↗
PubMedDate not supplied

Genomic instability in scleroderma.

Scleroderma is an enigmatic rheumatic disorder of uncertain etio-pathogenesis. Cancer has an approximately two-fold higher incidence in scleroderma patients than in the general population. There are preliminary data of acquired genetic damage in scleroderma but the significance of these observations are uncertain. To determine somatic mutation frequency at the glycophorin-A (GPA) locus in patients with limited and diffuse cutaneous scleroderma. The GPA assay measures the total somatic mutation frequency (Vf), composed of gene inactivating mutations (NO) and mutations arising from mitotic recombination (NN) in individuals heterozygous for the GPA MN blood group. Mutation frequency was determined using a validated GPA flow cytometric assay using fluorescent labeled monoclonal antibodies specific for the GPA blood groups M and N. This assay detects and enumerates progeny of red blood cell (rbc) precursor cells which have acquired genetic damage resulting in a loss of expression of one of the GPA alleles. It was found that patients with scleroderma (n = 23) had significantly elevated Vf as compared with young healthy controls (p < 0.001) and elderly controls (p = 0.03). Patients with diffuse scleroderma had higher mean Vf as compared with limited scleroderma (p = 0.055). In comparison with controls, patients with scleroderma exhibit a higher proportion of mitotic recombinant mutations than inactivating mutations (p < 0.002). There was no correlation between Vf and disease duration, age at onset or autoantibody status. We have documented evidence of acquired genetic damage at the GPA locus in scleroderma. Evidence of acquired genetic damage in this disorder may be importance in explaining both the etio-pathogenesis of scleroderma and the association of scleroderma with cancer.

Adolescent↗