Biomedical subjects

M D Singleton

Publications and source records attributed to M D Singleton.

4 recordsLinked to original sources

PubMed2001

Pharmacokinetics of para-aminosalicylic acid granules under four dosing conditions.

OBJECTIVE: To determine the pharmacokinetics and relative bioavailability of para-aminosalicylic acid (PAS) granules. DESIGN: Phase I pharmacokinetics study. SETTING: University of Arizona School of Pharmacy. PARTICIPANTS: Sixteen healthy male and female volunteers aged 36 +/- 8 years. INTERVENTIONS: Subjects received single doses of PAS granules (6 g) combined with cycloserine 500 mg, clofazimine 200 mg, ethionamide 500 mg, and pyridoxine 100 mg. Drugs were given on an empty stomach after an overnight fast (reference) with high-fat food, with orange juice, and with antacids. MEASUREMENTS AND RESULTS: Four subjects did not complete all four treatments due to adverse events or personal reasons. Plasma and urine samples were collected for 48 hours and measured by a validated HPLC assay. Pharmacokinetic data analysis was performed with WinNonlin using noncompartmental methods and a one-compartmental model. Bioequivalence testing was performed using the mean ratios of the maximum concentrations (Cmax) and AUC(0-infinity) of PAS, with 90% confidence intervals. Compared with the fasted condition, food increased Cmax 1.5-fold and AUC(0-infinity) 1.7-fold, and it doubled the time to maximum concentration (tmax). The least-squares mean ratios (treatment/reference) for Cmax were 0.90 (58% to 139% CI), 1.16 (75% to 179% CI), and 0.82 (52% to 127% CI) with orange juice, food, or antacid treatment, respectively. Corresponding ratios for AUC(0-infinity) were 1.05 (71% to 155% CI), 1.52 (103% to 224% CI), and 0.84 (57% to 125% CI), respectively. CONCLUSIONS: Food significantly enhanced the absorption of PAS, while orange juice and antacids had minor effects.

Adult↗

PubMed1999

Once-daily and twice-daily dosing of p-aminosalicylic acid granules.

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.

Adolescent↗

PubMed1999

Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids.

STUDY OBJECTIVES: Determine the intrasubject and intersubject variability in, and the effects of food or antacids on, the pharmacokinetics of rifampin (RIF). DESIGN: Randomized, four-period crossover phase I study. SUBJECTS: Fourteen healthy male and female volunteers. INTERVENTIONS: Subjects ingested single doses of RIF, 600 mg, under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. They also received standard doses of isoniazid, pyrazinamide, and ethambutol. MEASUREMENTS AND MAIN RESULTS: Serum was collected for 48 h and assayed by high-pressure liquid chromatography. Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean RIF maximal serum concentration (Cmax) of 10.54+/-3.18 microg/mL, the time at which it occurred (Tmax) of 2.42+/-1.32 h, and the area under the curve from time zero to infinity (AUC0-infinity) of 57.15+/-13.41 microg x h/mL. These findings are similar to those reported previously. Antacids did not alter these parameters (Cmax of 10.89+/-5.22 microg/mL, Tmax of 2.36+/-1.28 h, and AUC0-infinity of 58.37+/-18.49 microg x h/mL). In contrast, the Food and Drug Administration high-fat meal reduced RIF Cmax by 36% (7.27+/-2.29 microg/mL), nearly doubled Tmax (4.43+/-1.09 h), but reduced AUC0-infinity by only 6% (55.20+/-14.48 microg x h/mL). CONCLUSIONS: These changes in Cmax, Tmax, and AUC0-infinity can be avoided by giving RIF on an empty stomach whenever possible.

Adult↗

PubMed1996

Permissive recognition during positive selection.

In the periphery alpha beta T lymphocytes recognize antigens in conjunction with major histocompatibility complex (MHC) molecules. In the thymus immature T cells are positively selected on MHC molecules in the apparent absence of cognate peptides. Thus, at different developmental stages a T cell responds to different epitopes, yet uses the identical alpha beta T cell antigen receptor (TcR). To explain this paradox it has been hypothesized that during positive selection immature T cells see peptides/ligands unique to the thymus, are selected by specific antagonists related to their cognate peptides, or are driven by lowered affinity thresholds of their TcR. Though different in detail, these theories rely on defined peptides uniquely matched to select certain TcR. However, we find that in a TcR-transgenic (TcR(trans +)) mouse severely limiting the diversity of peptides does not impair positive selection. We show that many unrelated peptides, including some naturally occurring on the cell surface, induce maturation of CD4-CD8+TcR(high) thymocytes. The same peptides when presented in conjunction with the selecting MHC molecule, are not recognized by peripheral T cells expressing the same TcR(trans). Therefore, these findings point to a promiscuous rather than discriminate recognition mode used by immature T cells.

Amino Acid Sequence↗