Roles of basophils and mast cells infiltrating the lung by multiple antigen challenges in asthmatic responses of mice.

BACKGROUND AND PURPOSE: Mast cell hyperplasia has been observed in the lungs of mice with experimental asthma, but few reports have studied basophils. Here, we attempted to discriminate and quantify mast cells and basophils in the lungs in a murine asthma model, determine if both cells were increased by multiple antigen challenges and assess the roles of those cells in asthmatic responses. EXPERIMENTAL APPROACH: Sensitized Balb/c mice were intratracheally challenged with ovalbumin four times. Mast cells and basophils in enzymatically digested lung tissue were detected by flow cytometry. An anti-FcεRI monoclonal antibody, MAR-1, was i.p. administered during the multiple challenges. KEY RESULTS: The numbers of both mast cells (IgE(+) C-kit(+) ) and basophils (IgE(+) C-kit(-) CD49b(+) ) increased in the lungs after three challenges. Treatment with MAR-1 completely abolished the increases; however, a late-phase increase in specific airway resistance (sRaw), and airway eosinophilia and neutrophilia were not affected by the treatment, although the early-phase increase in sRaw was suppressed. MAR-1 reduced antigen-induced airway IL-4 production. Basophils infiltrating the lung clearly produced IL-4 after antigen stimulation in vitro; however, histamine and murine mast cell protease 1 were not increased in the serum after the challenge, indicating that mast cell activation was not evoked. CONCLUSION AND IMPLICATIONS: Both mast cells and basophils infiltrated the lungs by multiple intratracheal antigen challenges in sensitized mice. Neither mast cells nor basophils were involved in late-phase airway obstruction, although early-phase obstruction was mediated by basophils. Targeting basophils in asthma therapy may be useful for an early asthmatic response.

Urinary 11-dehydro-thromboxane B2: a quantitative index of platelet activation in cerebral infarction.

Thromboxane A2 (TXA2) biosynthesis was studied in healthy subjects, patients with chronic cerebral infarction, patients under chronic aspirin treatment and patients with atrial fibrillation. Urinary 11-dehydro-TXB2, as a major metabolite of TXA2, was measured by radioimmunoassay. The extent of carotid atherosclerosis was determined by B-mode ultrasonography. The mean +/- SD urinary excretion in patients with cerebral infarction and distinct carotid-atherosclerotic lesions (1,725 +/- 239 ng/g creatinine, n = 6) was significantly higher (p less than 0.01) than in healthy subjects (911 +/- 239 ng/g creatinine, n = 44) and patients with cerebral infarction who had no distinct carotid lesion (1,050 +/- 191 ng/g creatinine, n = 6). The urinary excretion of healthy subjects was higher (p less than 0.01) in smokers (1,063 +/- 244 ng/g creatinine, n = 17) than in non-smokers (815 +/- 183 ng/g creatinine, n = 27). Aspirin largely suppressed 11-dehydro-TXB2 excretion (266 +/- 114 ng/g creatinine, n = 7). Three of 5 patients with atrial fibrillation showed very high values. Our results indicated that platelet activation occurs in the atherosclerotic lesions, and that urinary 11-dehydro-TXB2 is the appropriate analytic target for detecting platelet activation.

Clinical pharmacokinetics and tolerance of fleroxacin in healthy male volunteers.

The tolerance and pharmacokinetics of fleroxacin were studied in healthy male adult volunteers. The peak serum concentrations of unchanged fleroxacin were about 1.5, 3 and 5 mg/l at 1-2 h after single oral doses of 100, 200 and 400 mg, respectively. The apparent serum elimination half-life was about 10 h, independent of the dose. Fleroxacin, demethyl fleroxacin and fleroxacin N-oxide excreted in urine over 3 days accounted for about 75%, 5% and 5%, respectively, of the doses. The urine concentrations of unchanged drug were dose-related; the mean concentrations, sustained over 24 h, were about 50, 100 and 150 mg/l after 100, 200 and 400 mg doses, respectively. Food intake did not significantly influence the serum concentration and urinary excretion. Steady state serum concentrations were achieved from day 3 onwards by repeated doses of twice-a-day dosage regimen and were 2-4 and 5-9 mg/l after 200 and 400 mg bid, respectively. The mean concentrations of unchanged drug in urine were about 200 and 300 mg/l at the respective dosages. The pattern of urinary metabolites was not changed by repeated doses and 90% of repeat doses was recovered in urine, including metabolites. The serum protein binding of fleroxacin was 32%. The saliva concentration was 40% of the total serum concentration or 60% of the free serum concentration. The faecal recovery over 3 days was 3% of the dose following a single 200 mg dose after a meal. The unchanged drug concentrations in faeces during 400 mg repeated dosing were 100-150 mg/kg. No severe dose-related side-effects were observed during the study.