Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males.

AIMS: The aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of bimosiamose disodium (TBC1269Z) administered by inhalation. METHODS: Two randomized, double-blind, placebo-controlled Phase I trials were performed in healthy males. In a single-dose escalating study 48 subjects received doses of 2-140 mg bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8-70 mg bimosiamose disodium twice daily. In both studies 4 ml of the drug solution was administered via nebulizer over 15 min. Adverse events, vital signs, ECG, clinical laboratory parameters and forced expiratory volume in 1 s (FEV(1)) data were recorded and nasopharyngeal examinations were performed to address the safety and tolerability. Blood was collected for the determination of plasma concentrations of bimosiamose. RESULTS: All subjects completed the study. No deaths or severe adverse events occurred. Eleven mild adverse events occurred in the dose-escalation study and 34 in the multiple-dose study after inhalation of bimosiamose disodium. Adverse events were more frequent at the highest dose (140 mg) of the dose-escalation study. For placebo treatment one moderate adverse event was observed in the dose-escalation study after placebo treatment, eight mild and three moderate adverse events occurred in the multiple-dose study. Bimosiamose was detected in plasma (maximum concentration 64 ng ml(-1)) only at doses > or =50 mg given twice daily and 105 mg once daily. For the highest dose a median value of 5746 h ng ml(-1) was determined for the AUC over the entire period of treatment of the multiple-dose study. CONCLUSION: The results suggest that single and multiple inhalation of bimosiamose disodium up to 70 mg is well tolerated in healthy males. Systemic bioavailability after inhalation is low.

Analysis of micronuclei in the transferrin-receptor positive reticulocytes from peripheral blood of nasopharyngeal cancer patients undergoing radiotherapy by a single-laser flow cytometer.

The automated micronucleus test is now accepted as a simple, objective, and accurate method for evaluating potential mutagenic effects caused by physical, chemical or biotic factors. This paper describes a single-laser flow cytometry, based on an immunomagnetic isolation technique in combination with acridine orange staining, to detect frequencies of micronucleated transferrin-receptor positive reticulocytes from human peripheral blood. Using this flow cytometric system, we detected the frequencies of micronucleated transferrin-receptor positive reticulocytes from 10 nasopharyngeal cancer patients undergoing radiotherapy and the baseline of the frequencies of micronucleated transferrin-receptor positive reticulocytes from 7 healthy donors. The results showed that the mean frequency of micronucleated transferrin-receptor positive reticulocytes from healthy donors was 0.236% and that from nasopharyngeal cancer patients before radiotherapy was 0.297%. After radiotherapy it was significantly elevated. When the cumulative dose of radiotherapy was about 20Gy, it reached a maximum of 6.905%, and then, as the cumulative dose of radiotherapy continued to increase to 30Gy, 40Gy and 50Gy, the frequency decreased to 6.258%, 5.119% and 5.007% respectively. Our results indicated that the single-laser flow cytometric system was quick, reasonable and acceptable for detecting the frequency of micronucleated transferrin-receptor positive reticulocytes from human peripheral blood.