These experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.
The novel method showed satisfactory assay performance in addition to drastically reduced analysis times and improved ease of use as compared to other methods. Clinical utility of HDL 2b was demonstrated supporting the findings of previous studies.
Lactate threshold is an important reference point when setting training intensities for endurance athletes. Ventilatory threshold has been used as a noninvasive estimate of lactate threshold, but appears to underestimate training intensity for many athletes. This study evaluated whether data obtained during a noninvasive, maximal exercise test could be used to predict lactate threshold. Maximal oxygen consumption (55+/-2 ml O(2) x kg(-1) x min(-1)) and heart rate at the ventilatory threshold (V-slope method) were determined for 19 cyclists (10 men, 9 women, 35+/-2 years). Cyclists also performed a lactate threshold test, consisting of 8 min stages at power outputs below, at, and above the ventilatory threshold. Heart rate associated with the lactate threshold was determined using the Dmax method. The correlation coefficient between heart rates at the ventilatory and lactate thresholds was 0.67, indicating 45% shared variance. The best fitting model to predict heart rate at the lactate threshold included heart rate at the ventilatory threshold, gender, body weight, and an interaction between gender and body weight. Using this model, R(2) was 0.70. Thus, heart rate at the ventilatory threshold may be adjusted to more accurately predict a heart rate that corresponds to the lactate threshold for recreational cyclists.
GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 µg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 µg/kg) serum t 1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t 1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 µg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (
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