Background: Leukotriene B4 (LTB 4 ) has a key role in the pathophysiology of rheumatoid arthritis (RA). Objective: To investigate the inhibition of ex vivo LTB 4 -induced Mac-1 (CD11b/CD18) expression in leucocytes of patients with RA by the new oral LTB 4 receptor antagonist BIIL 284. Methods: The pharmacokinetics and inhibition of LTB 4 -induced Mac-1 expression of BIIL 284 were characterised in 26 adult patients with RA who were treated with BIIL 284 25 mg, 150 mg, or placebo given once a day for 14 days according to a double blind, randomised, parallel group design. Results: T max of BIIL 315 in plasma (main metabolite and active principle of BIIL 284 in plasma) was achieved about four hours after drug administration, and C max,ss and AUC 0-6h,ss increased in proportion to the dosage. 100% inhibition of LTB 4 -induced MAC-1 expression was reached after two hours (150 mg) or four hours (25 mg), showing a statistically significant difference in comparison with placebo (p,0.005). A longlasting dynamic effect was seen consistently even when plasma concentrations declined to very low values 24 hours after administration. Secondary clinical efficacy end points remained unchanged probably owing to the short duration of treatment. Adverse events (AEs) were reported in 12 patients during the study. No serious AEs or laboratory AEs were seen. Conclusions: Both the 25 mg and 150 mg doses of BIIL 284 safely and effectively inhibit Mac-1 expression on neutrophils; thus longer treatment with BIIL 284 may result in clinical benefit for patients with RA.
Systemic and myocardial lactate production occurred at similar systemic oxygen delivery rates in hemodiluted and nonhemodiluted animals. Mixed venous oxygen saturation may be a less reliable indicator of inadequate oxygen delivery during hemodilution.
During progressive normovolemic hemodilution in pigs, hypothermia did not significantly change Hgb(CRIT), but it decreased the Hgb at death, i.e., short-term survival was prolonged.
Cooling to 32 degrees C significantly prolongs the myocardial action potential and the contraction duration. Dopamine increases the contractile force and prolongs the action potential both at 37 degrees C and at 32 degrees C.
isoflurane-induced cardiovascular depression had adverse effects on cardiac output and oxygen delivery during extreme hemodilution because: 1) The vasodilatory effect of isoflurane was insufficient to compensate for the myocardial depression, and also contributed to a critically low arterial blood pressure; 2) A decrease in cardiac output produced delivery-dependent oxygen consumption and hyperlactemia; and 3) A decrease in myocardial blood flow caused myocardial ischemia which may have exacerbated the myocardial depression.
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