Adalimumab is effective and well-tolerated for inducing and maintaining clinical remission in Japanese patients with moderate to severe Crohn's disease.
Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin–antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response.
A positive association between serum adalimumab concentration and remission was identified at several time points. A threshold concentration reliably associated with remission was not identified. Further prospective evaluations are needed before recommendations for adalimumab concentration monitoring can be made.
Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg).
to support physiologic functions, including gastric muco-Cyclooxygenase (COX) exists as two unique isoforms (that is, sal defense and platelet aggregation. The COX-2 isoform COX-1 and COX-2) which are poorly understood with regard also is constitutive in some tissues, but unlike COX-1, to their roles in renal function. The renal effects of conventional this isozyme is markedly induced by bacterial endotoxnon-steroidal anti-inflammatory drugs (NSAIDs) are believed to ins, cytokines and growth factors, and catalyzes the synresult from the inhibition of one or both isoforms. Drugs that selectively inhibit COX-2 provide useful pharmacological tools thesis of pro-inflammatory PGs. for discerning the effects associated with the inhibition of the The antagonism of inflammation and pain by NSAIDs individual isoforms, and may help clarify the renal roles of COX-1 is believed to result from the inhibition of COX-2, while and COX-2. This review summarizes the current data on the the antagonism of gastric mucosal defense and platelet agrenal expression of COX isoforms and their potential roles in gregation are the results of COX-1 inhibition [5-7]. Clinirenal function, and reviews the studies that have attempted to correlate renal functional changes with selective isoform cal doses of NSAIDs non-selectively inhibit COX-1 and inhibition. Since there are significant differences in the expres-COX-2 [8-13]. Thus, therapeutic use of these rather usesion of COX isoforms in the kidneys of laboratory animals and ful drugs is limited by significant clinical toxicity, includhumans, this review also examines the correlation of the results ing gastrointestinal (GI) ulceration, perforation, obstrucof COX inhibition in experimental studies in laboratory anition, and bleeding. Drugs that selectively inhibit COX-2 mals with clinical data. Because of potential interspecies differences in the roles of COX isoforms in renal function, animal now are available, including celecoxib (Celebrex), valmodels may have limited predictive value for patients, particudecoxib (Bextra), and rofecoxib (Vioxx). These possess larly those with renal risk factors. Accordingly, any uncertainty anti-inflammatory properties similar to naproxen, ibuproconcerning the safety or therapeutic benefit of COX-2-specific fen, and diclofenac; but unlike conventional non-selective drugs in these patient populations will need to be resolved with NSAIDs, they spare COX-1 at clinical doses. This greatly clinical investigations.
Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate.
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