Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Oct 2002
Randomized Controlled Trial Comparative Study Clinical TrialPharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans.
Inhibition of the tissue factor-factor VIIa pathway attenuated the activation of coagulation and prevented death in a gram-negative bacteremia primate model of sepsis. This lethal animal model suggested that tissue factor also influences inflammatory cascades. ⋯ In summary, ASIS effectively and selectively attenuates tissue factor-induced thrombin generation. Because ASIS was well tolerated, this study provides seminal data to further characterize its anticoagulant and putative anti-inflammatory effects in critically ill patients.
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Clin. Pharmacol. Ther. · Aug 2002
Randomized Controlled Trial Clinical TrialPeripheral prostanoid levels and nonsteroidal anti-inflammatory drug analgesia: replicate clinical trials in a tissue injury model.
Nonsteroidal anti-inflammatory drug (NSAID) analgesia is generally attributed to peripheral suppression of cyclooxygenase (COX) enzymes, leading to decreased products of the arachidonic acid cascade. This study evaluated the in vivo relationship between levels of prostanoids at the site of tissue injury and analgesia after systemic or local NSAID administration in a clinical model of tissue injury. ⋯ The temporal profile of PGE(2) and TxB(2) in the immediate postoperative period is consistent with constitutive COX-1 initially, followed by an increase in PGE(2) resulting from expression of COX-2. The temporal association between NSAID analgesia and decreased prostanoids at the site of injury is consistent with a dual COX-1/COX-2 peripheral site of action. The analgesic effects of 1 mg ketorolac tromethamine without a reduction in PGE(2) at the site of injury suggests an additional central site for NSAID analgesia.
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Clin. Pharmacol. Ther. · Jul 2002
Randomized Controlled Trial Clinical TrialIn vivo selectivity of a selective cyclooxygenase 2 inhibitor in the oral surgery model.
Prostanoids formed by cyclooxygenase play an important role in pain and the induction of inflammation. It is generally believed that COX-1 is constitutively expressed, whereas COX-2 is primarily inducible during inflammation. This study examined the in vivo selectivity of celecoxib, a COX-2 inhibitor, and evaluated whether estimates of selectivity that are based on in vitro and ex vivo analyses are reliable indicators of in vivo selectivity. ⋯ The suppression of products of COX-2 coincident with pain suppression and the absence of COX-1 inhibition suggest that celecoxib is a relatively selective COX-2 inhibitor in vivo.
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Clin. Pharmacol. Ther. · May 2002
Randomized Controlled Trial Comparative Study Clinical TrialDemonstration of dose response of flurbiprofen lozenges with the sore throat pain model.
The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). ⋯ For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent.
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Clin. Pharmacol. Ther. · May 2002
Randomized Controlled Trial Comparative Study Clinical TrialEffects of epinephrine compared with the combination of dobutamine and norepinephrine on gastric perfusion in septic shock.
In septic shock, the alteration of the gut barrier contributes to the development of multiple organ failure. The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock. ⋯ In patients with septic shock, at doses that induced the same mean arterial pressure, epinephrine enhanced more gastric mucosal blood flow than the combination of dobutamine at 5 microg/kg per minute and norepinephrine. This effect was probably a result of higher cardiac index.