Diclofenac plasma protein binding: PK-PD modelling in cardiac patients submitted to cardiopulmonary bypass

Abstract

Twenty-four surgical patients of both sexes without cardiac, hepatic, renal or endocrine dysfunctions were divided into two groups: 10 cardiac surgical patients submitted to myocardial revascularization and cardiopulmonary bypass (CPB), 3 females and 7 males aged 65 ± 11 years, 74 ± 16 kg body weight, 166 ± 9 cm height and 1.80 ± 0.21 m 2 body surface area (BSA), and control, 14 surgical patients not submitted to CPB, 11 female and 3 males aged 41 ± 14 years, 66 ± 14 kg body weight, 159 ± 9 cm height and 1.65 ± 0.16 m 2 BSA (mean ± SD). Sodium diclofenac (1 mg/kg, im Voltaren 75 ® twice a day) was administered to patients in the Recovery Unit 48 h after surgery. Venous blood samples were collected during a period of 0-12 h and analgesia was measured by the visual analogue scale (VAS) during the same period. Plasma diclofenac levels were measured by high performance liquid chromatography. A two-compartment open model was applied to obtain the plasma decay curve and to estimate kinetic parameters. Plasma diclofenac protein binding decreased whereas free plasma diclofenac levels were increased five-fold in CPB patients. Data obtained for analgesia reported as the maximum effect (E MAX ) were: 25% VAS (CPB) vs 10% VAS (control), P<0.05, median measured by the visual analogue scale where 100% is equivalent to the highest level of pain. To correlate the effect versus plasma diclofenac levels, the E MAX sigmoid model was applied. A prolongation of the mean residence time for maximum effect (MRTE MAX ) was observed without any change in lag-time in CPB in spite of the reduced analgesia reported for these patients, during the time-dose interval. In conclusion, the extent of plasma diclofenac protein binding was influenced by CPB with clinically relevant kinetic-dynamic consequences.

Synthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma

“…We also observed similar, though less robust, results in our screen with celecoxib in combination with sorafenib, suggesting that diclofenac was acting as a COX inhibitor. The sorafenib and diclofenac combination showed synergy in most cell lines tested at physiologically relevant doses (17,18). Both drugs are well tolerated and FDA approved (19,20).…”

An Update to Dialysis-Based Drug Release Testing—Data Analysis and Validation Using the Pharma Test Dispersion Releaser

“…The BSA molecule binds diclofenac with high affinity through ionic and hydrophobic interactions using two unspecific binding sites [30]. A direct comparison between BSA and human serum albumin (HSA) resulted in minor differences between these two proteins, and the plasma protein binding in humans was reported to be 99% [31]. Therefore, in equilibrium, diclofenac is expected to be bound to proteins at a stoichiometric ratio of 2:1 [30,32].…”

Single dose parecoxib significantly improves ventilatory function in early extubation coronary artery bypass surgery: a prospective randomized double blind placebo controlled trial

“…Whilst beneficial opioid sparing effects (typically 40% opioid sparing in first 24 h) have been demonstrated with indomethacin, none of the studies have specifically considered the value of non-steroidal agents in the immediate periextubation period. [3][4][5][6] No previous study has prospectively evaluated the potential benefit of opioid sparing on ventilatory function during the period of spontaneous ventilation preceding tracheal extubation. Arguably if opioids contribute to postoperative respiratory depression, opioid sparing analgesia should improve ventilatory function and provide earlier recovery.…”