Evaluation of separate role of intestine and liver in first pass metabolism of budesonide in rat

1. Budesonide, a potent topical corticosteroid, reported to have low oral bioavailability in mice, rat, dog and human due to rapid first pass metabolism. However, there is insufficient information available in literature regarding the role of intestine and or liver responsible for the first pass metabolism of budesonide.

2. Current study in rats investigates the role of intestine and liver in first pass metabolism of budesonide using two in vivo models. Additionally, budesonide was also evaluated in in vitro assays such as thermodynamic solubility, permeability in Caco-2 cells and stability in simulated gastric (SGF), intestinal fluids (SIF) to understand the underlaying cause for low oral bioavailability.

3. Budesonide showed low oral, intra-duodenal and high intra-portal bioavailability in rat. In a dual vein cannulated rat model, intestinal and hepatic extraction ratios calculated based upon intestinal availability (Fa·Fg) and hepatic availability (Fh), suggests hepatic extraction of budesonide is minimal compared to intestinal.

4. In vitro results suggest, solubility and permeability may not be a barrier for the observed low oral bioavailability in rats.

5. Correlating the in vitro and in vivo data together, it can be concluded that, intestine might be playing major role in first pass metabolism of budesonide.     

Validity and Reliability of the Fear-Avoidance Beliefs Questionnaire (FABQ) in Workers with Upper Extremity Injuries

Introduction Fear Avoidance Beliefs (FAB) have been associated with increased pain, dysfunction and difficulty returning to work in Upper Extremity (UE) injures. The FABQ is used to assess FAB, but its measurement properties have not been established in UE. The purpose of this study is to evaluate the reliability and validity of the FABQ to screen UE compensated injured workers for FAB. Methods Consenting workers attending a specialty clinic completed a modified FABQ, QuickDASH (Disability), SPADI Pain Score and von Korff Chronic Pain Grade (Pain), SF-36v2 (General Health), and Work Instability Scale (Job Instability). A sub-sample of workers (n = 48) completed the FABQ 2 weeks later for test–retest reliability. Results 187 workers; 54.0% male; mean age 45.2 (sd 9.68); 56% were currently working. Mean subscale scores (FABQ-Work [FABQ-W]/FABQ-Physical Activity [FABQ-PA]) were 35/42 and 20/24. Ceiling effects (23%/38%) existed in both subscales. Cronbach’s alphas were 0.75/0.78. Test–retest analysis (ICC(2,1)) was lower than desired (0.52/0.59). Construct validation was supported by a moderate correlation between FABQ-W/FABQ-PA and QuickDASH Work Module (0.51/0.42) and WIS (0.46/0.38) in those currently working. Low correlations were found between the subscales measures of pain (SPADI: 0.24/0.23; Chronic Pain Grade: 0.25/0.25), and SF-36 MCS (−0.25/−0.30). Conclusions Although FAB is an important concept to measure in compensated UE injured workers, the FABQ had limitations in this population as there was a high ceiling effect, and lower than desired reliability for individual discrimination. A priori hypotheses around construct validity were rejected for 16/22 concepts tested.     

Use of plasma level monitoring of antidepressants in clinical practice. Towards an analysis of clinical utility.

The use of therapeutic drug monitoring (TDM) in the authors' hospital was studied for various antidepressants (maprotoline, clomipramine, imipramine, desipramine, nortriptyline, amitriptyline) in a two part-study (retrospective and prospective). Criteria for appropriate requests for TDM from the resident psychiatrists and for appropriate interpretation of the results were defined according to a clinical effectiveness/toxicity model. For this purpose, a "therapeutic window" (between 150 and 250 ng/ml) was chosen. Whereas the quality of the TDM requests varied in the two studies (41% and 26% inappropriate requests in the retrospective and prospective study respectively), the interpretation of the results was the same in the two studies (19% inappropriate therapeutic adjustments). Considering both the inappropriate requests and the inappropriate therapeutic adjustments, if appears that 52% of the assays in the retrospective study and 40% in the prospective study are inappropriate. In common with previous studies with other drugs, the present study concludes that the use of the antidepressant TDM could be improved. To this end, closer attention must be given to the nature of TDM requests.