Fasted and fed state human duodenal fluids: Characterization, drug solubility, and comparison to simulated fluids and with human bioavailability.

Accurate in vivo predictions of intestinal absorption of low solubility drugs require knowing their solubility in physiologically relevant dissolution media. Aspirated human intestinal fluids (HIF) are the gold standard, followed by simulated intestinal HIF in the fasted and fed state (FaSSIF/FeSSIF). However, current HIF characterization data vary, and there is also some controversy regarding the accuracy of FaSSIF and FeSSIF for predicting drug solubility in HIF. This study aimed at characterizing fasted and fed state duodenal HIF from 16 human volunteers with respect to pH, buffer capacity, osmolarity, surface tension, as well as protein, phospholipid, and bile salt content. The fasted and fed state HIF samples were further used to investigate the equilibrium solubility of 17 representative low-solubility small-molecule drugs, six of which were confidential industry compounds and 11 were known and characterized regarding chemical diversity. These solubility values were then compared to reported solubility values in fasted and fed state HIF, FaSSIF and FeSSIF, as well as with their human bioavailability for both states. The HIF compositions corresponded well to previously reported values and current FaSSIF and FeSSIF compositions. The drug solubility values in HIF (both fasted and fed states) were also well in line with reported solubility data for HIF, as well as simulated FaSSIF and FeSSIF. This indicates that the in vivo conditions in the proximal small intestine are well represented by simulated intestinal fluids in both composition and drug equilibrium solubility. However, increased drug solubility in the fed vs. fasted states in HIF did not correlate with the human bioavailability changes of the same drugs following oral administration in either state.

Pre-operative femoral nerve block for hip fracture-A systematic review with meta-analysis.

BACKGROUND: Pre-operative pain management of hip fracture patients is complex. Femoral nerve block (FNB) is used for hip fractures to reduce pain and demand for systematic analgesia. The objective of the study was to systematically investigate the efficacy of single-shot FNB for hip fracture patients. METHODS: Five databases were searched from inception until 8 May 2019. We included randomized controlled trials (RCT's) assessing pain relief in patients with hip fractures. Intervention was pre-operative FNB compared to any systemic analgesic (eg opioids, non-steroidal anti-inflammatory drugs or paracetamol). Primary outcomes assessed were pre-operative pain and use of rescue analgesics. Secondary outcome was cognitive impairment. We present a bias assessment, a meta-analysis and a grading of certainty of evidence. RESULTS: We included five trials (n = 254), where participants received FNB 30 minutes or more prior to surgery; all were judged as having high risk of bias. All studies found significantly decreased pain scores at least once in the intervention group compared to the control group. Meta-analysis on the primary outcome of pain showed significance. Mean difference was -2.13 point (in cm) (CI:-3.53,-0.72) on visual analogue scale in the intervention group, but is judged low on certainty. CONCLUSIONS: The quantity of evidence supporting pre-operative single-shot FNB for hip fractures is very low, and the certainty of evidence supporting pre-operative single-shot FNB for hip fractures is low. No studies using ultrasound guided technique were identified. Data on non-ultrasound guided FNB's suggest a decreased pain score compared to the use of systemic analgesia.