The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.

BACKGROUND: Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. AIM: To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. METHODS: After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7α-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. RESULTS: In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133-237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (-24% after 2 weeks treatment, P = 0.03), stool form (-14%, P = 0.05) and diarrhoea index (-34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL-cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. CONCLUSIONS: This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025.

Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention.

BACKGROUND: Bile acid diarrhoea is a common, under-diagnosed cause of chronic watery diarrhoea, responding to specific treatment with bile acid sequestrants. We previously showed patients with bile acid diarrhoea have lower median levels compared with healthy controls, of the ileal hormone fibroblast growth factor 19 (FGF19), which regulates bile acid synthesis. AIM: To measure serum FGF19 and SeHCAT retention prospectively in patients with chronic diarrhoea. METHODS: One hundred and fifty-two consecutive patients were grouped according to (75) Se-homocholic acid taurine (SeHCAT) 7-day retention: normal (>15%) in 72 (47%) diarrhoea controls; ≤15% in 54 (36%) with primary bile acid diarrhoea, and in 26 (17%) with secondary bile acid diarrhoea. Fasting blood was assayed for FGF19, 7α-hydroxy-4-cholesten-3-one (C4) and total bile acids. RESULTS: FGF19 was significantly lower in the primary bile acid diarrhoea group compared with the diarrhoea control group (median 147 vs. 225 pg/mL, P < 0.001), and also in the secondary group (P < 0.006). FGF19 and SeHCAT values were positively correlated (rs = 0.44, P < 0.001); both were inversely related to C4. Other significant relationships included SeHCAT and body mass index (BMI)(P = 0.02), and FGF19 with age (P < 0.01). The negative and positive predictive values of FGF19 ≤ 145 pg/mL for a SeHCAT <10% were 82% and 61%, respectively, and were generally improved in an index including BMI, age and C4. In a subset of 28 primary patients, limited data suggested that FGF19 could predict response to sequestrant therapy. CONCLUSIONS: Reduced fibroblast growth factor 19 is a feature of bile acid diarrhoea. Further studies will fully define its role in predicting the response of these patients to therapy.

Prehospital and resuscitative airway care: should the gold standard be reassessed?

In the context of prehospital care and resuscitation, tracheal intubation has been regarded as the standard in airway treatment. The evidence for this status is rather weak. It does not take into account the level of training and experience of the personnel attempting intubation, and whether they use neuromuscular blockers. In unskilled hands, attempted tracheal intubation is harmful; unrecognized esophageal intubation is disastrous. When healthcare providers lack adequate skills in tracheal intubation, alternative airway devices, such as the laryngeal mask airway or the Combitube, may be better options than a simple facemask. Healthcare personnel using any of these devices should be adequately trained and maintain frequent practice.

Conceptual organization and memory in nonretarded, mildly retarded, and moderately retarded adults.

Moderately retarded, mildly retarded, and nonretarded adults learned a list of 12 items from three categories to a criterion of 75% correct recall in a free-recall learning paradigm. Retention was measured 1 week later. The moderately retarded took more trials and had lower retention and clustering scores than the others. The mildly retarded took more trials and had lower retention than the nonretarded. The results violate Murdock's total time hypothesis (Cooper & Pantle, 1967) but support Mandler's (1967) contention that learning is enhanced by the mental capacity for organization.

The effects of fading procedures on discrimination shifts.

Human discrimination learning is frequently characterized as a "two-link process" consisting of an instrumental response and a covert dimensional attention or mediation response. In subsequent conceptual shift problems, reversal shift facilitation is attributed to partial reinforcement of the covert response in the original problem. Unlike standard trial and error learning conditions, a fading design eliminated the partial reinforcement of covert responding and, consistent with the hypothesis, reduced reversal shift facilitation. Although fading procedures facilitate discrimination learning, they may retard subsequent trial and error learning, a cost that warrants further exploration. Trial and error conditions produced the expected reversal facilitation.

MSH/ACTH 4-10 influences behavioral and physiological measures of attention.

Eleven healthy male volunteers were infused with MSH/ACTH 4-10 and a control solution in a completely crossed and balanced procedure. Perception, attention and memory were tested as were heart rate and cephalic pulse amplitude in response to changes in the environment. Treatment of subjects with MSH/ACTH 4-10 raised their perceptual threshold for detection of simple stimuli and facilitated perceptual integration of patterned information. Administration of the heptapeptide improved the subjects' ability to discriminate tests of relevant from irrelevant information and augmented the heart-rate deceleratory response during presentation of novel stimuli. It was speculated that MSH/ACTH 4-10 has a predominant influence on attentional processes and that it may be uniquely coded for attentional/perceptual functioning.

Neuropeptide MSH/ACTH 4-10 enhances attention in the mentally retarded.

Twenty adult mentally retarded men were randomly assigned to receive MSH/ACTH 4-10 or a vehicle control solution in a double blind procedure. After an intravenous injection the subjects were presented with an orienting sequence and a series of behavioral tests. Treatment with the peptide resulted in a significant decelerative heart rate response during the test stimulus of the orienting sequence. Improved performance of the intradimensional and extradimensional shift of a visual discrimination procedure was significant for subjects receiving MSH/ACTH 4-10. The pattern of response on the subproblem analysis of the extradimensional shift reflected greater dimensional attention in the subjects treated with the peptide. Attentive subjects given MSH/ACTH 4-10 evidenced significant improvement on a rhythm matching test, a test of spatial localization and a visual retention test. The data were interpreted as indicating that the peptide resulted in improved attention of stimulus processing. It was speculated that MSH/ACTH 4-10 may be unquely coded for perceptor/attentional functioning and may be useful as a treatment for disorders of attention.

Enhancement of attention in man with ACTH/MSH 4-10.

Normal men were infused for 4 hr with ACTH/MSH 4-10 or a control solution. Behavioral testing after the infusion indicated that subjects who received ACTH/MSH 4-10 were less anxious and had better visual memory than control subjects but the predominant effect of the heptapeptide was to increase visual attention. It was speculated that ACTH/MSH 4-10 may be uniquely coded for attentional functioning.