47 research outputs found
Replication of functional serotonin receptor type 3A and B variants in bipolar affective disorder: a European multicenter study
Serotonin type 3 receptors (5-HT3) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P=0.009, 95% confidence intervals=0.802–0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR=0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT3 receptor function in BPAD
Genetic polymorphisms and their association with brain and behavioural measures in heterogeneous stock mice
UK Medical Research Council Career Establishment Award (G0000170) to LS, MRC PhD Studentship Award to MJ (MR/J500380/1) and EU-FP7 Marie Curie ITN EpiTrain (REA grant agreement n° 316758) to SJM
T is associated with severe dyspepsia
Contains fulltext :
96333.pdf (publisher's version ) (Open Access
Natural compounds boldine and menthol are antagonists of human 5-HT
Background Impaired 5-HT3 receptor function is likely involved in the pathogenesis of functional gastrointestinal disorders (FGID) and 5-HT3 receptor antagonists are effective treatments for chemotherapy-induced nausea and vomiting (CINV) and irritable bowel syndrome (IBS). The monoterpene alcohol menthol and the aporphine alkaloid boldine combat symptoms of gastrointestinal diseases; both interact with other members of the Cys-loop ligand-gated ion channel family and may therefore also act on 5-HT3 receptors. Methods The impact of boldine and menthol on human recombinant homomeric 5-HT(3)A- and heteromeric 5-HT(3)AB receptors in HEK293 cells was determined by radioligand binding, a luminescence-based Ca2+ assay, and a membrane potential assay. 5-HT3 protein and mRNA expression was assessed in human colon tissue. Key Results Boldine and menthol inhibited the 5-HT-induced activation of 5-HT3 receptors in the low and middle micromolar range, respectively. Boldine was a competitive antagonist of both receptors being 6.5- to 10-fold more potent at 5-HT(3)A- vs 5-HT(3)AB receptors. Menthol non-competitively and stereoselectively inhibited both receptors: In contrast to (+)-menthol, (-)-menthol was significantly more potent toward 5-HT(3)A- vs 5-HT(3)AB receptors. We show co-expression of 5-HT3A and 5-HT3B subunits in the human gut epithelium, the lamina propria, the myenteric plexus, and the muscular cell layer. Conclusions & Inferences The demonstrated 5-HT3 inhibitory effects may be relevant for boldine's and menthol's alleviating properties on FGID and may encourage clinical studies with the compounds or the plant extracts for CINV and IBS treatment. The found receptor-discriminative properties make boldine and (-)-menthol to potentially useful tools for analyzing structural differences between these receptor subtypes
The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference
The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by
the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised
together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop
US-FDA joined as co-sponsor – to support global harmonisation of regulatory recommendations for bioequivalence
(BE) assessment.
At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main
conclusions were drawn:
(1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly
variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to
support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a
majority of the workshop participants were in favour of a more frequent application of such approaches. The
regulatory conditions relevant in this context need further concretisation and harmonisation between the regions.
Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE
development programmes.
(2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed
only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously,
BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants
or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions.
Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation
of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in
fed state.
(3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential
benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In
addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.
g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and,
despite significant progress already achieved during previous years, more research is needed before they may be
fully accepted for regulatory purposes.
(4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in
necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure
into BE assessment with more restrictive criteria and the importance of comparison of the product-related within subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were
presented and discussed but need further consideration before harmonisation can be achieved.
The highly interactive meeting and extensive exchange between regulators and scientists from industry and
academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation