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.

Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study.

Background: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit () genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS).

Aim: To assess the association of polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS.

Methods: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland.

The Global Bioequivalence Harmonisation Initiative (GBHI): Report of EUFEPS/AAPS fourth conference.

This report provides a summary of the 4 International Conference on Global Bioequivalence Harmonisation Initiative (GBHI) that was co-organised by the European Federation of Pharmaceutical Sciences (EUFEPS) and the American Association of Pharmaceutical Scientists (AAPS). The goal of the GBHI conference is to offer the most informative and up to date science and regulatory thinking of bioequivalence (BE) in global drug development to support the intended process of a scientific global harmonisation. The workshop provided an open forum for pharmaceutical scientists from academia, industry and regulatory agencies to discuss three BE topics of interest, (a) BE assessment for long-acting injectables and implants, (b) necessity of fed BE studies for immediate-release products and (c) procedures to demonstrate equivalence of orally inhaled products.

Epigenome-wide analysis in newborn blood spots from monozygotic twins discordant for cerebral palsy reveals consistent regional differences in DNA methylation.

Background: Cerebral palsy (CP) is a clinical description for a group of motor disorders that are heterogeneous with respect to causes, symptoms and severity. A diagnosis of CP cannot usually be made at birth and in some cases may be delayed until 2-3 years of age. This limits opportunities for early intervention that could otherwise improve long-term outcomes.

Quality of life in young adults with cerebral palsy.

Background: Little is known about the quality of life (QOL) of young adults with cerebral palsy.

Objective/hypothesis: This cross-sectional analysis compares the QOL of a cohort of young Australian adults with CP with a cohort of able-bodied peers to explore the relationship between QOL and impairments, functioning, and social participation.

Methods: Young adults identified from the Victorian Cerebral Palsy Register were invited to complete a survey about QOL, gross motor function, independence in self-care, and social participation.

Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders.

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-HT3 A- and heteromeric 5-HT3 AB receptors in HEK293 cells was determined by radioligand binding, a luminescence-based Ca(2+) assay, and a membrane potential assay.

Social outcomes of young adults with cerebral palsy.

Background: Functional abilities and social outcomes of young adults with cerebral palsy (CP) are relatively under-researched. Improvements in paediatric care have extended the expectation of achieving adulthood to 90%.

Method: Young adults aged 20-30 years with CP (n = 335) were compared to a population-based control group (n = 2,152) of the same age.

Ginger and its pungent constituents non-competitively inhibit activation of human recombinant and native 5-HT3 receptors of enteric neurons.

Background: Beneficial effects of ginger in the treatment of gastrointestinal (GI) problems and chemotherapy-induced nausea and vomiting are well accepted. In rodents, the action of ginger seems to be mediated by the inhibition of 5-HT3 receptors, which are established targets to combat emesis and irritable bowel syndrome.

Methods: Heterologously expressed human 5-HT3 A or 5-HT3 AB receptors were characterized by means of Ca(2+) influx studies using HEK293 cells.

Immunisation coverage in children with cerebral palsy compared with the general population.

Aim: To compare immunisation coverage of a cerebral palsy (CP) cohort with the known general population vaccination coverage statistics.

Methods: A cohort of children with CP aged less than 7 years was extracted from the Victorian Cerebral Palsy Register. The vaccination status of these children was compared with the general population using the Australian Childhood Immunisation Register (ACIR).

Secondary effects of botulinum toxin injections into salivary glands for the management of pediatric drooling.

This study aimed to assess the secondary benefits and adverse effects of botulinum toxin A injections into the parotid and submandibular glands in children with developmental disability and to determine whether these effects are related to reduction in drooling. Twenty-six children were injected (14 boys and 12 girls; mean age, 11 years 3 months). The Drooling Impact Scale and a secondary effects questionnaire covering aspects of eating, speech, saliva management, and sleep, were administered to the main carer at specific times before and after injection.

Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization.

The aim of this study was to analyze functional properties of the naturally occurring C23S variant of the human 5-HT2C receptor. In HEK293 cells transiently expressing the unedited forms of the variant receptor (VR) or the wild-type receptor (WTR), surface expression was determined by [3H]mesulergine binding to membrane fragments. Function was examined by an aequorin luminescence-based Ca2+ assay.

5-HT(3) receptors: role in disease and target of drugs.

Serotonin type 3 (5-HT(3)) receptors are pentameric ion channels belonging to the superfamily of Cys-loop receptors. Receptor activation either leads to fast excitatory responses or modulation of neurotransmitter release depending on their neuronal localisation. 5-HT(3) receptors are known to be expressed in the central nervous system in regions involved in the vomiting reflex, processing of pain, the reward system, cognition and anxiety control.

RIC-3 exclusively enhances the surface expression of human homomeric 5-hydroxytryptamine type 3A (5-HT3A) receptors despite direct interactions with 5-HT3A, -C, -D, and -E subunits.

Although five 5-hydroxytryptamine type 3 (5-HT3) subunits (A-E) have been cloned, knowledge on the regulation of their assembly is limited. RIC-3 has been identified as a chaperone specific for the pentameric ligand-gated nicotinic acetylcholine and 5-HT(3) receptors. Therefore, we examined the impact of RIC-3 on differently composed 5-HT(3) receptors with the focus on 5-HT3C, -D, and -E subunits.

Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied.

Characterization of the naturally occurring Arg344His variant of the human 5-HT 3A receptor.

The present study aimed at examining the function and pharmacological properties of the naturally occurring Arg344His variant of the human 5-HT(3A) receptor, identified in a schizophrenic patient. In intact human embryonic kidney (HEK) 293 cells expressing the wild-type (WT) or the variant receptor, the function was analyzed by indirect measurement of agonist-induced Ca(2+) current through the 5-HT(3A) receptor channel by an aequorin luminescence-based Ca(2+) assay. In cell membrane patches cation currents were determined electrophysiologically including technically demanding single channel analyses.

One-year follow-up of the outcome of a randomized controlled trial of a home-based intervention programme for children with autism and developmental delay and their families.

Introduction: There is debate about the type and intensity of early childhood intervention that is most helpful for children with developmental problems. The aim of the study was to determine whether a home-based programme provided over 12 months resulted in sustained improvement in development and behaviour 12 months after the intervention ceased. The characteristics of the children and families who benefited most from the intervention were also studied.

Naturally occurring variants in the HTR3B gene significantly alter properties of human heteromeric 5-hydroxytryptamine-3A/B receptors.

Objectives: The 5-hydroxytryptamine-3 (5-HT3) receptor, a ligand-gated ion channel, is known to be involved in gut motility and peristalsis, the mediation of pain and psychiatric diseases. 5-HT3 receptor antagonists are effectively used to treat chemotherapy-induced emesis and irritable bowel syndrome. We have characterized the impact of four naturally occurring variants in the HTR3B gene leading to amino acid exchanges within the respective subunit of heteromeric 5-HT3A/B receptors on a functional and expressional level.

First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome.

Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK.

Learning and memory in 5-HT(1A)-receptor mutant mice.

The serotonin 1A (5-HT(1A))-receptor is involved in a wide range of physiological functions, but has also been implicated in the pathophysiology of anxiety disorders and depression. Although the 5-HT(1A)-receptor is one of the best described receptor subtypes of the serotonergic system, its complex distribution pattern, pre- and postsynaptic localisation, and its impact on various neurotransmitters aggravate the attribution of 5-HT(1A)-agonistic effects to behavioural outcomes. The role of 5-HT(1A)-receptors for cognitive processes seems undisputed.

A randomized, controlled trial of a home-based intervention program for children with autism and developmental delay.

Objective: This study aimed to (1) investigate whether provision of a home-based program in addition to a center-based program improves development in young children with disabilities and coping abilities of their families and (2) describe the characteristics of children and families who benefit most from the intervention.

Methods: Fifty-nine children, aged 3-5 years, with no cerebral palsy, participated in the study. Half of the group was randomized to receive an additional program in their homes.

Aequorin luminescence-based assay for 5-hydroxytryptamine (serotonin) type 3 receptor characterization.

The classical electrophysiological method to measure the function of the 5-hydroxytryptamine (serotonin) type 3 (5-HT(3)) receptor, a cation-permeable ligand-gated ion channel, is time-consuming and not suitable for high-throughput screening. Therefore, we have optimized the conditions for a sensitive assay suitable to measure 5-HT(3) receptor responses in cell suspension based on aequorin bioluminescence caused by Ca(2+) influx. The assay, carried out in 96-well plates, was applied for the pharmacological characterization of 5-HT(3) receptors on human embryonic kidney (HEK) 293 cells transiently coexpressing apoaequorin and either the human homopentameric 5-HT(3A) receptor or the human heteromeric 5-HT(3A/B) receptor in the same subset of cells.

Characterization of the novel human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E.

Within the family of serotonin receptors, the 5-hydroxytryptamine-3 (5-HT(3)) receptor is the only ligand-gated ion channel. It is composed of five subunits, of which the 5-HT(3A) and 5-HT(3B) subunits are best characterized. Several studies, however, have reported on the functional diversity of native 5-HT(3) receptors, which cannot solely be explained on the basis of the 5-HT(3A) and 5-HT(3B) subunits.

Inpatient care of children with cerebral palsy as perceived by their parents.

Objectives: Children with cerebral palsy (CP) have special health care needs. The aim of the study was to evaluate the inpatient care of children with CP, as perceived by their parents.

Methods: Forty parents of children with CP and 90 parents of able-bodied children completed a questionnaire designed to evaluate their perception of their child's hospital admission, including the care provided.