Cannabinoid signalling

The general aim of the study was to investigate the signalling pathways utilised by cannabinoids. Cannabinoid CB1 receptor stimulation in DDT, MF-2 smooth muscle cells induces a rise in [Ca21;, which is dependent on extracellular Cat' and modulated by thapsigargin-sensitive stores and MAP kinase suggesting capacitative Ca2+ entry (CCE). Non-capacitative calcium entry (NCCE) stimulated by arachidonic acid (AA) partly mediates histamine Hl receptor-evoked increases in [Ca2+]; in DDTI MF-2 cells. In the current study both Ca 2+ entry mechanisms and a possible link between MAP kinase activation and increasing [Ca2+];, were investigated. In the whole-cell patch clamp configuration, the cannabinoid receptor agonist CP 55,940 evoked a transient Cat+-dependent K+ current, which was not blocked by inhibitors of CCE, 2-APB and SKF 96365, although SKF 96365 did inhibit the outward current evoked by the refilling component of the response to histamine. AA but not its metabolites evoked a transient outward current and inhibited the response to CP 55,940 in a concentration-dependent manner. CP 55,940 induced a concentration-dependent release of AA, which was inhibited by the CB1 receptor antagonist SR 141716A. The non-specific Ca2+ channel blockers, La3+ and Gd3+, inhibited the CP 55,940-induced current at concentrations that had no effect on thapsigargin-evoked CCE. La3+ also inhibited AA-mediated currents. The effect of CP 55,940 on AA release was abolished by phospholipase A2 inhibition with quinacrine. This compound also inhibited outward currents mediated by CP 55,940. The data supports the possibility that in DDT, MF-2 cells AA is an integral component of the CBI receptor signalling pathway, upstream of NCCE and, via PLA2, downstream of MAP kinase. In a parallel line of work the present study aimed to identify the signalling events that might mediate a cannabinoid-induced inhibition of neurotransmission in the myenteric plexus, leading to a reduction in intestinal motility. Myenteric neurons were grown in primary culture enabling electrophysiological recordings to be made from individual cells to study the effects of cannabinoids on ion conductance. Immunohistochemistry validated these neurons as a model for those in situ, demonstrating that all CB1 receptor-positive cells express the cholinergic marker choline acetyltransferase. CP 55,940 was not shown to activate G-protein inwardly rectifying K+ channels but did inhibit evoked Ca2+ currents in myenteric cultures, a signalling mechanism that may underlie the CB1 receptor-mediated inhibition of neurotransmitter release from presynaptic sites. Nicotinic ACh (nACh) receptors are also expressed on cultured myenteric neurons. Stimulation of these receptors by nicotine evoked a transient inward current, which was inhibited by CP 55,940 and the endogenous cannabinoid anandamide, in an SR 14716A-insensitive manner. In fact, SR 141716A alone inhibited currents mediated by nACh receptors. PEA, a cannabinoid ligand whose effects are thought to occur independently of CB1/ CB2 receptor activation, also inhibited nicotine-induced currents. Pertussis toxin, a Gil,, inhibitor, did not reverse the cannabinoid-induced inhibition of nicotinic currents. In addition, CP 55,940 inhibited the sustained inward current evoked by 5-11T application in cultured myenteric neurons. The results suggest that cannabinoids inhibit nACh channels through a CB1 receptor-independent pathway in myenteric neurons, which would lead to a reduction in excitatory neurotransmission in the intact myenteric plexus. The inhibitory effect on the 5-HTinduced sustained inward current also suggests a cannabinoid-evoked inhibition of currents possibly mediated by the 5-HT1p receptor

a retrospective cohort analysis

Background Allergy immunotherapy is an effective treatment for patients with allergic rhinitis whose symptoms are unresolved with pharmacotherapy. Allergy immunotherapy for grass pollen-induced allergic rhinitis is available in three modalities: subcutaneous immunotherapy and sublingual immunotherapy as a tablet or drop. This study aimed to understand trends in allergy immunotherapy prescribing and practice patterns for grass allergies in adult and paediatric patients in Germany. Methods A retrospective cohort study was conducted using IMS Disease Analyzer in Germany. Patients with an allergy immunotherapy prescription for grass pollen (Anatomical Therapeutic Chemical [ATC] classification code V01AA02) from September 2005 to December 2012 were included in the study. General Practitioners (GPs), dermatologists, Ear, Nose and Throat (ENT)-specialists, paediatricians and pneumologists were included as the allergy immunotherapy prescribing physicians in the study. Descriptive analyses were conducted on patient characteristics at index and prescribing physician specialty; a test for trend was conducted for timing of initiation of first allergy immunotherapy prescription in each annual prescribing season. Results Eighteen thousand eight hundred fifty eligible patients were identified during the study period. The majority of patients received subcutaneous immunotherapy; however, the proportion of patients receiving sublingual immunotherapy tablets increased from 8 % in 2006/2007 to 29 % in 2011/2012 (p < 0.001). Initiation of subcutaneous immunotherapy and Oralair® generally peaked during each prescribing year in two seasons (September- October and January) while GRAZAX® prescriptions peaked in autumn (September- October). ENT-specialists and dermatologists were the largest allergy immunotherapy prescribers in adults, while paediatricians and ENT-specialists were the largest prescribers of allergy immunotherapy in paediatric patients. Conclusions Subcutaneous immunotherapy remained the dominant allergy immunotherapy modality for grass pollen-induced allergic rhinitis in Germany for adult and paediatric patients; however, there was a marked increase in proportion of patients receiving sublingual immunotherapy tablets from 2006/2007 to 2011/2012, after their introduction to the market in 2006. ENT- specialists, dermatologists and paediatricians were responsible for the majority of prescribing. The predominance of particular modalities within certain physician specialties likely reflects different treatment goals or needs

The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the Clinical Practice Research Datalink (CPRD)

AbstractBackgroundTuberous Sclerosis Complex (TSC) is a multi-system genetic disorder characterised by the development of benign growths and diverse clinical manifestations, varying in severity, age at onset and with high clinical burden.AimsThis longitudinal study aims to describe the broad spectrum of clinical manifestation profiles in a large, representative cohort of TSC patients in the UK in order to better understand disease complexity.MethodsTSC patients in the Clinical Practice Research Datalink (CPRD) and linked Hospital Episodes Statistics (CPRD-HES) were retrospectively identified between 1987 and 2013. Available history was extracted for each patient and clinical diagnosis, procedure and medication records reviewed. A random selection of patients from the CPRD-HES was used as a Comparator cohort.ResultsThree hundred and thirty-four TSC patients with a mean (SD) age of 30.3 (18.6) years were identified (53% female). TSC was diagnosed at mean age 3.2 (4.2) years. Epilepsy and psychiatric manifestations were reported frequently in paediatric (77% and 55%, respectively) and adult patients (66% and 68%, respectively). The prevalence of manifestations in the TSC cohort was markedly higher versus the Comparator cohort. The majority of paediatric (46%) and adult TSC patients (62%) developed clinical manifestations affecting at least three organ systems and forty-nine distinctive organ system manifestation profiles were identified.ConclusionsTSC patients present with multiple and complex clinical manifestations and profiles that necessitate the co-ordinated action of a multidisciplinary team in order to improve the quality and efficiency of care

Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: The EXPLORE study

Abstract Background Incidence of inflammatory bowel disease (IBD) is increasing in newly industrialised countries (NICs); however, data on suboptimal response to anti-tumor necrosis factor (anti-TNF) agents are limited. Objectives To assess incidence and indicators of suboptimal response to first anti-TNF therapy in IBD patients in NICs. Methods A chart review was conducted in ten countries from Asia-Pacific (APAC), Latin America (LatAm), and Russia and the Middle East (RME) regions among patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD), initiating anti-TNF therapy in 2010–2015. The cumulative incidence of suboptimal response to anti-TNF therapy was assessed using the following indicators: dose escalation or discontinuation, augmentation with non-biologic therapy, IBD-related hospitalization, or surgery. Results The study included 1,674 patients (570 UC; 1,104 CD). At 24 months, 32.9% of UC (APAC: 45.1%; LatAm: 38.2%; RME: 23.8%) and 41.2% of CD patients (APAC: 54.1%; LatAm: 42.5%; RME: 29.5%) had experienced suboptimal response. The most frequent first indicator was non-biologic therapy augmentation in LatAm (41.7%), IBD-related hospitalization in RME (UC: 50.7%; CD:37.3%) and in APAC for CD (39.1%), and anti-TNF discontinuation in APAC for UC (38.3%). Conclusion Suboptimal response to anti-TNF agents is common in IBD patients in NICs. Observed regional differences in the incidence and indicators may reflect local practice and anti-TNF restrictions in IBD management. NCT Registration Number NCT03090139