Therapeutic drug monitoring in perianal fistulizing Crohn\u27s disease

Perianal fistulas are a common complication of Crohn\u27s disease (CD) that has, historically, been challenging to manage. Despite the strong available evidence that anti-tumor necrosis factor (anti-TNF) agents are useful in the treatment of perianal fistulizing Crohn\u27s disease (PFCD), a significant number of these patients do not respond to therapy. The use of therapeutic drug monitoring (TDM) in patients with CD receiving biologic agents has evolved and is currently positioned as an important tool to optimize and guide biologic treatment. Considering the treatment of PFCD can represent a challenge; identifying novel tools to improve the efficacy of current treatments is an important unmet need. Given its emerging role in other phenotypes of Crohn\u27s disease, the use of TDM could also offer an opportunity to enhance the effectiveness of available therapies and improve outcomes in the subset of patients with PFCD receiving biologics. Overall, there is mounting evidence that higher anti-TNF drug levels are associated with better rates of fistula healing . However, studies have been limited by their use of subjective outcomes and observational designs. Ultimately, further interventional, randomized controlled trials looking into the relationship between drug exposure and fistula outcomes are needed

Functional Interplay of Type-2 Corticotrophin Releasing Factor and Dopamine Receptors in the Basolateral Amygdala-Medial Prefrontal Cortex Circuitry

Background: Basolateral amygdala (BLA) excitatory projections to medial prefrontal cortex (PFC) play a key role controlling stress behavior, pain, and fear. Indeed, stressful events block synaptic plasticity at the BLA-PFC circuit. The stress responses involve the action of corticotrophin releasing factor (CRF) through type 1 and type 2 CRF receptors (CRF1 and CRF2). Interestingly, it has been described that dopamine receptor 1 (D1R) and CRF peptide have a modulatory role of BLA-PFC transmission. However, the participation of CRF1 and CRF2 receptors in BLA-PFC synaptic transmission still is unclear. Methods: We used in vivo microdialysis to determine dopamine and glutamate (GLU) extracellular levels in PFC after BLA stimulation. Immunofluorescence anatomical studies in rat PFC synaptosomes devoid of postsynaptic elements were performed to determine the presence of D1R and CRF2 receptors in synaptical nerve endings. Results: Here, we provide direct evidence of the opposite role that CRF receptors exert over dopamine extracellular levels in the PFC. We also show that D1R colocalizes with CRF2 receptors in PFC nerve terminals. Intra-PFC infusion of antisauvagine-30, a CRF2 receptor antagonist, increased PFC GLU extracellular levels induced by BLA activation. Interestingly, the increase in GLU release observed in the presence of antisauvagine-30 was significantly reduced by incubation with SCH23390, a D1R antagonist. Conclusion: PFC CRF2 receptor unmasks D1R effect over glutamatergic transmission of the BLA-PFC circuit. Overall, CRF2 receptor emerges as a new modulator of BLA to PFC glutamatergic transmission, thus playing a potential role in emotional disorders. Keywords: CRF2 receptor; D1 receptor; dopaminergic transmission; glutamatergic transmission; prefrontal cortex

Hepatobiliary manifestations of inflammatory bowel disease

Patients with inflammatory bowel diseases (IBDs) may present with several hepatic abnormalities. Some of these liver diseases are benign and only require observation, whereas others may cause liver failure and require liver transplantation. The aim of this review was to present and summarize the latest evidence on the most common liver diseases seen in patients with IBD. These manifestations can be divided in to 3 groups: those that are seen in association with IBD, those that are due to metabolic and physiologic changes induced by the IBD and those that are secondary to the drugs used in the treatment of IBD. Primary sclerosing cholangitis is one of the most common hepatobiliary manifestations of IBD that is more prevalent in patients with ulcerative colitis. There is no approved medical treatment for primary sclerosing cholangitis and about 50% of patients will require liver transplantation within 10 to 15 years from the time of diagnosis. Among the drugs that are commonly used in the treatment of IBD, thiopurines and methotrexate impose the higher risk of hepatotoxicity. In most cases, dose adjustment and avoidance of hepatotoxins will normalize the liver tests and discontinuation of the drug is required in a minority of cases. Reactivation of hepatitis B virus during immunosuppressive therapy is a major concern and adequate screening and vaccination is warranted. The approach to a patient with IBD who presents with abnormal liver chemistries can be challenging not only because 2 or more conditions can co-exist but also because management must be individualized