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Therapeutic drug monitoring with vedolizumab in inflammatory bowel disease.
Pugliese, D, Privitera, G, Pizzolante, F, Gasbarrini, A, Guidi, L, Armuzzi, A
Minerva gastroenterologica e dietologica. 2019;(4):280-290
Abstract
Therapeutic drug monitoring (TDM) is a useful tool for decision-making process in patients with inflammatory bowel disease (IBD) treated with anti TNF-α drugs, especially when experiencing loss of response. Growing evidences support the existence of exposure-response relationship with vedolizumab, but the utility and the appropriate use of TDM in clinical practice is still under debate. In this review, we summarize all evidences supporting a TDM-guided approach for patients treated with vedolizumab, suggesting three potential scenarios: 1) early prediction of long-term outcomes; 2) verifying the best strategy in case of loss of response; 3) maximizing therapeutic efficacy during maintenance treatment. Vedolizumab through concentrations <20 µg/mL at week 6 and >12 µg/mL seem to be associated with more favorable outcomes. No comparative studies have been conducted so far to demonstrate the advantage of adopting a TDM-guided versus an empirical approach for managing primary or secondary nonresponses. The frequency of antibodies to vedolizumab detection is quite low (up to 4% in pivotal trials), suggesting, unlike of anti TNF-α agents, a low probability of experiencing an immune-mediated pharmacokinetic failure in clinical practice. Future prospective and controlled studies are warranted to establish the guidance on the use of a TDM-guided approach with vedolizumab in clinical practice.
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2.
Irritable bowel syndrome and colonic diverticular disease: overlapping symptoms and overlapping therapeutic approaches.
Alamo, RZ, Quigley, EMM
Current opinion in gastroenterology. 2019;(1):27-33
Abstract
PURPOSE OF REVIEW Irritable bowel syndrome (IBS) is a common symptomatic disorder in the Western world and colonic diverticula are also prevalent; however, relationships between IBS-type symptoms and diverticula have been a source of much debate. Our goal was to reassess these relationships in the light of new data. RECENT FINDINGS On removing from consideration clinical scenarios which are directly related to diverticula (i.e., diverticulitis, diverticular hemorrhage, and complications of diverticulitis, such as stricture and fistula), relationships between IBS and diverticula can be seen to revolve around a number of questions. First, are IBS and symptomatic uncomplicated diverticular disease (SUDD) the same condition? Or, in other words is SUDD no more than IBS in an individual who just happens to have diverticula? Although coincident IBS and diverticula inevitably do occur there is some evidence to indicate that SUDD may be somewhat distinctive with SUDD being characterized by more frequent and severe pain. Second, and analogous to interactions between IBS and inflammatory bowel disease or celiac disease, can an episode of acute diverticulitis lead to the de novo development of IBS? There is now epidemiological and pathophysiological evidence to support this occurrence. SUMMARY Although relationships between uncomplicated diverticular disease and IBS have been reexamined their status remains unclear. As yet, however, none of the newer concepts related to this relationship have led to new therapeutic approaches in IBS or diverticular disease.
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Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia.
Banerjee, I, Salomon-Estebanez, M, Shah, P, Nicholson, J, Cosgrove, KE, Dunne, MJ
Diabetic medicine : a journal of the British Diabetic Association. 2019;(1):9-21
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Abstract
Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic β cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the KATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.
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Updates on the pathophysiology and therapeutic targets for hepatic encephalopathy.
Alsahhar, JS, Rahimi, RS
Current opinion in gastroenterology. 2019;(3):145-154
Abstract
PURPOSE OF REVIEW Hepatic encephalopathy is one of the most debilitating clinical manifestations of cirrhosis and associated with increased morbidity and mortality. Treatment modalities available include the nonabsorbable disaccharides (lactulose) and the nonabsorbable antibiotics (rifaximin). RECENT FINDINGS Newer therapeutic targets under evaluation include ammonia scavengers (ornithine phenylacetate) and modulation of gut microbiota (fecal microbiota transplantation). SUMMARY This review will focus on the pathophysiology of hepatic encephalopathy along with an update on therapeutic targets under investigation.
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Hepatic Encephalopathy Challenges, Burden, and Diagnostic and Therapeutic Approach.
Yanny, B, Winters, A, Boutros, S, Saab, S
Clinics in liver disease. 2019;(4):607-623
Abstract
Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with cirrhosis. The impact of HE on the health care system is similarly profound. The number of hospital admissions for HE has increased in the last 10-year period. HE is a huge burden to the patients, care givers, and the health care system. HE represents a "revolving door" with readmission, severely affects care givers, and has effects on cognition that can persists after liver transplant. This article reviews the current literature to discuss the challenges and diagnostic and therapeutic approaches to HE.
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Pharmacologic Management of Portal Hypertension.
Bunchorntavakul, C, Reddy, KR
Clinics in liver disease. 2019;(4):713-736
Abstract
Terlipressin, somatostatin, or octreotide are recommended as pharmacologic treatment of acute variceal hemorrhage. Nonselective β-blockers decrease the risk of variceal hemorrhage and hepatic decompensation, particularly in those 30% to 40% of patients with good hemodynamic response. Carvedilol, statins, and anticoagulants are promising agents in the management of portal hypertension. Recent advances in the pharmacologic treatment of portal hypertension have mainly focused on modifying an increased intrahepatic resistance through nitric oxide and/or modulation of vasoactive substances. Several novel pharmacologic agents for portal hypertension are being evaluated in humans.
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Any news from the prokinetic front?
Deane, AM, Chapman, MJ, Abdelhamid, YA
Current opinion in critical care. 2019;(4):349-355
Abstract
PURPOSE OF REVIEW This review provides an update of recently conducted studies and randomized controlled trials evaluating prokinetic drugs. RECENT FINDINGS Prokinetic drugs accelerate gastric emptying and, particularly in patients with gastric dysmotility and enteral feed intolerance, their use increases the delivery of enteral nutrition. However, prokinetic drugs have not been shown to improve patient-centered outcomes in trials but benefit is assumed on the basis of observational studies, which report close associations between gastric dysmotility, enteral feed intolerance and poor outcomes, and improvement in surrogate physiological outcomes when prokinetic drugs are administered. SUMMARY It may not be feasible to establish superiority of a prokinetic drug within a randomized controlled trial with a patient-centered event as the primary outcome. The use of metoclopramide and erythromycin as prokinetic drugs is based on observations from trials measuring surrogate physiological outcomes. Randomized controlled trials of alternative drug regimens and novel prokinetic drugs have recently been completed and results outlined.
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Managing Risks with Biologics.
Click, B, Regueiro, M
Current gastroenterology reports. 2019;(2):1
Abstract
PURPOSE OF REVIEW With a rapidly evolving complement of advanced targeted therapies in inflammatory bowel disease, additional safety and side effect concerns emerge. It is the purpose of this review to consider various risks with biologic therapies in inflammatory bowel disease and discuss mitigating strategies. RECENT FINDINGS Two recently approved monoclonal antibodies (vedolizumab and ustekinumab) and a Janus kinase inhibitor small molecule (tofacitnib) have introduced a number of novel safety and risk considerations. We review the clinical trial and real-world safety data to date on these agents as well as review new data and considerations with anti-tumor necrosis factor agents. New vaccines for varicella zoster virus, hepatitis B virus, and high-dose influenza have been studied, and we discuss the clinical importance of these findings. Lastly, we make management recommendations in the event of particular side effects or complications. Understanding the risks of new agents in inflammatory bowel disease, potential mitigating strategies, and management considerations is important to achieving and maintaining clinical outcomes in IBD patients.
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New treatments and therapeutic targets for IBS and other functional bowel disorders.
Simrén, M, Tack, J
Nature reviews. Gastroenterology & hepatology. 2018;(10):589-605
Abstract
Functional bowel disorders (FBDs) are a spectrum of disorders characterized by combinations of symptoms attributable to the lower gastrointestinal tract. Most current first-line therapies for IBS and other FBDs target the predominant symptom and mainly affect one symptom in the symptom complex. Additional broadly effective treatment alternatives targeting the entire symptom complex are needed. New drugs for FBDs (such as lubiprostone, linaclotide, plecanatide, prucalopride, eluxadoline and rifaximin) target key mechanisms in the pathophysiology of these disorders and improve both the abnormal bowel habit and other key symptoms, such as abdominal pain and bloating. The current development of new treatment alternatives is focusing on different aspects of the complex pathophysiology of IBS and other FBDs: gut microenvironment (via diet and modulation of gut microbiota), enterohepatic circulation of bile acids, gastrointestinal secretion, motility and sensation, gut-brain interactions, gut barrier function and the immune system within the gastrointestinal tract. Studies also suggest that personalized treatment of IBS and other FBDs is possible using various diagnostic markers.
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10.
Advances in glucagon like peptide-2 therapy. physiology, current indications and future directions.
Sigalet, DL
Seminars in pediatric surgery. 2018;(4):237-241
Abstract
The treatment paradigm for pediatric patients with short bowel syndrome (SBS) and intestinal failure (IF) has changed significantly over recent years; the development of dedicated IF teams, refinements in PN and surgical treatments have greatly improved survival. The majority of SBS patients undergo intestinal adaptation such that nutrient absorption from enteral feeds increases and the child can come off of PN. This "adaptation" or upregulation in nutrient absorptive capacity is still poorly understood; the enteric hormone Glucagon like peptide 2 (GLP-2) appears to be a key regulator in this process. The development of Teduglutide, a long acting GLP-2 ligand as a therapy to specifically enhance adaptation has been anticipated as a further shift in the paradigm. This article reviews the physiology of GLP-2 with an emphasis on the known or potential roles in infants and children with SBS and IF. The results and implications of the present studies and approved indications for GLP-2 and its ligands are discussed. Finally, the potential future uses of GLP-2 ligands in the pediatric population are considered.