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The Role of TNF-α and Anti-TNF-α Agents during Preconception, Pregnancy, and Breastfeeding.
Romanowska-Próchnicka, K, Felis-Giemza, A, Olesińska, M, Wojdasiewicz, P, Paradowska-Gorycka, A, Szukiewicz, D
International journal of molecular sciences. 2021;(6)
Abstract
Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.
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Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.
Chen, L, He, Y, Wang, X, Ge, J, Li, H
Clinical and translational medicine. 2021;(10):e530
Abstract
Cardiac voltage-gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC-related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life-threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart-related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well-studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.
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The Treatment of Pediatric Inflammatory Bowel Disease with Biologic Therapies.
Conrad, MA, Kelsen, JR
Current gastroenterology reports. 2020;(8):36
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PURPOSE OF REVIEW Biologics for the treatment of inflammatory bowel disease (IBD) have been transformative to the therapeutic goals in the pediatric population. We review the biologics used to treat IBD, highlighting the importance of patient selection, dosing considerations, and therapeutic drug monitoring in children. RECENT FINDINGS Infliximab is well-established as a safe and efficacious therapy for Crohn's disease and ulcerative colitis. Both dose escalation strategies and therapeutic drug monitoring increase the likelihood of response to anti-TNFα therapies. Early real-world experience of vedolizumab and ustekinumab in pediatric IBD shows promising results, including clinical response rates comparable to what is seen in adults, but there are limited data using them as first-line therapies. Biologic therapies have improved outcomes in pediatric IBD, including achieving mucosal healing as well as improved growth and pubertal development. Therapeutic drug monitoring improves likelihood of response to anti-TNFα therapies, but further studies for vedolizumab and ustekinumab are necessary.
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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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Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis.
Green, J, Gilchrist, FJ, Carroll, W
The Cochrane database of systematic reviews. 2018;(6):CD012619
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Abstract
BACKGROUND Cystic fibrosis (CF) is the most common, life-limiting, genetically inherited disease. It affects multiple organs, particularly the respiratory system. However, gastrointestinal problems such as constipation and distal intestinal obstruction syndrome (DIOS) are also important and well-recognised complications in CF. They share similar symptoms e.g. bloating, abdominal pain, but are distinct conditions. Constipation occurs when there is gradual faecal impaction of the colon, but DIOS occurs when there is an accumulation of faeces and sticky mucus, forming a mass in the distal part of the small intestine. The mass may partially block the intestine (incomplete DIOS) or completely block the intestine (complete DIOS). Symptoms of DIOS can affect quality of life and other aspects of CF health, such as airway clearance, exercise, sleep and nutritional status. Treatment of constipation and prevention of complete bowel obstruction are required for gastrointestinal management in CF. However, many different strategies are used in clinical practice and there is a lack of consensus. The importance of this topic was highlighted in a recent research priority setting exercise by the James Lind Alliance. OBJECTIVES To evaluate the effectiveness and safety of laxative agents of differing types for preventing DIOS (complete and incomplete) in children and adults with CF. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 22 May 2018.We also searched online trial registries. Date of last search: 10 June 2018. SELECTION CRITERIA Randomised and quasi-randomised controlled parallel trials comparing laxative therapy for preventing DIOS (including osmotic agents, stimulants, mucolytics and substances with more than one action) at any dose to placebo, no treatment or an alternative laxative therapy, in people of any age with pancreatic sufficient or insufficient CF and any stage of lung disease. Randomised cross-over trials were judged on an individual basis. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials for inclusion, extracted outcome data and performed a risk of bias assessment for the included data. We judged the quality of the evidence using GRADE criteria. MAIN RESULTS We included one cross-over trial (17 participants) with a duration of 12 months, in which participants were randomly allocated to either cisapride (a gastro-prokinetic agent) or placebo for six months each. The trial had an unclear risk of bias for most domains but had a high risk of reporting bias.Radiograph scores revealed no difference in occurrence of DIOS between cisapride and placebo (narrative report, no data provided). There were no adverse effects. Symptom scores were the only secondary outcome within the review that were reported. Total gastrointestinal symptom scores favoured cisapride with a statistically significant mean difference (MD) of -7.60 (95% confidence interval (CI) -14.73 to -0.47). There was no significant difference at six months between cisapride and placebo for abdominal distension, MD -0.90 (95% CI -2.39 to 0.59) or abdominal pain, MD -0.4 (95% CI -2.05 to 1.25). The global symptom scores (whether individuals felt better or worse) were reported in the paper to favour cisapride and be statistically significant (P < 0.05).We assessed the available data to be very low quality. There was a great deal of missing data from the included trial and the investigators failed to report numerical data for many outcomes. The overall risk of bias of the trial was unclear and it had a high risk for reporting bias. There was also indirectness; the trial drug (cisapride) has since been removed from the market in several countries due to adverse effects, thus it has no current applicability for preventing DIOS. The included trial also had very few participants, which downgraded the quality a further level for precision. AUTHORS' CONCLUSIONS There is an absence of evidence for interventions for the prevention of DIOS. As there was only one included trial, we could not perform a meta-analysis of the data. Furthermore, the included trial compared a prokinetic agent (cisapride) that is no longer licensed for use in a number of countries due to the risk of serious cardiac events, a finding that came to light after the trial was conducted. Therefore, the limited findings from the trial are not applicable in current clinical practice.Overall, a great deal more research needs to be undertaken on gastrointestinal complications in CF, as this is a very poorly studied area compared to respiratory complications in CF.
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Infant cholestasis patient with a novel missense mutation in the AKR1D1 gene successfully treated by early adequate supplementation with chenodeoxycholic acid: A case report and review of the literature.
Wang, HH, Wen, FQ, Dai, DL, Wang, JS, Zhao, J, Setchell, KD, Shi, LN, Zhou, SM, Liu, SX, Yang, QH
World journal of gastroenterology. 2018;(35):4086-4092
Abstract
Steroid 5β-reductase [aldo-keto reductase family 1 member D1 (AKR1D1)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in AKR1D1 leads to life-threatening neonatal hepatitis and cholestasis. There is still limited experience regarding the treatment of this disease. We describe an infant who presented with hyperbilirubinemia and coagulopathy but normal bile acid and γ-glutamyltransferase. Gene analysis was performed using genomic DNA from peripheral lymphocytes from the patient, his parents, and his elder brother. The patient was compound heterozygous for c.919C>T in exon 8 and exhibited a loss of heterozygosity of the AKR1D1 gene, which led to an amino acid substitution of arginine by cysteine at amino acid position 307 (p.R307C). Based on these mutations, the patient was confirmed to have primary 5β-reductase deficiency. Ursodeoxycholic acid (UDCA) treatment did not have any effect on the patient. However, when we changed to chenodeoxycholic acid (CDCA) treatment, his symptoms and laboratory tests gradually improved. It is therefore crucial to supplement with an adequate dose of CDCA early to improve clinical symptoms and to normalize laboratory tests.
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Obeticholic acid for severe bile acid diarrhea with intestinal failure: A case report and review of the literature.
Hvas, CL, Ott, P, Paine, P, Lal, S, Jørgensen, SP, Dahlerup, JF
World journal of gastroenterology. 2018;(21):2320-2326
Abstract
Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn's disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24 h and improved the patient's quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.
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8.
Management Options for Irritable Bowel Syndrome.
Camilleri, M
Mayo Clinic proceedings. 2018;(12):1858-1872
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Irritable bowel syndrome (IBS) is associated with diverse pathophysiologic mechanisms. These mechanisms include increased abnormal colonic motility or transit, intestinal or colorectal sensation, increased colonic bile acid concentration, and superficial colonic mucosal inflammation, as well as epithelial barrier dysfunction, neurohormonal up-regulation, and activation of secretory processes in the epithelial layer. Novel approaches to treatment include lifestyle modification, changes in diet, probiotics, and pharmacotherapy directed to the motility, sensation, and intraluminal milieu of patients with IBS. Despite recent advances, there is a need for development of new treatments to relieve pain in IBS without deleterious central or other adverse effects.
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Fetal death in utero and miscarriage in a patient with Crohn's disease under therapy with ustekinumab: case-report and review of the literature.
Venturin, C, Nancey, S, Danion, P, Uzzan, M, Chauvenet, M, Bergoin, C, Roblin, X, Flourié, B, Boschetti, G
BMC gastroenterology. 2017;(1):80
Abstract
BACKGROUND Ustekinumab is a fully human monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 which is involved in the pathogenesis of several inflammatory diseases. Ustekinumab is approved for psoriasis and psoriatic arthritis treatment and has been successfully evaluated in phase II and III trials for patients with Crohn's disease (CD). CASE PRESENTATION We report here the case of a patient who became pregnant during treatment with ustekinumab for a refractory CD and which ended in miscarriage. CONCLUSION Ustekinumab is a relatively new pharmacotherapy and in addition to this clinical case, we reviewed the published literature concerning the use of this treatment during pregnancy and its consequences on pregnancy and fetus outcome.
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Premedication Use Before Infliximab Administration: A Cross-sectional Analysis.
Picoraro, J, Winberry, G, Siegel, CA, El-Matary, W, Moses, J, Grossman, A, Park, KT
Inflammatory bowel diseases. 2017;(1):174-180
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BACKGROUND Premedications are commonly given to patients with inflammatory bowel disease before intravenous infliximab administration. We aimed to (1) describe practice variability; and (2) determine clinician rationale for premedicating patients with inflammatory bowel disease before infliximab administration. METHODS We developed a cross-sectional electronic survey after comprehensive literature review to assess practice variability and clinician rationale for premedication use before infliximab. An optional postsurvey quiz assessed clinicians' understanding of the available literature. The survey was distributed through members-only NASPGHAN and Crohn's and Colitis Foundation of America (CCFA) listservs and American Gastroenterological Association (AGA) and American College of Gastroenterology (ACG) web-based discussion boards. RESULTS Three hundred seventy-nine unique respondents with a 93.3% survey completion rate comprised 331 (87%) and 45 (12%) pediatric and adult gastroenterologists. Among numerous options for premedications, acetaminophen (66%) and diphenhydramine (64%) were most often given before each infliximab infusion. Only 20% did not routinely use premedications. There was heterogeneity of premedication use between gastroenterologists within the same clinical practice. Of 328 (87%) respondents who completed the knowledge assessment quiz, only 18% identified the association of diphenhydramine use with increased reaction. CONCLUSIONS There is high interpractice and intrapractice variability for premedication use before infliximab administration. Clinician rationale for premedicating patients seems to be driven by individual preference or group practice habit. Improved knowledge of the evidence may assist in decreasing overuse of premedications, particularly diphenhydramine.