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Drugs Jan 2022Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the... (Review)
Review
Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.
Topics: Humans; Alagille Syndrome; Biliary Atresia; Carrier Proteins; Cholestasis, Intrahepatic; Clinical Trials as Topic; Drug Approval; Membrane Glycoproteins; United States; United States Food and Drug Administration; Benzothiepins
PubMed: 34813049
DOI: 10.1007/s40265-021-01649-0 -
Drugs Oct 2021Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic... (Review)
Review
Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic diseases, including progressive familial intrahepatic cholestasis (PFIC). In July 2021, odevixibat received its first approval in the EU for the treatment of PFIC in patients aged ≥ 6 months, followed shortly by its approval in the USA for the treatment of pruritus in patients aged ≥ 3 months with PFIC. Odevixibat is also in clinical development for the treatment of other cholestatic diseases, including Alagille syndrome and biliary atresia, in various countries. This article summarizes the milestones in the development of odevixibat leading to this first approval for PFIC.
Topics: Benzodiazepines; Butyrates; Carrier Proteins; Cholestasis; Drug Approval; Drug Development; Humans; Membrane Glycoproteins; Pruritus
PubMed: 34499340
DOI: 10.1007/s40265-021-01594-y -
Urology Annals 2015Orthotopic neobladder reconstruction is becoming an increasingly common urinary diversion following cystectomy for bladder cancer. This is in recognition of the... (Review)
Review
Orthotopic neobladder reconstruction is becoming an increasingly common urinary diversion following cystectomy for bladder cancer. This is in recognition of the potential benefits of neobladder surgery over creation of an ileal conduit related to quality of life (QoL), such as avoiding the need to form a stoma with its cosmetic, psychological and other potential complications. The PubMed database was searched using relevant search terms for articles published electronically between January 1994 and April 2014. Full-text articles in English or with English translation were assessed for relevance to the topic before being included in the review. Patients with neobladders have comparable or better post-operative sexual function than those with ileal conduits. They also have comparable QoL to those with ileal conduits. Orthotopic neobladder is a good alternative to ileal conduit in suitable patients who do not want a stoma and are motivated to comply with neobladder training. However, the selection of a neobladder as the urinary diversion of choice requires that patients have good renal and liver functions and are likely to be compliant with neobladder training. With benefits also come potential risks of neobladder formation. These include electrolyte abnormalities and nocturnal incontinence. This short review highlights current aspects of neobladder formation and its potential advantages.
PubMed: 25657535
DOI: 10.4103/0974-7796.148553 -
Brain, Behavior, and Immunity Jan 2021Chronic stress disrupts immune homeostasis while gut microbiota-derived metabolites attenuate inflammation, thus promoting resilience to stress-induced immune and...
Chronic stress disrupts immune homeostasis while gut microbiota-derived metabolites attenuate inflammation, thus promoting resilience to stress-induced immune and behavioral abnormalities. There are both peripheral and brain region-specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of stress-induced psychological impairment. This study shows that a combination of probiotics and polyphenol-rich prebiotics, a synbiotic, attenuates the chronic-stress induced inflammatory responses in the ileum and the prefrontal cortex promoting resilience to the consequent depressive- and anxiety-like behaviors in male mice. Pharmacokinetic studies revealed that this effect may be attributed to specific synbiotic-produced metabolites including 4-hydroxyphenylpropionic, 4-hydroxyphenylacetic acid and caffeic acid. Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the prefrontal cortex and hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic's effect on the ileum's inflammatory response to stress. Synbiotic treatment indiscriminately attenuated the stress-induced immune and behavioral aberrations in both the ileum and the brain while in a gut-immune co-culture model, the synbiotic-specific metabolites promoted anti-inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic-stress induced behavioral impairments while defining a putative mechanism of gut-microbiota host interaction for modulating the peripheral and brain immune systems.
Topics: Animals; Anxiety; Gastrointestinal Microbiome; Male; Mice; Microbiota; Prebiotics; T-Lymphocytes, Regulatory
PubMed: 33096252
DOI: 10.1016/j.bbi.2020.10.013