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Binita M. Kamath Philip Stein Roderick H. J. Houwen Henkjan J. Verkade 《Liver international》2020,40(8):1812-1822
Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver‐damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC. 相似文献
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Frank S. Pidcock 《Developmental neurorehabilitation》2013,16(4):298-302
Purpose: To review the use of therapeutic botulinum toxin type A (BoNT-A) treatments in uncommon neurogenetic syndromes.Method: A retrospective questionnaire and interview study of a selected case series to assess the efficacy and safety following initial BoNT-A treatment (50–400 units per subject) was conducted to determine the response of families to treatment. Twelve male and six female subjects with ages from 2–19 years were included. The reasons for treatments were based on both patient-related and caregiver-related objectives. Satisfaction with achievement of stated goals was assessed by follow-up interviews.Results: Beneficial effects were reported in 56%, some effects in 22% and no to minimal effects in 22%. The duration of effect ranged from 10 days to 12 months with an average of 3.16 months. Ten families would repeat the injections as needed, four would not and four were not sure. Unanticipated effects of BoNT-A treatments were reported by some families. Adverse effects did not occur with the doses that were used.Conclusions: The results suggest that obtaining family input may be useful when treating spasticity in unusual circumstances. The use of BTX-A in uncommon neurogenetic syndromes was supported by the majority of families interviewed. 相似文献
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Application of a physiologically‐based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate 下载免费PDF全文
Maria D. Donovan Khaled Abduljalil John F. Cryan Geraldine B. Boylan Brendan T. Griffin 《Biopharmaceutics & drug disposition》2018,39(3):125-134
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates. 相似文献
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