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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Miglustat, an inhibitor of glycosphingolipids synthesis, has shown some benefit (stabilization or improvement) for the neurological manifestations of NPC, and it has been approved for this indication in some countries.
Gaucher disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Another approach, called substrate reduction therapy, is possible with an inhibitor of ceramide glucosyltransferase, and the agent N-butyldeoxynojirimycin was approved in 2004 (miglustat) for adult patients with Gaucher disease for whom IV enzyme replacement is not practical [90–92]. Results are similar to those [93] with enzyme therapy [19]. Studies are underway using a more specific glucosylceramide synthase inhibitor, eliglustat tartrate [94].
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Interestingly, by following a similar strategy starting from N-butylglucamine 119, it was possible to produce Miglustat (N-butyl-deoxynojirimycin 120, Fig. 11.41, marketed as Zavesca™), another glycosidase inhibitor acting as a pharmacological chaperone for brain glucosylceramide synthase, therefore avoiding the accumulation of glucosylceramide leading to Gaucher’s disease (Yu et al., 2007). Synthesis of Miglustat 120 via regioselective biooxidation of N-butylglucamine 119.
Current advancements in therapy for Niemann-Pick disease: progress and pitfalls
Published in Expert Opinion on Pharmacotherapy, 2023
Tatiana Bremova-Ertl, Susanne Schneider
Several disease-modifying agents have been investigated for NPC, including intrathecal HPβCD (adrabetadex) and the heat-shock protein production stimulator arimoclomol. Unfortunately, the clinical trials for intrathecal HPβCD were not successful and arimoclomol did not obtain FDA and EMA marketing authorizations, despite promising early findings (for the status of other trials see clinicaltrials.gov). However, there are promising, late-stage drug trials ongoing and other agents that warrant further development. ALL (IB1001) is an orally administered drug that has a benign safety profile and has both symptomatic and disease-modifying effects. ALL is therefore expected to offer a substantial benefit to patients, and can be used with miglustat given the compounds’ believed synergistic mechanisms [44]. In addition, an intravenous cyclodextrin can be a therapeutic option, once and if the efficacy is demonstrated in a clinical trial. Further adjuvant therapies, e. g. antioxidants that demonstrate a very good safety profile, can be combined with disease-modifying treatments. Re-purposed drugs, such as fingolimod, used in the management of MS, or its derivative, fingolimod-phosphate as well as efavirenz, an antiretroviral agent, might be agents for future development.
Hematological manifestations and complications of Gaucher disease
Published in Expert Review of Hematology, 2021
Shoshana Revel-Vilk, Jeff Szer, Ari Zimran
Of the two approved SRT drugs, only eliglustat is approved as first-line therapy (based on CYP2D6 metabolism status) [51]. Miglustat is approved only for patients with mild to moderate GD1, for whom ERT is not suitable or not a therapeutic option [52]. While ERT can be administered to any patient, eliglustat should not be prescribed to children, pregnant or lactating women, patients with existing cardiac disease, patients with severe hepatic impairment, and CYP2D6 ultra-rapid metabolizers [53,54]. The dose of eliglustat is not dependent on body weight but on the CYP2D6 status, once a day for poor metabolizers and twice a day for extensive and intermediate metabolizers. The use of SRT was associated with a higher prevalence of adverse effects, and therefore in our algorithm, it is offered for patients unwilling and unable to get ERT [48].
Systematic review of psychiatric signs in Niemann-Pick disease type C
Published in The World Journal of Biological Psychiatry, 2019
Olivier Bonnot, Hans-Hermann Klünemann, Christian Velten, Juan Vicente Torres Martin, Mark Walterfang
As is the case with other treatable IEMs, delays to the diagnosis of NPC are of particular importance because a targeted, disease modifying therapy is available (Sedel et al. 2007; Imrie et al. 2015; van Egmond et al. 2015). Miglustat has been shown to stabilize neurological disease and improve outcomes (Patterson et al. 2007; Pineda et al. 2009; Wraith et al. 2010; Walterfang et al. 2012; Bowman et al. 2015; Sedel et al. 2016). More effective detection of NPC in psychiatric practice will help avoid missed/overlooked cases that might benefit from treatment. The earlier initiation of targeted therapy can bring better long-term outcomes, helping to minimize irreversible neuronal damage early on in the course of disease, and to optimize beneficial long-term effects on patient quality of life (Wraith et al. 2009; Wraith and Imrie 2009; Pineda et al. 2010; Patterson et al. 2012).