Miglustat

Miglustat Uses, Dosage, Side Effects, Food Interaction and all others data.

Miglustat, commonly marketed under the trade name Zavesca, is a drug used to treat Gaucher disease. It inhibits the enzyme glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids. It is only used for patients who cannot be treated with enzyme replacement therapy with imiglucerase. Miglustat is now the first and only approved therapy for patients with Niemann-Pick disease type C (NP-C). It has recently been approved for treatment of progressive neurological symptoms in adult and pediatric patients in the European Union, Brazil, and South Korea. Miglustat was first developed as an anti-HIV agent in the 1990s. However, clinical experience with miglustat showed that therapeutic levels of the drug could not be achieved in patients without a high incidence of adverse effect.

Miglustat, an N-alkylated imino sugar, is a synthetic analogue of D-glucose. Miglustat is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for catalyzing the formation of glucosylceramide (glucocerebroside). Glucosylceramide is a substrate for the endogenous glucocerebrosidase, an enzyme that is deficient in Gaucher's disease. The accumulation of glucosylceramide due to the absence of glucocerebrosidase results in the storage of this material in the lysosomes of tissue macrophages, leading to widespread pathology due to infiltration of lipid-engorged macrophages in the viscera, lymph nodes, and bone marrow. This results in secondary hematologic consequences including sever anemia and thrombocytopenia, in addition to the characteristic progressive hepatosplenomegaly, as well as skeletal complications including osteonecrosis and osteopenia with secondary pathological fractures.

Miglustat
Uses
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Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
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Trade Name	Miglustat
Availability	Prescription only
Generic	Miglustat
Miglustat Other Names	BuDNJ, Butyldeoxynojirimycin, Miglustat, Miglustatum, n-Butyl deoxynojirimycin, N-Butylmoranoline, NB-DNJ
Related Drugs	VPRIV, eliglustat, Cerezyme, Elelyso, imiglucerase, velaglucerase alfa
Weight	100mg
Type	Capsule, Oral Capsule
Formula	C₁₀H₂₁NO₄
Weight	Average: 219.278 Monoisotopic: 219.147058165
Protein binding	Miglustat does not bind to plasma proteins.
Groups	Approved
Therapeutic Class
Manufacturer	Accord Healthcare Limited
Available Country	United Kingdom, United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Miglustat is a glucosylceramide synthase inhibitor used for the management of mild to moderate type I Gaucher disease for patients who are not candidates for whole enzyme replacement.

For the treatment of adult patients with mild to moderate type 1 (nonneuropathic) Gaucher's disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access). Now approved in some countries for the treatment of progressive neurological symptoms in adult and pediatric patients with Niemann-Pick disease type C (NP-C).

Miglustat is also used to associated treatment for these conditions: Gaucher Disease, Type 1

How Miglustat works

Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. The goal of treatment with miglustat is to reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy), reducing the accumulation of glucocerebroside in macrophages. In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. In clinical trials, miglustat improved liver and spleen volume, as well as hemoglobin concentration and platelet count. Inhibition of glycosphingolipid synthesis has also shown to reduce intracellular lipid storage, improve fluid-phase endosomal uptake and normalize lipid transport in peripheral blood B lymphocytes of NP-C patients, which results in a decrease in the potentially neurotoxic accumulation of gnagliosides G_M2 and G_M3, lactosylceramide and glucosylceramide, possibly preventing further neuronal damage. Other studies have also suggested that miglustat may indirectly modulate intracellular calcium homeostasis through its effects on glucosylceramide levels, and evidence has shown that an initiating factor in the pathogenesis of NP-C may be impaired calcium homeostasis related to sphingosine storage. Therefore, the effect that miglustat exerts on intracellular calcium levels may influence an important underlying pathogenic mechanism of NP-C.

Toxicity

Miglustat has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended starting dose administered to Gaucher patients) for up to six months in Human Immunodeficiency Virus (HIV)-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above.