Miglustat, sold under the brand name Zavesca, is a medication used to treat type I

Gaucher disease Gaucher's disease or Gaucher disease () (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low ...

(GD1). It is also known as N-butyldeoxynojirimycin, and is a derivative of the anti-diabetic

1-deoxynojirimycin 1-Deoxynojirimycin (DNJ or 1-DNJ), also called duvoglustat or moranolin, is an alpha-glucosidase inhibitor, most commonly found in mulberry leaves. Although it can be obtained in small quantities by brewing an herbal tea from mulberry leaves, int ...

. It was developed by Oxford GlycoSciences and is marketed by

Actelion Actelion is a pharmaceuticals and biotechnology company established in December 1997, headquartered in Allschwil near Basel, Switzerland. Actelion focuses on the manufacture of drugs that treat rare diseases and orphan diseases. Some of the dru ...

. Miglustat has been approved in the EU, Japan, and Canada for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC). It was approved for medical use in the European Union in November 2002, and for medical use in the United States in July 2003.

Medical uses

Miglustat is indicated to treat adults with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable.

Contraindications

Miglustat is contraindicated for people with neurological conditions, kidney problems, women who are pregnant, and men and women planning to conceive a child.

Adverse effects

Serious side effects include pain, burning, numbness or tingling in the hands, arms, legs, or feet; shaking hands that cannot be controlled; changes in vision; and easy bruising or bleeding. Common side effects include gastrointestinal effects (including diarrhea, stomach pain or bloating, gas, loss of appetite, weight loss, upset stomach, vomiting, constipation), dry mouth, muscular effects (including weakness, muscle cramps, especially in the legs, feeling of heaviness in the arms or legs, unsteadiness when walking), back pain, dizziness, nervousness, headache, memory problems, and difficult or irregular menstruation (period).American Society of Health-System Pharmacists, Inc. for the Public Library of Medicine
Miglustat on MedlinePlus
Accessed 1 September 2014

Mechanism of action

Type I Gaucher's disease is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorder; parents are generally healthy carriers with one functional and one mutated (nonfunctioning) copy of the Gaucher disease gene, ''GBA''. People with type I Gaucher have a defect in the enzyme called

glucocerebrosidase β-Glucocerebrosidase (also called acid β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, or GCase) is an enzyme with glucosylceramidase activity () that is needed to cleave, by hydrolysis, the beta-glycosidic linkage of the chemical g ...

(also known as acid β-glucosidase). Glucocerebrosidase is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

, and its function is to convert

glucocerebroside Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose. Clinical significance In Gaucher disease, the enzyme glucocerebrosidase is nonfunctional and cannot break down glucocer ...

(also known as

glucosylceramide Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose. Clinical significance In Gaucher disease, the enzyme glucocerebrosidase is nonfunctional and cannot break down glucoc ...

) into ceramide and glucose. When this enzyme doesn't work, glucocerebroside accumulates, which in turn causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. It 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. Earlier treatments on the market (

imiglucerase Imiglucerase is a medication used in the treatment of Gaucher's disease. It is a recombinant DNA-produced analogue of the human enzyme β-glucocerebrosidase. Cerezyme is a freeze-dried medicine containing imiglucerase, manufactured by Genzyme C ...

(approved in 1995),

velaglucerase Velaglucerase alfa, sold under the brand name Vpriv and manufactured by Shire plc, is a hydrolytic lysosomal glucocerebroside-specific enzyme, which is a recombinant form of glucocerebrosidase indicated as a long-term enzyme replacement therapy f ...

(approved in 2010), taliglucerase alfa (Elelyso) (approved in 2012)) are

enzyme replacement therapy Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme. ERT is availab ...

- they are functioning versions of the enzyme that doesn't work. Miglustat works differently - it prevents the formation of the substance that builds up when the enzyme doesn't work; this is called

substrate reduction therapy Substrate reduction therapy offers an approach to treatment of certain metabolic disorders, especially glycogen storage diseases and lysosomal storage disorders. In a storage disorder, a critical failure in a metabolic pathway prevents cellular br ...

Chemistry

Miglustat is an

iminosugar An iminosugar, also known as an iminosaccharide, is any analog of a sugar where a nitrogen atom has replaced the oxygen atom in the ring of the structure. Iminosugars are common components of plants and may be responsible for some of their medicin ...

, a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste.European Medicines Agency 1 April 200
Scientific discussion related to approval of Zavesca

Society and culture

Legal status

Miglustat has been approved in the EU, Canada, and Japan for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC). Miglustat has not received approval for this indication outside of these countries and use for this disease, including the US, is off-label.

Research

In July 2004, Actelion started a clinical trial of miglustat to treat

Tay–Sachs disease Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around three to six months of age, with the baby ...

, particularly late-onset Tay–Sachs with an estimated enrollment of 10 subjects; the trial ended August 2007. In November 2007, Actelion initiated a clinical trial with miglustat in people with

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

(CF) who have the

ΔF508 Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...

in both copies of the

cystic fibrosis transmembrane conductance regulator Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...

(CFTR) gene; the study ended in March 2008. The cystic fibrosis trial showed no effect.

References

External links

* {{Portal bar , Medicine Iminosugars Transferase inhibitors Orphan drugs Piperidines