Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C10H21NO4 |
Molecular Weight | 219.278 |
Optical Activity | ( - ) |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CCCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
InChI
InChIKey=UQRORFVVSGFNRO-UTINFBMNSA-N
InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9-,10-/m1/s1
DescriptionSources: http://www.drugbank.ca/drugs/DB00419Curator's Comment: Description was created based on several sources, including
https://www.drugs.com/cdi/miglustat.html
Sources: http://www.drugbank.ca/drugs/DB00419
Curator's Comment: Description was created based on several sources, including
https://www.drugs.com/cdi/miglustat.html
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 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 GM2 and GM3, 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. Miglustat is used 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 marketed under the trade name Zavesca.
CNS Activity
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL2063 Sources: http://www.drugbank.ca/drugs/DB00419 |
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Target ID: CHEMBL2074 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7608901 |
2.1 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Zavesca Approved UseGaucher disease: Treatment of adult patients with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (eg, due to allergy, hypersensitivity, or poor venous access)
Canadian labeling: Additional use (not in U.S. labeling): Treatment to delay the progression of neurological manifestations in Niemann-Pick type C disease Launch Date2003 |
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Primary | Zavesca Approved UseGaucher disease: Treatment of adult patients with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (eg, due to allergy, hypersensitivity, or poor venous access)
Canadian labeling: Additional use (not in U.S. labeling): Treatment to delay the progression of neurological manifestations in Niemann-Pick type C disease Launch Date2003 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1328 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17720777 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
MIGLUSTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
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843 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17720777 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
MIGLUSTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
10868 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17720777 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
MIGLUSTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
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9320 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17720777 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
MIGLUSTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
7.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17720777 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
MIGLUSTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17720777 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
MIGLUSTAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
100% |
MIGLUSTAT plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
100 mg 3 times / day multiple, oral Recommended Dose: 100 mg, 3 times / day Route: oral Route: multiple Dose: 100 mg, 3 times / day Sources: |
unhealthy, 44 Health Status: unhealthy Age Group: 44 Sex: M+F Sources: |
Disc. AE: Neuritis, Neuropathy... AEs leading to discontinuation/dose reduction: Neuritis (grade 3-4) Sources: Neuropathy (grade 3-4) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Neuritis | grade 3-4 Disc. AE |
100 mg 3 times / day multiple, oral Recommended Dose: 100 mg, 3 times / day Route: oral Route: multiple Dose: 100 mg, 3 times / day Sources: |
unhealthy, 44 Health Status: unhealthy Age Group: 44 Sex: M+F Sources: |
Neuropathy | grade 3-4 Disc. AE |
100 mg 3 times / day multiple, oral Recommended Dose: 100 mg, 3 times / day Route: oral Route: multiple Dose: 100 mg, 3 times / day Sources: |
unhealthy, 44 Health Status: unhealthy Age Group: 44 Sex: M+F Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
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OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-348_Zavesca_BioPharmr.pdf#page=15 Page: 15.0 |
no |
PubMed
Title | Date | PubMed |
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6-0-butanoylcastanospermine (MDL 28,574) inhibits glycoprotein processing and the growth of HIVs. | 1991 Jun |
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Inhibition of HIV and SIV infectivity by blockade of alpha-glucosidase activity. | 1991 Mar |
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Differential effects of glycolipid biosynthesis inhibitors on ceramide-induced cell death in neuroblastoma cells. | 1999 Mar |
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N -butyldeoxynojirimycin reduces growth and ganglioside content of experimental mouse brain tumours. | 2001 Apr 20 |
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Critical role for glycosphingolipids in Niemann-Pick disease type C. | 2001 Aug 21 |
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Substrate reduction therapy for glycosphingolipid storage disorders. | 2001 Mar |
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Regulation of apoptosis during neuronal differentiation by ceramide and b-series complex gangliosides. | 2001 Nov 30 |
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pH-sensitive liposomes are efficient carriers for endoplasmic reticulum-targeted drugs in mouse melanoma cells. | 2002 May 10 |
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Calnexin, calreticulin, and ERp57 cooperate in disulfide bond formation in human CD1d heavy chain. | 2002 Nov 22 |
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Miglustat. Oxford GlycoSciences/Actelion. | 2003 Apr |
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Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease. | 2004 |
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[Type 1 Gaucher's disease in the adult. Nutritional management during initiation of treatment with miglustat]. | 2004 Apr 10 |
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C-glycosides and aza-C-glycosides as potential glycosidase and glycosyltransferase inhibitors. | 2005 |
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An open-label, noncomparative study of miglustat in type I Gaucher disease: efficacy and tolerability over 24 months of treatment. | 2005 Aug |
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Absence of pathogenic mitochondrial DNA mutations in mouse brain tumors. | 2005 Aug 16 |
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Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. | 2005 Nov |
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Miglustat: new drug. In type 1 Gaucher's disease : a slight benefit after imiglucerase therapy. | 2005 Oct |
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Imino sugar inhibitors for treating the lysosomal glycosphingolipidoses. | 2005 Oct |
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Synthesis and glycosidase inhibitory activity of new hexa-substituted C8-glycomimetics. | 2005 Oct 7 |
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Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in cells transfected with several Gaucher disease mutations. | 2005 Sep-Oct |
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Gaucher disease: multiple lessons from a single gene disorder. | 2006 Apr |
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D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains. | 2006 Apr 11 |
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Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat. | 2006 Apr 3 |
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Substrate reduction therapy of glycosphingolipid storage disorders. | 2006 Apr-Jun |
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Inhibition of hybrid- and complex-type glycosylation reveals the presence of the GlcNAc transferase I-independent fucosylation pathway. | 2006 Aug |
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Miglustat: substrate reduction therapy for lysosomal storage disorders associated with primary central nervous system involvement. | 2006 Jan |
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Miglustat: substrate reduction therapy for glycosphingolipid lysosomal storage disorders. | 2006 Jan |
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Substrate reduction therapy in the infantile form of Tay-Sachs disease. | 2006 Jan 24 |
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Gateways to clinical trials. | 2006 Jan-Feb |
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Gangliosides do not affect ABC transporter function in human neuroblastoma cells. | 2006 Jun |
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Therapeutic goals in Gaucher disease. | 2006 Mar |
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[Clinical study of the French cohort of Gaucher disease patients]. | 2006 Mar |
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Short-term effect of miglustat in every day clinical use in treatment-naïve or previously treated patients with type 1 Gaucher's disease. | 2006 May |
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Long-term non-hormonal male contraception in mice using N-butyldeoxynojirimycin. | 2006 May |
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Clinical experience with substrate reduction therapy. | 2006 Nov |
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Effective treatment of an elderly patient with Gaucher's disease and Parkinsonism: a case report of 24 months' oral substrate reduction therapy with miglustat. | 2007 Aug |
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[Osteoarticular manifestations of Gaucher disease in adults: pathophysiology and treatment]. | 2007 Dec |
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[Iminosugars: current and future therapeutic applications]. | 2007 Jan |
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The sensitivity of murine spermiogenesis to miglustat is a quantitative trait: a pharmacogenetic study. | 2007 Jan 22 |
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Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism. | 2007 Jun |
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The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat. | 2007 Mar |
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[Organization of Gaucher disease management in France]. | 2007 Oct |
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[Therapeutic objectives in Gaucher disease]. | 2007 Oct |
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Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. | 2007 Oct 1 |
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Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease. | 2007 Sep |
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Gaucher disease: improving management. | 2008 Apr |
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Proteasome-dependent pharmacological rescue of cystic fibrosis transmembrane conductance regulator revealed by mutation of glycine 622. | 2008 Apr |
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N-butyldeoxynojirimycin causes weight loss as a result of appetite suppression in lean and obese mice. | 2008 Feb |
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Parallel improvement of sodium and chloride transport defects by miglustat (n-butyldeoxynojyrimicin) in cystic fibrosis epithelial cells. | 2008 Jun |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.drugs.com/dosage/miglustat.html
100 mg orally 3 times a day at regular intervals
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/14580684
50 uM Miglustat reduced MEB4 cell GlcCer synthase activity (by 70%), ganglioside synthesis (by 61%), and shedding (by 37%)
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
756020
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FDA ORPHAN DRUG |
270708
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EMA ASSESSMENT REPORTS |
ZAVESCA (AUTHORIZED: NIEMANN-PICK DISEASE)
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WHO-ATC |
A16AX06
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FDA ORPHAN DRUG |
798620
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NDF-RT |
N0000020019
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EMA ASSESSMENT REPORTS |
ZAVESCA (AUTHORIZED: GAUCHER DISEASE)
Created by
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EMA ASSESSMENT REPORTS |
ZAVESCA (AUTHORIZED: NIEMANN-PICK DISEASES)
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NCI_THESAURUS |
C2846
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FDA ORPHAN DRUG |
795420
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EU-Orphan Drug |
EU/3/06/351
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NDF-RT |
N0000175783
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FDA ORPHAN DRUG |
112198
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WHO-VATC |
QA16AX06
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FDA ORPHAN DRUG |
601617
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FDA ORPHAN DRUG |
112598
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C1222
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51634
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Miglustat
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50381
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4841
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Miglustat
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SUB20049
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100000089526
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PP-68
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8138
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402316
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72599-27-0
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CHEMBL1029
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m7538
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DTXSID6045618
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DB00419
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ADN3S497AZ
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ADN3S497AZ
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C059896
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ACTIVE MOIETY