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==Medical uses==
==Medical uses==
Miglustat is used to treat adults with mild-to-moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable.<ref>Cox TM et al.: Advisory Council to the European Working Group on Gaucher Disease. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. ''J Inherit Metab Dis.'' 2003;26(6):513-26. PMID 14605497</ref> It was approved in Europe in 2002<ref>European Medicines Agency. Human Medicines Database. [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000435/human_med_001171.jsp&mid=WC0b01ac058001d124 Zavesca (miglustat)] Page Accessed 1 September 2014.</ref> and by the US FDA in 2003.<ref>Actelion Press Release August 2003. [http://www.drugs.com/news/zavesca-approved-first-oral-option-type-1-gaucher-3351.html Zavesca approved -- first oral treatment option for type 1 Gaucher disease]</ref>
Miglustat is used to treat adults with mild-to-moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable.<ref>{{cite journal | last1 = Cox | first1 = TM | display-authors = 1 | last2 = et al | year = 2003 | title = : Advisory Council to the European Working Group on Gaucher Disease. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement | url = | journal = J Inherit Metab Dis. | volume = 26 | issue = 6| pages = 513–26 | pmid = 14605497 }}</ref> It was approved in Europe in 2002<ref>European Medicines Agency. Human Medicines Database. [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000435/human_med_001171.jsp&mid=WC0b01ac058001d124 Zavesca (miglustat)] Page Accessed 1 September 2014.</ref> and by the US FDA in 2003.<ref>Actelion Press Release August 2003. [http://www.drugs.com/news/zavesca-approved-first-oral-option-type-1-gaucher-3351.html Zavesca approved -- first oral treatment option for type 1 Gaucher disease]</ref>


Miglustat is the first treatment to be approved for treating progressive neurological complications in people with [[Niemann–Pick disease, type C]] (NPC); it has been approved in Europe in 2009, Canada in 2010, and Japan in 2012, but not in the US where the FDA declined to approve it in 2010 and called for more data.<ref>UK Medicines Information. [http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4475 New Drugs Online Report for miglustat]</ref><ref>Staff, The Pharma Letter. 4 April 2012. [http://www.thepharmaletter.com/article/actelion-drops-setipiprant-gets-miglustat-approval-in-japan Actelion drops setipiprant, gets miglustat approval in Japan]</ref><ref>Kevin Grogan for PharmaTimes. 10 March 2010. [http://www.pharmatimes.com/article/10-03-10/FDA_rejects_Actelion_s_Zavesca_for_rare_NP-C_disease.aspx FDA rejects Actelion's Zavesca for rare NP-C disease]</ref><ref>Actelion Press Release. 23 March 2010 [http://www.marketwired.com/press-release/Zavesca-Miglustat-First-Treatment-Available-Canada-Rare-Progressive-Niemann-Pick-Type-SIX-ATLN-1136457.htm Zavesca® (Miglustat) First Treatment Available in Canada for Rare Progressive Niemann-Pick Type C Disease]</ref>
Miglustat is the first treatment to be approved for treating progressive neurological complications in people with [[Niemann–Pick disease, type C]] (NPC); it has been approved in Europe in 2009, Canada in 2010, and Japan in 2012, but not in the US where the FDA declined to approve it in 2010 and called for more data.<ref>UK Medicines Information. [http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4475 New Drugs Online Report for miglustat]</ref><ref>Staff, The Pharma Letter. 4 April 2012. [http://www.thepharmaletter.com/article/actelion-drops-setipiprant-gets-miglustat-approval-in-japan Actelion drops setipiprant, gets miglustat approval in Japan]</ref><ref>Kevin Grogan for PharmaTimes. 10 March 2010. [http://www.pharmatimes.com/article/10-03-10/FDA_rejects_Actelion_s_Zavesca_for_rare_NP-C_disease.aspx FDA rejects Actelion's Zavesca for rare NP-C disease]</ref><ref>Actelion Press Release. 23 March 2010 [http://www.marketwired.com/press-release/Zavesca-Miglustat-First-Treatment-Available-Canada-Rare-Progressive-Niemann-Pick-Type-SIX-ATLN-1136457.htm Zavesca® (Miglustat) First Treatment Available in Canada for Rare Progressive Niemann-Pick Type C Disease]</ref>
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==Mechanism of action==
==Mechanism of action==
Type I Gaucher's disease is an [[autosomal recessive]] 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]] (also known as acid β-glucosidase). Glucocerebrosidase is an [[enzyme]], and its function is to destroy [[glucocerebroside]] (also known as [[glucosylceramide]]). 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.<ref name=Graboswki>Grabowski GA. Gaucher disease and other storage disorders. Hematology Am Soc Hematol Educ Program. 2012;2012:13-8. doi: 10.1182/asheducation-2012.1.13. PMID 23233555 (free full text)</ref>
Type I Gaucher's disease is an [[autosomal recessive]] 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]] (also known as acid β-glucosidase). Glucocerebrosidase is an [[enzyme]], and its function is to destroy [[glucocerebroside]] (also known as [[glucosylceramide]]). 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.<ref name=Graboswki>Grabowski GA. "Gaucher disease and other storage disorders. ''Hematology Am Soc Hematol Educ Program'' 2012;2012:13-8. doi: 10.1182/asheducation-2012.1.13. PMID 23233555 </ref>


Other treatments on the market ([[Imiglucerase]] (approved in 1995)<ref name=Deegan>Deegan PB, Cox TM. "Imiglucerase in the treatment of Gaucher disease: a history and perspective. ''Drug Des Devel Ther.'' 2012;6:81-106. doi: 10.2147/DDDT.S14395. PMID 22563238</ref> [[Velaglucerase]] (approved in 2010),<ref>{{cite web|url=http://www.medicalnewstoday.com/articles/180630.php |title=Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type I Gaucher Disease |publisher=Medicalnewstoday.com |accessdate=2012-08-13}}</ref> [[Taliglucerase alfa]] (Elelyso) (approved in 2012) <ref>{{cite news|last=Yukhananov|first=Anna|title=U.S. FDA approves Pfizer/Protalix drug for Gaucher|url=http://www.chicagotribune.com/health/sns-rt-us-fda-gaucherbre8401jz-20120501,0,5155428.story|accessdate=2 May 2012|newspaper=[[Chicago Tribune]]|date=1 May 2012|agency=[[Reuters]]}}</ref>) are [[enzyme replacement therapy]] - they are functioning versions of the enzyme that doesn't work. Migulstat works differently - it prevents the formation of the substance that builds up when the enzyme doesn't work; this is called [[substrate reduction therapy]].<ref>Actelion. [http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM196758.pdf FDA Advisory Briefing Book for Miglustat (Ogt 918, Zavesca®) in Niemann-Pick Type C Disease NDA 021-348/S-007] Prepared for the Endocrinologic and Metabolic Drugs Advisory Committee meeting, 1 December 2009</ref>
Other treatments on the market ([[Imiglucerase]] (approved in 1995)<ref name=Deegan>{{cite journal | last1 = Deegan | first1 = PB | last2 = Cox | first2 = TM | year = 2012 | title = Imiglucerase in the treatment of Gaucher disease: a history and perspective | url = | journal = Drug Des Devel Ther. | volume = 6 | issue = | pages = 81–106 | doi = 10.2147/DDDT.S14395 | pmid = 22563238 }}</ref> [[Velaglucerase]] (approved in 2010),<ref>{{cite web|url=http://www.medicalnewstoday.com/articles/180630.php |title=Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type I Gaucher Disease |publisher=Medicalnewstoday.com |accessdate=2012-08-13}}</ref> [[Taliglucerase alfa]] (Elelyso) (approved in 2012) <ref>{{cite news|last=Yukhananov|first=Anna|title=U.S. FDA approves Pfizer/Protalix drug for Gaucher|url=http://www.chicagotribune.com/health/sns-rt-us-fda-gaucherbre8401jz-20120501,0,5155428.story|accessdate=2 May 2012|newspaper=[[Chicago Tribune]]|date=1 May 2012|agency=[[Reuters]]}}</ref>) are [[enzyme replacement therapy]] - they are functioning versions of the enzyme that doesn't work. Migulstat works differently - it prevents the formation of the substance that builds up when the enzyme doesn't work; this is called [[substrate reduction therapy]].<ref>Actelion. [http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM196758.pdf FDA Advisory Briefing Book for Miglustat (Ogt 918, Zavesca®) in Niemann-Pick Type C Disease NDA 021-348/S-007] Prepared for the Endocrinologic and Metabolic Drugs Advisory Committee meeting, 1 December 2009</ref>


==Physical and chemical properties==
==Physical and chemical properties==
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In July 2004 Actelion started a clinical trial of miglustat to treat [[Tay–Sachs disease]], particularly late-onset Tay–Sachs with an estimated enrollment of 10 subjects; the trial ended August 2007.<ref>Clinicaltrials.gov [http://www.clinicaltrials.gov/ct2/show/NCT00672022?term=tay-sachs&rank=3 Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses] Accessed 1 September 2014</ref>
In July 2004 Actelion started a clinical trial of miglustat to treat [[Tay–Sachs disease]], particularly late-onset Tay–Sachs with an estimated enrollment of 10 subjects; the trial ended August 2007.<ref>Clinicaltrials.gov [http://www.clinicaltrials.gov/ct2/show/NCT00672022?term=tay-sachs&rank=3 Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses] Accessed 1 September 2014</ref>


In November 2007, Actelion initiated a clinical trial with miglustat in people with [[cystic fibrosis]] (CF) who have the [[ΔF508]] in both copies of the [[cystic fibrosis transmembrane conductance regulator]] (CFTR) gene; the study ended in March 2008.<ref>Clinicaltrials.gov [http://www.clinicaltrials.gov/ct2/show/NCT00537602 Miglustat / OGT 918 in the Treatment of Cystic Fibrosis] Accessed 1 September 2014</ref> The cystic fibrosis trial showed no effect.<ref>Leonard A et al. A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference. ''J Cyst Fibros.'' 2012 May;11(3):231-6. doi: 10.1016/j.jcf.2011.12.004. PMID 22281182</ref>
In November 2007, Actelion initiated a clinical trial with miglustat in people with [[cystic fibrosis]] (CF) who have the [[ΔF508]] in both copies of the [[cystic fibrosis transmembrane conductance regulator]] (CFTR) gene; the study ended in March 2008.<ref>Clinicaltrials.gov [http://www.clinicaltrials.gov/ct2/show/NCT00537602 Miglustat / OGT 918 in the Treatment of Cystic Fibrosis] Accessed 1 September 2014</ref> The cystic fibrosis trial showed no effect.<ref>{{cite journal | last1 = Leonard | first1 = A | display-authors = 1 | last2 = et al | date = May 2012 | title = A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference | url = | journal = J Cyst Fibros | volume = 11 | issue = 3| pages = 231–6 | doi = 10.1016/j.jcf.2011.12.004 | pmid = 22281182 }}</ref>


==See also==
==See also==

Revision as of 07:58, 21 July 2015

Miglustat
Clinical data
Trade namesZavesca
Other names1,5-(butylimino)-1,5-dideoxy-D-glucitol, N-butyl-deoxynojirimycin
AHFS/Drugs.comMonograph
MedlinePlusa604015
License data
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability97%
Protein bindingNil
MetabolismNil
Elimination half-life6–7 hours
ExcretionRenal, unchanged
Identifiers
  • (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.216.074 Edit this at Wikidata
Chemical and physical data
FormulaC10H21NO4
Molar mass219.28 g/mol g·mol−1
3D model (JSmol)
  • OC[C@H]1N(CCCC)C[C@H](O)[C@@H](O)[C@@H]1O
  • 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 checkY
  • Key:UQRORFVVSGFNRO-UTINFBMNSA-N checkY
  (verify)

Miglustat (OGT 918, N-butyl-deoxynojirimycin) is a drug developed by Oxford GlycoSciences and marketed by Actelion and is used primarily to treat type I Gaucher disease (GD1). It is marketed under the trade name Zavesca.

Medical uses

Miglustat is used to treat adults with mild-to-moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable.[1] It was approved in Europe in 2002[2] and by the US FDA in 2003.[3]

Miglustat is the first treatment to be approved for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC); it has been approved in Europe in 2009, Canada in 2010, and Japan in 2012, but not in the US where the FDA declined to approve it in 2010 and called for more data.[4][5][6][7]

Contraindications

Miglustat is contraindicated for people with neurological conditions, kidney problems, women who are pregnant, and men and women planning to conceive a child.[8]

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).[8]

Mechanism of action

Type I Gaucher's disease is an autosomal recessive 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 (also known as acid β-glucosidase). Glucocerebrosidase is an enzyme, and its function is to destroy glucocerebroside (also known as glucosylceramide). 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.[9]

Other treatments on the market (Imiglucerase (approved in 1995)[10] Velaglucerase (approved in 2010),[11] Taliglucerase alfa (Elelyso) (approved in 2012) [12]) are enzyme replacement therapy - they are functioning versions of the enzyme that doesn't work. Migulstat works differently - it prevents the formation of the substance that builds up when the enzyme doesn't work; this is called substrate reduction therapy.[13]

Physical and chemical properties

Miglustat is an iminosugar, a synthetic analogue of D-glucose[14] and a white to off-white crystalline solid that has a bitter taste.[15]

Research

In July 2004 Actelion started a clinical trial of miglustat to treat Tay–Sachs disease, particularly late-onset Tay–Sachs with an estimated enrollment of 10 subjects; the trial ended August 2007.[16]

In November 2007, Actelion initiated a clinical trial with miglustat in people with cystic fibrosis (CF) who have the ΔF508 in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene; the study ended in March 2008.[17] The cystic fibrosis trial showed no effect.[18]

See also

  • Miglitol, an oral antidiabetic drug with a similar structure

References

  1. ^ Cox, TM; et al. (2003). ": Advisory Council to the European Working Group on Gaucher Disease. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement". J Inherit Metab Dis. 26 (6): 513–26. PMID 14605497. {{cite journal}}: Explicit use of et al. in: |last2= (help)
  2. ^ European Medicines Agency. Human Medicines Database. Zavesca (miglustat) Page Accessed 1 September 2014.
  3. ^ Actelion Press Release August 2003. Zavesca approved -- first oral treatment option for type 1 Gaucher disease
  4. ^ UK Medicines Information. New Drugs Online Report for miglustat
  5. ^ Staff, The Pharma Letter. 4 April 2012. Actelion drops setipiprant, gets miglustat approval in Japan
  6. ^ Kevin Grogan for PharmaTimes. 10 March 2010. FDA rejects Actelion's Zavesca for rare NP-C disease
  7. ^ Actelion Press Release. 23 March 2010 Zavesca® (Miglustat) First Treatment Available in Canada for Rare Progressive Niemann-Pick Type C Disease
  8. ^ a b American Society of Health-System Pharmacists, Inc. for the Public Library of Medicine. Miglustat on MedlinePlus Accessed 1 September 2014
  9. ^ Grabowski GA. "Gaucher disease and other storage disorders. Hematology Am Soc Hematol Educ Program 2012;2012:13-8. doi: 10.1182/asheducation-2012.1.13. PMID 23233555
  10. ^ Deegan, PB; Cox, TM (2012). "Imiglucerase in the treatment of Gaucher disease: a history and perspective". Drug Des Devel Ther. 6: 81–106. doi:10.2147/DDDT.S14395. PMID 22563238.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ "Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type I Gaucher Disease". Medicalnewstoday.com. Retrieved 2012-08-13.
  12. ^ Yukhananov, Anna (1 May 2012). "U.S. FDA approves Pfizer/Protalix drug for Gaucher". Chicago Tribune. Reuters. Retrieved 2 May 2012.
  13. ^ Actelion. FDA Advisory Briefing Book for Miglustat (Ogt 918, Zavesca®) in Niemann-Pick Type C Disease NDA 021-348/S-007 Prepared for the Endocrinologic and Metabolic Drugs Advisory Committee meeting, 1 December 2009
  14. ^ Abian O, Alfonso P, Velazquez-Campoy A, Giraldo P, Pocovi M, Sancho J (December 2011). "Therapeutic strategies for Gaucher disease: miglustat (NB-DNJ) as a pharmacological chaperone for glucocerebrosidase and the different thermostability of velaglucerase alfa and imiglucerase". Molecular Pharmaceutics. 8 (6): 2390–7. doi:10.1021/mp200313e. PMID 21988669.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ European Medicines Agency 1 April 2003 Scientific discussion related to approval of Zavesca.
  16. ^ Clinicaltrials.gov Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses Accessed 1 September 2014
  17. ^ Clinicaltrials.gov Miglustat / OGT 918 in the Treatment of Cystic Fibrosis Accessed 1 September 2014
  18. ^ Leonard, A; et al. (May 2012). "A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference". J Cyst Fibros. 11 (3): 231–6. doi:10.1016/j.jcf.2011.12.004. PMID 22281182. {{cite journal}}: Explicit use of et al. in: |last2= (help)
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