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'''Givinostat''' ([[International Nonproprietary Name|INN]]<ref>{{cite journal | year = 2010 | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63 | url =https://www.who.int/medicines/publications/druginformation/innlists/RL63.pdf | journal = WHO Drug Information | volume = 24 | issue = 1| pages = 58–9 }}</ref>) or '''gavinostat''' (originally '''ITF2357''') is a [[histone deacetylase inhibitor]] with potential [[anti-inflammatory]], [[anti-angiogenic]], and [[antineoplastic]] activities.<ref>[[National Cancer Institute]] (2010). [http://www.cancer.gov/drugdictionary/?CdrID=560751 "Gavinostat".] ''NCI Cancer Dictionary''. U.S. National Institutes of Health. Retrieved 2010-09-15.</ref> It is a [[hydroxamic acid]] used in the form of its [[hydrochloride]].
'''Givinostat''' ([[International Nonproprietary Name|INN]]<ref>{{cite journal | year = 2010 | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63 | url =https://www.who.int/medicines/publications/druginformation/innlists/RL63.pdf | journal = WHO Drug Information | volume = 24 | issue = 1| pages = 58–9 }}</ref>) or '''gavinostat''' (originally '''ITF2357''') is a [[histone deacetylase inhibitor]] with potential [[anti-inflammatory]], [[anti-angiogenic]], and [[antineoplastic]] activities.<ref>[[National Cancer Institute]] (2010). [http://www.cancer.gov/drugdictionary/?CdrID=560751 "Gavinostat".] ''NCI Cancer Dictionary''. U.S. National Institutes of Health. Retrieved 2010-09-15.</ref> It is a [[hydroxamic acid]] used in the form of its [[hydrochloride]].


Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),<ref>{{cite web|url=http://clinicaltrials.gov/ct2/results?term=ITF2357|publisher=ClinicalTrials.gov|title=Search results for ITF2357}}</ref> and has been granted [[orphan drug]] designation in the [[European Union]] for the treatment of [[juvenile idiopathic arthritis|systemic juvenile idiopathic arthritis]],<ref name=JIA>{{cite web|author=Committee for Orphan Medicinal Products|date=23 February 2010|url=http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/02/WC500074739.pdf|title=Public summary of opinion on orphan designation: Givinostat for the treatment of systemic-onset juvenile idiopathic arthritis|publisher=[[European Medicines Agency]]|access-date=2010-09-15}}</ref> [[polycythaemia vera]].<ref name=PV>{{cite web|author=Committee for Orphan Medicinal Products|date=3 March 2010|url=http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/03/WC500075167.pdf|title=Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera|publisher=European Medicines Agency}}</ref> and [[Duchenne muscular dystrophy]].<ref>https://www.ajmc.com/view/givinostat-receives-full-fda-approval-for-duchenne-muscular-dystrophy</ref>
Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),<ref>{{cite web|url=http://clinicaltrials.gov/ct2/results?term=ITF2357|publisher=ClinicalTrials.gov|title=Search results for ITF2357}}</ref> and has been granted [[orphan drug]] designation in the [[European Union]] for the treatment of [[juvenile idiopathic arthritis|systemic juvenile idiopathic arthritis]],<ref name=JIA>{{cite web|author=Committee for Orphan Medicinal Products|date=23 February 2010|url=http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/02/WC500074739.pdf|title=Public summary of opinion on orphan designation: Givinostat for the treatment of systemic-onset juvenile idiopathic arthritis|publisher=[[European Medicines Agency]]|access-date=2010-09-15}}</ref> [[polycythaemia vera]].<ref name=PV>{{cite web|author=Committee for Orphan Medicinal Products|date=3 March 2010|url=http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/03/WC500075167.pdf|title=Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera|publisher=European Medicines Agency}}</ref> and [[Duchenne muscular dystrophy]].<ref>{{Cite web|url=https://www.ajmc.com/view/givinostat-receives-full-fda-approval-for-duchenne-muscular-dystrophy|title=Givinostat Receives Full FDA Approval for Duchenne Muscular Dystrophy|date=March 21, 2024|website=AJMC}}</ref>


A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.<ref>{{Cite news|url=https://www.sciencedaily.com/releases/2018/02/180207164033.htm|title=Potential treatment for diastolic dysfunction in heart failure|work=ScienceDaily|access-date=2018-08-19|language=en}}</ref>
A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.<ref>{{Cite news|url=https://www.sciencedaily.com/releases/2018/02/180207164033.htm|title=Potential treatment for diastolic dysfunction in heart failure|work=ScienceDaily|access-date=2018-08-19|language=en}}</ref>

Revision as of 14:11, 23 March 2024

Givinostat
Clinical data
ATC code
Identifiers
  • {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.258.524 Edit this at Wikidata
Chemical and physical data
FormulaC24H27N3O4
Molar mass421.497 g·mol−1
3D model (JSmol)
  • O=C(OCc2cc1ccc(cc1cc2)CN(CC)CC)Nc3ccc(cc3)C(=O)NO
  • InChI=1S/C24H27N3O4/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28) ☒N
  • Key:YALNUENQHAQXEA-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Givinostat (INN[1]) or gavinostat (originally ITF2357) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.[2] It is a hydroxamic acid used in the form of its hydrochloride.

Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),[3] and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis,[4] polycythaemia vera.[5] and Duchenne muscular dystrophy.[6]

A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.[7]

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.[8][9]

Adverse effects

In clinical trials of givinostat as a salvage therapy for advanced Hodgkin's lymphoma, the most common adverse reactions were fatigue (seen in 50% of participants), mild diarrhea or abdominal pain (40% of participants), moderate thrombocytopenia (decreased platelet counts, seen in one third of patients), and mild leukopenia (a decrease in white blood cell levels, seen in 30% of patients). One-fifth of patients experienced prolongation of the QT interval, a measure of electrical conduction in the heart, severe enough to warrant temporary suspension of treatment.[10]

Mechanism of action

Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6.[9]

It also has activity against cells expressing JAK2(V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera.[11][12] In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease.[5]

References

  1. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63" (PDF). WHO Drug Information. 24 (1): 58–9. 2010.
  2. ^ National Cancer Institute (2010). "Gavinostat". NCI Cancer Dictionary. U.S. National Institutes of Health. Retrieved 2010-09-15.
  3. ^ "Search results for ITF2357". ClinicalTrials.gov.
  4. ^ Committee for Orphan Medicinal Products (23 February 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of systemic-onset juvenile idiopathic arthritis" (PDF). European Medicines Agency. Retrieved 2010-09-15.
  5. ^ a b Committee for Orphan Medicinal Products (3 March 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera" (PDF). European Medicines Agency.
  6. ^ "Givinostat Receives Full FDA Approval for Duchenne Muscular Dystrophy". AJMC. March 21, 2024.
  7. ^ "Potential treatment for diastolic dysfunction in heart failure". ScienceDaily. Retrieved 2018-08-19.
  8. ^ WO 9743251, "Compounds with anti-inflammatory and immunosuppressive activities", published 20 November 1997, assigned to Italfarmaco S.p.A. 
  9. ^ a b Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al. (2005). "The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo". Molecular Medicine. 11 (1–12): 1–15. doi:10.2119/2006-00005.Dinarello. PMC 1449516. PMID 16557334.
  10. ^ Tan J, Cang S, Ma Y, Petrillo RL, Liu D (February 2010). "Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents". Journal of Hematology & Oncology. 3: 5. doi:10.1186/1756-8722-3-5. PMC 2827364. PMID 20132536.
  11. ^ Vannucchi AM, Guglielmelli P, Pieri L, Antonioli E, Bosi A (February 2009). "Treatment options for essential thrombocythemia and polycythemia vera". Expert Review of Hematology. 2 (1): 41–55. doi:10.1586/17474086.2.1.41. PMID 21082994. S2CID 28311699.
  12. ^ Guerini V, Barbui V, Spinelli O, Salvi A, Dellacasa C, Carobbio A, et al. (April 2008). "The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F)". Leukemia. 22 (4): 740–7. doi:10.1038/sj.leu.2405049. PMID 18079739.

Further reading

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