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Givinostat
Clinical data
Trade namesDuvyzat
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
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, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy.[1][2] It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.[3] It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle.[2]

The most common side effects include diarrhea, abdominal pain, a decrease in platelets—which can lead to increased bleeding—nausea/vomiting, an increase in triglycerides (a type of fat in the body) and fever.[2]

Givinostat was approved for medical use in the United States in March 2024.[2] Givinostat is the first nonsteroidal medication approved by the FDA to treat people with all genetic variants of Duchenne Muscular Dystrophy.[2]

Medical uses[edit]

Givinostat is indicated for the treatment of Duchenne muscular dystrophy in people six years of age and older.[1][2]

Adverse effects[edit]

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.[4]

Mechanism of action[edit]

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.[5]

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.[6][7] 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.[8]

History[edit]

Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),[9] and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis,[10] polycythaemia vera.[8] and Duchenne muscular dystrophy.

A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.[11]

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.[12][5]

The efficacy of givinostat for the treatment of Duchenne muscular dystrophy was evaluated in a randomized, double-blind, placebo-controlled 18-month phase III study.[2] The primary endpoint was the change from baseline to month 18 using a four stair climb to measure muscle function.[2] All participants continued to receive a standard of care steroid regimen throughout the study and, after 18 months of treatment, participants treated with givinostat showed statistically significant less decline in the time it took to climb four stairs compared to placebo.[2] The mean change from baseline to month 18 in time to climb four stairs was 1.25 seconds for participants receiving givinostat compared to 3.03 seconds for participants receiving placebo.[2] A secondary efficacy endpoint was the change from baseline to month 18 in physical function as assessed by the North Star Ambulatory Assessment (NSAA)—a scale commonly used to rate the motor function in boys with Duchenne muscular dystrophy who are capable of walking.[2] Compared to placebo, participants treated with givinostat saw less worsening in their NSAA score after 18 months.[2] The US Food and Drug Administration (FDA) granted the application for givinostat priority review, fast track, orphan drug, and rare pediatric disease designations.[2] The FDA granted the approval of Duvyzat to Italfarmaco S.p.A.[2]

Society and culture[edit]

Names[edit]

Givinostat is the international nonproprietary name.[13]

References[edit]

  1. ^ a b c "Duvyzat- givinostat suspension". DailyMed. 29 March 2024. Retrieved 25 April 2024.
  2. ^ a b c d e f g h i j k l m n "FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy". U.S. Food and Drug Administration (FDA). 21 March 2024. Archived from the original on 23 March 2024. Retrieved 23 March 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ "NCI Drug Dictionary". National Cancer Institute. Archived from the original on 29 June 2023. Retrieved 23 March 2024.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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. Archived from the original on 1 July 2015. Retrieved 18 September 2010.
  7. ^ 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.
  8. ^ 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. Archived from the original (PDF) on 26 April 2012. Retrieved 17 September 2010.
  9. ^ "Search results for ITF2357". ClinicalTrials.gov. Archived from the original on 13 June 2011. Retrieved 13 September 2010.
  10. ^ 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. Archived from the original (PDF) on 3 March 2016. Retrieved 15 September 2010.
  11. ^ "Potential treatment for diastolic dysfunction in heart failure". ScienceDaily. Archived from the original on 19 August 2018. Retrieved 19 August 2018.
  12. ^ WO 9743251, "Compounds with anti-inflammatory and immunosuppressive activities", published 20 November 1997, assigned to Italfarmaco S.p.A. 
  13. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63" (PDF). WHO Drug Information. 24 (1): 58–9. 2010. Archived (PDF) from the original on 15 August 2020. Retrieved 4 October 2020.

Further reading[edit]

source: https://en.wikipedia.org/wiki/Givinostat

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