Cannabaceae

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Deulinoleate ethyl
Clinical data
Other namesRT001; Di-deuterated ethyl linoleate; Di-deuterated linoleic acid ethyl ester, 11,11-d2-Ethyl linoleate, or Ethyl 11,11-d2-linoleate
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
  • Ethyl (9Z,12Z)-9,12-11,11-d2-octadecadienoate
CAS Number
PubChem CID
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H34D2O2
Molar mass310.517 g·mol−1
3D model (JSmol)
Density0.88 g/cm3
Boiling point173–177 °C (343–351 °F)
  • CCCCCC=CCC=CCCCCCCCC(=O)OCC
  • InChI=1S/C20H36O2/c1-3-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(21)22-4-2/h8-9,11-12H,3-7,10,13-19H2,1-2H3/b9-8-,12-11-/i10D2
  • Key:FMMOOAYVCKXGMF-XMCVDNGOSA-N
 ☒NcheckY (what is this?)

Deulinoleate ethyl (also known as di-deuterated ethyl linoleate, di-deuterated linoleic acid ethyl ester, 11,11-d2-ethyl linoleate, or ethyl 11,11-d2-linoleate)[1] is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), a part of reinforced lipids. It is an isotopologue of linoleic acid, an essential omega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.

Mechanism of action[edit]

Further information: Isotope effect on lipid peroxidation
An animated illustration of a chain reaction with slow elements

Deulinoleate ethyl is recognized by cells as identical to normal linoleic acid. But when taken up, it is converted into 13,13-d2-arachidonic acid, a heavy isotope version of arachidonic acid, that gets incorporated into lipid membranes. The deuterated compound resists the non-enzymatic lipid peroxidation (LPO) through isotope effect — a non-antioxidant based mechanism that protects mitochondrial, neuronal and other lipid membranes, thereby greatly reducing the levels of numerous LPO-derived toxic products such as reactive carbonyls.[2][3]

Deulinoleate ethyl inhibits ferroptosis by stopping the autoxidation process through the kinetic isotope effect. The protective effect of D-PUFAs was verified in erastin- and RSL3-induced ferroptosis models, with demonstrated efficacy in various disease models, particularly neurodegenerative disorders and clinical trials of deulinoleate ethyl begun in 2018.[4]

Clinical development[edit]

Friedreich's ataxia[edit]

A double-blind comparator-controlled Phase I/II clinical trial for Friedreich's ataxia, sponsored by Retrotope and Friedreich's Ataxia Research Alliance, was conducted to determine the safety profile and appropriate dosing for consequent trials.[5] Deulinoleate ethyl was promptly absorbed and was found to be safe and tolerable over 28 days at the maximal dose of 9 g/day. It improved peak workload and peak oxygen consumption in the test group compared to the control group who received the equal doses of normal, non-deuterated ethyl linoleate.[6] Another randomized, double-blind, placebo-controlled clinical study began in 2019.[7]

Infantile neuroaxonal dystrophy[edit]

An open-label clinical study for infantile neuroaxonal dystrophy evaluating long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of deulinoleate ethyl, which, when taken with food, can protect the neuronal cells from degeneration, started in the Summer 2018.[8]

Phospholipase 2G6-associated neurodegeneration[edit]

In 2017, the FDA granted deulinoleate ethyl orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).[9]

Amyotrophic lateral sclerosis[edit]

In 2018, deulinoleate ethyl was given to a patient with amyotrophic lateral sclerosis (ALS) under a "compassionate use scheme".[10]

Progressive supranuclear palsy[edit]

In 2020, the FDA granted orphan drug designation deulinoleate ethyl for the treatment of patients with progressive supranuclear palsy (PSP). PSP is a disease involving modification and dysfunction of tau protein; mechanism of action of deulinoleate ethyl both lowers lipid peroxidation and prevents mitochondrial cell death of neurons which is associated with disease onset and progression.[11]

Preclinical research[edit]

Alzheimer's disease[edit]

Deulinoleate ethyl has been shown to be effective in a model of Alzheimer's disease in mice.[12]

References[edit]

  1. ^ "9-cis, 12-cis-11,11-D2-Linoleic acid ethyl ester". PubChem.
  2. ^ Hill S, Lamberson CR, Xu L, To R, Tsui HS, Shmanai VV, et al. (August 2012). "Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation". Free Radical Biology & Medicine. 53 (4): 893–906. doi:10.1016/j.freeradbiomed.2012.06.004. PMC 3437768. PMID 22705367.
  3. ^ Demidov VV (August 2020). "Site-specifically deuterated essential lipids as new drugs against neuronal, retinal and vascular degeneration". Drug Discovery Today. 25 (8): 1469–1476. doi:10.1016/j.drudis.2020.03.014. PMID 32247036. S2CID 214794450.
  4. ^ Scarpellini C, Klejborowska G, Lanthier C, Hassannia B, Vanden Berghe T, Augustyns K (September 2023). "Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors". Trends in Pharmacological Sciences: S0165–6147(23)00182–7. doi:10.1016/j.tips.2023.08.012. hdl:1854/LU-01HJ90DJVXAJ7NPCGA09GG3NFR. PMID 37770317.
  5. ^ Clinical trial number NCT02445794 for "A First in Human Study of RT001 in Patients With Friedreich's Ataxia" at ClinicalTrials.gov
  6. ^ Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J, Shchepinov MS (July 2018). "Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia". Movement Disorders. 33 (6): 1000–1005. doi:10.1002/mds.27353. PMID 29624723. S2CID 4664990.
  7. ^ Clinical trial number NCT04102501 for "A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects With Friedreich's Ataxia" at ClinicalTrials.gov
  8. ^ Clinical trial number NCT03570931 for "A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy" at ClinicalTrials.gov
  9. ^ "US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Phospholipase 2G6 (PLA2G6)-Associated Neurodegeneration". Global Newswire. 2 November 2017. Archived from the original on 1 April 2019. Retrieved 12 March 2019.
  10. ^ Inacio P (2018-09-18). "Experimental RT001 Now Available for ALS Under Expanded Access". ALS News Today.
  11. ^ "RT001 Gets Orphan Drug Designation in Progressive Supranuclear Palsy".
  12. ^ Butterfield DA, Halliwell B (March 2019). "Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease". Nature Reviews. Neuroscience. 20 (3): 148–160. doi:10.1038/s41583-019-0132-6. PMC 9382875. PMID 30737462. S2CID 59617957.
source: https://en.wikipedia.org/wiki/RT001

One thought on “Cannabaceae”

  1. Well, that’s interesting to know that Psilotum nudum are known as whisk ferns. Psilotum nudum is the commoner species of the two. While the P. flaccidum is a rare species and is found in the tropical islands. Both the species are usually epiphytic in habit and grow upon tree ferns. These species may also be terrestrial and grow in humus or in the crevices of the rocks.
    View the detailed Guide of Psilotum nudum: Detailed Study Of Psilotum Nudum (Whisk Fern), Classification, Anatomy, Reproduction

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