HU-308
HU-308.png
Clinical data
Routes of
administration
injection, oral, eyedrops
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver
ExcretionKidneys
Identifiers
  • [(1R,2R,5R)-2-[2,6-Dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H42O3
Molar mass414.630 g·mol−1
3D model (JSmol)
  • CCCCCCC(C)(C)C1=CC(=C(C(=C1)OC)[C@H]2C=C([C@@H]3C[C@H]2C3(C)C)CO)OC
  • InChI=1S/C27H42O3/c1-8-9-10-11-12-26(2,3)19-14-23(29-6)25(24(15-19)30-7)20-13-18(17-28)21-16-22(20)27(21,4)5/h13-15,20-22,28H,8-12,16-17H2,1-7H3/t20-,21-,22+/m0/s1
  • Key:CFMRIVODIXTERW-FDFHNCONSA-N
 ☒NcheckY (what is this?)  (verify)

HU-308, aka HU308, PPP-003 and ARDS-003, is a cannabidiol (CBD)-derivative drug that acts as a potent cannabinoid agonist. It is highly selective for the CB2 receptor subtype in particular, with a selectivity of over 5,000 times greater for the CB2 receptor versus the CB1 receptor.[1][2][3] The synthesis and characterization took place in the laboratory of Prof. Mechoulam at the Hebrew University of Jerusalem, (the HU in HU-308), in the late 1990s. The pinene dimethoxy-DMH-CBD derivative HU-308 was identified decades ago as a potent peripheral CB2-selective agonist in Mechoulam et al. 1990,[1] and in Hanus et al. 1999.[2] HU-308 has shown very interesting properties such as anti-inflammatory, analgesic, neuroprotective, antitumor and anti-osteoporitic (anti-bone-loss) effects, and has been used as a pharmacological tool in numerous cannabinoid studies contributing to the progress in this field (e.g., Hanus et al. 1999;[2] Ofek et al. 2006;[4] Rajesh et al. 2007a,[5] Morales 2017[6]), including being named a pivotal advance in the NIH database in Rafesh 2007b for its discoveries, findings and results in attenuating oxidative stress, inflammatory response, and apoptosis (programmed cell death).[7] HU-308 is also classified as a non-steroidal anti-inflammatory drug (NSAID).[8]

Pharmacology[edit]

Osteoporosis[edit]

Cannabinoid receptors were first implicated in the regulation of bone mass by Karsak et al. (2004),[9] who found that CB2 knockout mice had markedly accelerated age-related trabecular bone loss and cortical expansion accompanied by increased activity of trabecular osteoblasts, increased numbers of osteoclasts, and decreased numbers of diaphyseal osteoblast precursors (Ofek et al. 2006).[4] CB2 receptors were expressed in osteoblasts, osteocytes, and osteoclasts. The selective CB2 agonist HU-308, but not the CB1 receptor agonist noladin ether, attenuated ovariectomy-induced bone loss and markedly stimulated cortical thickness through the suppression of osteoclast number and stimulation of endocortical bone formation.[4] Furthermore, HU-308 dose dependently increased the number and activity of endocortical osteoblasts and restrained trabecular osteoclastogenesis by inhibiting proliferation of osteoclast precursors.[4] These results, coupled with CB2 but not CB1 receptor mRNA expression during osteoblastic differentiation, suggested a role for CB2 receptors in bone remodeling. Such a role of CB2 but not CB1 receptors is also supported by a systematic genetic association study by Karsak et al. (2005) in human samples of postmenopausal osteoporosis patients and matched female control subjects, which found a very statistically significant association of single polymorphisms (P=0.0014) and haplotypes (P=0.0001) that encompassed the CNR2 gene on human chromosome 1p36, while finding no convincing association for the psychotropic CNR1 gene.[10] It is the non-psychotropic cannabinoid receptor type 2 gene that is found to be so strongly associated with human osteoporosis as P value of 0.0001.[10]

NeuroInflammation[edit]

HU308 promotes neural progenitor (NP) proliferation and neurogenesis of neural stem cells,[11] promotes neuroprotection and neurorepair, activates Phosphatidyl Inositol, and has important implications for neuronal survival under neuroinflammatory conditions occurring in animal models of neurodegenerative diseases, such as multiple sclerosis, Alzheimer disease, and Huntington's Disease,[12][13][14][15] and upon acute ischemic brain injury.[16] Attenuation of the inflammatory response in the brain has also been reported by activation of CB2 receptors in a study of pial vessels forming the blood–brain barrier, using a model of lipopolysaccharide-induced encephalitis (Ramirez et al. 2012), wherein activation of CB2 receptors decreased adhesion molecules in the brain tissue and leukocyte-endothelial adhesion in the pial vessels.[17] HU-308 protects both liver and blood vessel tissues against hepatic ischemia and reperfusion (blood circulatory system) injury by attenuating oxidative stress, inflammatory response and apoptosis via inhibition of TNF-α.[5] The role of CB2 receptors in endothelial cell activation and endothelial/inflammatory cell interactions, being critical steps not only in reperfusion injury, but also atherosclerosis and other inflammatory disorders, turned out to be very important, because selective CB2 cannabinoid agonist HU-308 decreased TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) expressing CB2 receptors, as well as the adhesion of human neutrophils to HLSECs in vitro.[18] HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity.[2][19] Currently, CBD (especially potent CBD derivatives like HU-308) generate considerable interest due to their beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory and pain-relieving properties, therefore, the CBD scaffold becomes of increasing interest for medicinal chemists.[6]

Inflammation & Immune Modulation[edit]

HU-308 has an important functional outcome ~ the secretion of interleukin 6 (IL-6) and interleukin 10 (IL-10) with therapeutic immunomodulatory properties in vitro.[20] There is evidence that IL-6 may be used as an inflammatory marker for the more severe COVID-19 infections that have a poor prognosis for a favorable outcome because raised levels of IL-6 as well as troponin are associated with a poor prognosis in COVID-19.[21] Researchers Dr. Melanie Kelly and Dr. C. Lehmann at Panag Pharma, now merged with Tetra Bio-Pharma,[22][23][24][25] which owns the IP rights to HU-308,[26][27][28] showed with Drs. J Sardinha and J Zhou that HU 308 also mediates immune modulation in sepsis,[29] as well as displays antiallodynic activity (alleviates allodynic pain) in the rat hindpaw incision model of post-operative pain, is neuroprotective and improves motor performance in a mouse model of Huntington's Disease.[30] Continued work by Dr. MEM Kelly et al. showed HU-308 also dramatically fights the Cytokine Release Syndrome (CRS), also called cytokine release storm, that is seen in many diseases and conditions, including Acute Respiratory Distress Syndrome (ARDS), COVID-19, Sepsis, Septic Shock, Systemic Inflammatory Response Syndrome (SIRS), Cytokine Storm Syndrome (CSS), Multi-Organ Dysfunction Syndrome (MODS), Pneumonia, Uveitis, Corneal Neuropathic Pain Hyperalgesia, Photo-allodynia, Burning, Stinging, Dryness and Inflammation. The antinociceptive and anti-inflammatory effects of HU-308, but not Δ8THC or CBD, were mediated through CB2R, and it reduces cytokine storms in the eye, importantly, where corneal damage can result in an inflammatory response that involves the production of proinflammatory cytokines, neovascularization, recruitment of leukocytes, and release of neuropeptides producing inflammatory pain.[31][32][33] The Thapa et al. study on HU-308 in reducing Corneal Pain in 2018 is the first time a CB2R agonist has been demonstrated to reduce corneal pain.[33] HU-308 is a selective and highly potent agonist at CB2R and has previously been shown to reduce lipopolysaccharide-induced intraocular inflammation.[33][34]

Multi-Organ Dysfunction & Damage[edit]

While CB2 knockout mice developed enhanced inflammation and tissue injury from cisplatin-induced kidney damage, HU-308, working through the endocannabinoid system and the CB2 receptor, protected against cisplatin-induced kidney damage by attenuating inflammation and oxidative or nitrosative stress, and such selective CB2 agonists may represent a promising novel approach to prevent this devastating complication of chemotherapy.[35] Activation of the cannabinoid-2 (CB2) receptors (expressed predominantly in immune cells, and also to a much less extent in other cell types, e.g., endothelial and parenchymal cells) by recently recognized endogenous lipid mediators (the endocannabinoids) produced and present in virtually all tissues/organ systems,[36][37][38] or by selective synthetic CB2 agonists such as HU-308 in the pivotal advance by Rajesh et al. (2007),[7] has been shown to protect against tissue damage in various experimental models of ischemic-reperfusion injury,[7][39] atherosclerosis/cardiovascular inflammation,[40][41][42] and neurodegenerative,[43] gastrointestinal[44][45] and other disorders by limiting inflammatory cell chemotaxis/infiltration, activation and interrelated oxidative/nitrosative stress.[46][47][48][49] In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice.[44] Furthermore, CB2 receptors are over-expressed in a variety of cancers, and CB2 activation may decrease the proliferation and growth of various cancer cells and tumors.[35][50] HU-308 was shown to reduce swelling, synovial join inflammation and destruction, in addition to lowering circulating antibodies against Collagen I.[51]

ARDS-003[edit]

HU-308, aka ARDS-03 for its ARDS fighting abilities, is currently in a collaboration study by Tetra Bio-Pharma, Targeted Pharmaceutical, LLC, George Mason University and the NIH at the university's top-level National Center for Biodefense and Infectious Diseases Biomedical Research Laboratory (BRL) against the lethal condition Acute Respiratory Distress Syndrome (ARDS) seen in COVID-19 patients.[52][53][54][55][56][57] Regulatory filings show that in late 2020 Tetra and Targeted designed short- to mid- term studies to gather additional data on the benefits of ARDS-003 in Sars-CoV-2 infected animal models for the prevention of ARDS in COVID-19.[58] A former Deputy Director of the NIH is heading the GMU research on ARDS-003, which is a novel, sterile, injectable, optimized, nanoemulsion form of HU-308 that has successfully undergone stringent safety and toxicology studies in accordance with U.S. FDA oversight, which were required before submitting an investigational new drug (IND) application in the US and a clinical trial application (CTA) in Canada for a Phase 1 research study through the Sars-CoV-2 regulatory fast track pathway.[56][59] The toxicology program was designed to the standards of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) for enabling a first-in-human clinical trial; and included general toxicology data for two species-specific studies to assess toxicity in major organ systems (cardiovascular, respiratory, nervous system) and genotoxicity, as well as the metabolism and pharmacokinetic distribution of the drug.[59] Tetra Bio-Pharma is the first endocannabinoid system (ECS) biotechnology company researching a cannabinoid treatment for ARDS and sepsis linked to COVID-19, pneumonia and other critical conditions, and the ARDS-003 pharmaceutical drug now has FDA approval to begin Phase I and Phase II clinical trials in human subjects for the reduction of cytokine storm, sepsis, and ARDS in COVID-19.[52][59] GMU researchers including the Co-Director, Center for Applied Proteomics and Molecular Medicine (CAPMM), are conducting three studies to assess the therapeutic efficacy of candidate interventions for COVID-19 in mouse models of angiotensin-converting enzyme 2 (ACE2) animals infected intranasally with SARS-CoV-2 to determine the survival advantage conferred by a therapeutic, to determine the survival advantage conferred by a therapeutic if an alternate course or dosing strategy needs to be followed, and to determine viral levels on day three post-infection when viral load in the lungs is expected to peak.[60] Dalton Pharma is producing the injectable drug for the GMU effort.[61]

Ocular Diseases[edit]

A 50-50 joint venture collaboration of Tetra Bio-Pharma and Altus Formulations, named TALLC, is developing a fast onset, long-duration form of HU-308, called TA-A001, which is a non-opioid, non-steroidal small molecule of low molecular weight: (< 900 daltons) that selectively activates CB2 receptors mediating the human anti-inflammatory response, as an alternative to opioid medications and NSAIDs for ocular pain and dry eye disease.[62] TA-A001 uses the JV's patented SmartCelle nanotechnology, and a second formulation, called TA-P2005, is shown in preclinical studies to have twelve times more efficacy than if conventionally formulated and is expected to increase corneal access to the medication.[62] Ongoing studies seek to determine analgesic and anti-inflammatory effects of various dosages of TA-A001 in a corneal hyperalgesia model.[62] TA-A002 is a further topical treatment for treating the glaucoma and dry-eye disease.[62] TALLC's lead indication is the orphan disease keratoconus, for which it is submitting its application for orphan drug status.[62] On July 7, 2020, the United Kingdom Intellectual Property Office granted the TALLC patent GB2561009 for its novel SmartCelle nanotechnology.[63] It is the first patent granted in the series of SmartCelleT “smart micelle” patents applied for and the TA-A001 reformulation of HU-308 is considered, like HU-308, to also be a nonsteroidal anti-inflammatory drug (NSAID), which is a drug class that reduces pain and fever, prevents blood clots, and in higher doses decreases inflammation.[62]

Legal status[edit]

HU-308 is non-psychoactive and not scheduled at the federal level in the United States.[64] It is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess there.[65]

References[edit]

  1. ^ a b Mechoulam R, Lander N, Breuer A, Zahalka J (1990-04-11). "Synthesis of the individual, pharmacologically distinct enantiomers of a tetrahydrocannabinol derivative". Tetrahedron Asymmetry. 1 (5): 315–318. doi:10.1016/S0957-4166(00)86322-3.
  2. ^ a b c d Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E (December 1999). "HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor". Proceedings of the National Academy of Sciences of the United States of America. 96 (25): 14228–33. Bibcode:1999PNAS...9614228H. doi:10.1073/pnas.96.25.14228. PMC 24419. PMID 10588688.
  3. ^ "Properties of HU-308 ~ Formula C27H42O3". Pitt Quantum Repository. University of Pittsburgh Department of Chemistry.
  4. ^ a b c d Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I (2006-01-17). "Peripheral cannabinoid receptor, CB2, regulates bone mass". Proc Natl Acad Sci U S A. 103 (3): 696–701. doi:10.1073/pnas.0504187103. PMC 1334629. PMID 16407142.
  5. ^ a b Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, et al. (2007-10-01). "CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion". American Journal of Physiology: Heart & Circulatory Physiology. 293 (4): H2210–H2218. doi:10.1152/ajpheart.00688.2007. PMC 2229632. PMID 17660390.
  6. ^ a b Morales P, Reggio PH, Jagerovic N (2017-06-28). "An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol". Frontiers in Pharmacology. 8: 422. doi:10.3389/fphar.2017.00422. PMC 5487438. PMID 28701957.
  7. ^ a b c Rajesh M, Pan H, Mukhopadhyay P, Bátkai S, Osei-Hyiaman D, Haskó G, et al. (December 2007). "Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic Ischemia-reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis". Journal of Leukocyte Biology. 82 (6): 1382–9. doi:10.1189/jlb.0307180. PMC 2225476. PMID 17652447.
  8. ^ Lynch, Mary; Kelly, Melanie. "Spanish Patent ES2784229T3 HU-308, HU-433, CBD-DMH Compositions and procedures for the treatment of eye inflammation and pain". Google Patents. Panag Pharma. Retrieved 22 February 2021. A61P29/00 Non-central analgesic, antipyretic or anti-inflammatory agents, e.g antirheumatic agents; Non-steroidal anti-inflammatory drugs (NSAIDs)
  9. ^ Karsak M, Ofek O, Fogel M, Wright K, Tam J, Gabet Y, Birenboim R, Attar-Namdar M, Müller R, Cohen-Solal M (October 2004). "The cannabinoid CB2 receptor: a potential target for the treatment of osteoporosis". Journal of Bone and Mineral Research. 19 (S1): S383. doi:10.1002/jbmr.5650191306.
  10. ^ a b Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, Essig J, Erxlebe E, Bab I, Kubisch C, de Vernejoul MC, Zimmer A (15 November 2005). "Cannabinoid receptor type 2 gene is associated with human osteoporosis". Human Molecular Genetics. 14 (22): 3389–96. doi:10.1093/hmg/ddi370. PMID 16204352.
  11. ^ Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzmán M, Galve-Roperh I (November 2006). "Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation". FASEB Journal. 20 (13): 2405–7. doi:10.1096/fj.06-6164fje. PMID 17015409. S2CID 4885167.
  12. ^ Fernández-Ruiz J, González S, Romero J, Ramos JA (2005). "Cannabinoids in Neurodegeneration and Neuroprotection". In: Mechoulam, R.(Ed.), Cannabinoids as Therapeutics (MDT) Birkhaüser Verlag; Switzerland: 79–109.
  13. ^ Fernández-Ruiz J, Romero J, Velasco G, Tolón RM, Ramos JA, Guzmán M (Jan 2007). "Cannabinoid CB2 receptor: a new target for the control of neural cell survival". Trends Pharmacol Sci. 28 (1): :39–45. doi:10.1016/j.tips.2006.11.001. PMID 17141334.
  14. ^ Esposito G, Scuderi C, Savani C, Steardo L, Jr, De Filippis D, Cottone P, Iuvone T, Cuomo V, Steardo L (Aug 2007). "Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression". British Journal of Pharmacology. 151 (8): 1272–1279. doi:10.1038/sj.bjp.0707337. PMC 2189818. PMID 17592514.
  15. ^ Fernández-López D, Pazos MR, Tolón RM, Moro MA, Romero J, Lizasoain I, Martínez-Orgado J (Sep 2007). "The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats". Pediatric Research. 62 (3): 255–60. doi:10.1203/PDR.0b013e318123fbb8. PMID 17622949.
  16. ^ Palazuelos J, Ortega Z, Díaz-Alonso J, Guzmán M, and Galve-Roperh I (January 2012). "CB2 Cannabinoid Receptors Promote Neural Progenitor Cell Proliferation via mTORC1 Signaling". Journal of Biological Chemistry. 287 (2): 1198–1209. doi:10.1074/jbc.M111.291294. PMID 22102284.
  17. ^ Ramirez SH, Haskó J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y (21 March 2012). "Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions". J Neuroscience. 32 (12): 4000–16. doi:10.1523/JNEUROSCI.4628-11.2012. PMC 3325902. PMID 22442067.
  18. ^ Pacher P, Gao B (Apr 2008). "Endocannabinoids and Liver Disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases". Am J Physiol Gastrointest Liver Physiol. 294 (4): G850–G854. doi:10.1152/ajpgi.00523.2007. PMC 2376822. PMID 18239059.
  19. ^ LaBuda CJ, Koblish M, Little PJ (December 2005). "Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain". European Journal of Pharmacology. 527 (1–3): 172–4. doi:10.1016/j.ejphar.2005.10.020. PMID 16316653.
  20. ^ Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL (2019-10-19). "Cannabinoid Receptor 2 (CB 2 ) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes". ACS Pharmacology & Translational Science. 2 (6): 414–428. doi:10.1021/acsptsci.9b00049. ISSN 2575-9108. PMC 7088898. PMID 32259074.
  21. ^ "Raised troponin and interleukin-6 levels are associated with a poor prognosis in COVID-19. 2 April 2020. Graham Cole (Imperial College Healthcare NHS Trust, London, UK)". Cardiac Rhythm News. Graham Cole, CRN. Retrieved 21 February 2021.
  22. ^ Nov 2018, Tetra Bio-Pharma Enters into Non-Binding Proposal to Acquire Panag Pharma Inc.
  23. ^ Jan 2019, Tetra Bio-Pharma Enters into Definitive Agreement to Acquire Panag Pharma Inc.
  24. ^ Apr 2019, Tetra Bio-Pharma Shareholders Approve the Acquisition of Panag Pharma
  25. ^ May 2019, Tetra Bio-Pharma Closes the Acquisition of Panag Pharma
  26. ^ USPTO, Compositions and methods for treatment of ocular inflammation and/or pain (Lynch & Kelly Jan 2017). In certain embodiments, the non-psychotropic phytocannabinoid is beta-caryophyllene or cannabidiol [CBD] and the synthetic cannabinoid is HU-433, HU-308, or a modified CBD such as CBD-DMH.
  27. ^ Justia, Compositions and methods for treatment of ocular inflammation and/or pain (Lynch & Kelly May 2015)
  28. ^ Lynch, Mary; Kelly, Melanie. "Patent 9549906 Composition & Methods for Treatment of Ocular Inflammation &/or Pain Jan 2017". U.S. Patent & Trademark Office. USPTO, Panag Pharma. Retrieved 20 February 2021.
  29. ^ Sardinha, Kelly, Zhou, Lehmann (2014). "Experimental cannabinoid 2 receptor-mediated immune modulation in sepsis". Mediators of Inflammation. PMID 24803745.
  30. ^ https://www.tocris.com/products/hu-308_3088
  31. ^ https://www.cas.org/blog/covid-19-cytokine-storms
  32. ^ https://pubmed.ncbi.nlm.nih.gov/31613449/
  33. ^ a b c Thapa, Cairns, Szczesniak, Toguri, Caldwell, Kelly (2018). "The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation". Cannabis & Cannabinoid Research. PMID 29450258.
  34. ^ Toguri, Lehmann, Laprairie, Szczesniak, Zhou, Denovan-Wright, Kelly (March 2014). "Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis". British Journal of Pharmacology. 171 (6): 1448–61. doi:10.1111/bph.12545. PMC 3954484. PMID 24308861.
  35. ^ a b Mukhopadhyay P, Rajesh M, Pan H, Patel V, Mukhopadhyay B, Bátkai S, Gao B, et al. (February 2010). "Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress and cell death in nephropathy". Free Radical Biology and Medicine. 48 (3): 457–67. doi:10.1016/j.freeradbiomed.2009.11.022. PMC 2869084. PMID 19969072.
  36. ^ Mechoulam R, Fride E, DiMarzo V (1998). "Endocannabinoids". Eur J Pharmacol. 359 (1): 1–18. doi:10.1016/s0014-2999(98)00649-9. PMID 9831287.
  37. ^ Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002). "International Union of Pharmacology. XXVII. Classification of cannabinoid receptors". Pharmacol Rev. 54 (2): 161–202. doi:10.1124/pr.54.2.161. PMID 12037135.
  38. ^ Pacher P, Batkai S, Kunos G (Sep 2006). "International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. The Endocannabinoid System as an Emerging Target of Pharmacotherapy". Pharmacol Rev. 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
  39. ^ Batkai S, Osei-Hyiaman D, Pan H, El-Assal O, Rajesh M, Mukhopadhyay P, Hong F, Harvey-White J, Jafri A, Hasko G, Huffman JW, Gao B, Kunos G, Pacher P (Jun 2007). "Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury". FASEB J. 21 (8): 1788–1800. doi:10.1096/fj.06-7451com. PMC 2228252. PMID 17327359.
  40. ^ Gallily R, Breuer A, Mechoulam R (2000-10-06). "2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice". Eur J Pharmacol. 406 (1): R5-7. doi:10.1016/s0014-2999(00)00653-1. PMID 11011050.
  41. ^ Gaoni Y, Mechoulam R (1971-01-13). "The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish". J Am Chem Soc. 93 (1): 217–24. doi:10.1021/ja00730a036. PMID 5538858.
  42. ^ García-Arencibia M, González S, de Lago E, Ramos JA, Mechoulam R, Fernández-Ruiz J (2007-02-23). "Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: importance of antioxidant and cannabinoid receptor-independent properties". Brain Res. 1134 (1): 162–70. doi:10.1016/j.brainres.2006.11.063. PMID 17196181.
  43. ^ Sagredo O, González S, Aroyo I, Pazos M, Benito C, Lastres-Becker I, Romero J, Tolón R, Mechoulam R, Brouillet E, Romero J, Fernández-Ruiz J (2009-08-15). "Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease". Glia. 57 (11): 1154–67. doi:10.1002/glia.20838. PMC 2706932.
  44. ^ a b Ke P, Shao BZ, Xu ZQ, et al. (2016-09-09). "Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages". PLoS One. 11 (9): e0155076. doi:10.1371/journal.pone.0155076. PMC 5017608. PMID 27611972.
  45. ^ Storr MA, Keenan CM, Zhang H, Patel KD, Makriyannis A, Sharkey KA (Nov 2009). "Activation of the cannabinoid 2 receptor (CB(2)) protects against experimental colitis". Inflammable Bowel Disease. 15 (11): 1678–1685. doi:10.1002/ibd.20960. PMC 5531765. PMID 19408320.
  46. ^ Pacher P, Batkai S, Kunos G (Sep 2006). "The endocannabinoid system as an emerging target of pharmacotherapy". Pharmacol Rev. 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
  47. ^ Bátkai S, Járai Z, Wagner JA, Goparaju SK, Varga K, Liu J, Wang L, Mirshahi F, Khanolkar AD, Makriyannis A, Urbaschek R, Garcia N Jr, Sanyal AJ, Kunos G (July 2001). "Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis". Nat Med. 7 (7): 827–32. doi:10.1038/89953. PMID 11433348.
  48. ^ Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, Pacher P, Harvey-White J, Luft FC, Sharma AM, Jordan J (October 2005). "Activation of the Peripheral Endocannabinoid System in Human Obesity". Diabetes. 54 (10): 2838–2843. doi:10.2337/diabetes.54.10.2838. PMC 2228268. PMID 16186383.
  49. ^ Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L (May 2005). "Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". J Clin Invest. 115 (5): 1298–305. doi:10.1172/JCI23057. PMC 1087161. PMID 15864349.
  50. ^ Kunikowska G, Jenner P (2001-12-13). "6-Hydroxydopamine-lesioning of the nigrostriatal pathway in rats alters basal ganglia mRNA for copper, zinc- and manganese-superoxide dismutase, but not glutathione peroxidase". Brain Res. 922 (1): 51–64. doi:10.1016/s0006-8993(01)03149-3. PMID 11730701.
  51. ^ Gui H, Liu X, Liu LR, Su DF, Dai SM (Jun 2015). "Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis". Immunobiology. 220 (6): 817–22. doi:10.1016/j.imbio.2014.12.012. PMID 25601571.
  52. ^ a b https://www.forbes.com/sites/emilyearlenbaugh/2020/08/20/synthetic-cannabinoid-drug-for-covid-19-approved-for-phase-1-clinical-trials/
  53. ^ https://s24.q4cdn.com/136309390/files/doc_presentation/2020/12/Tetra-Bio-Pharma-Milestones-Update-Dec.-30-2020.pdf
  54. ^ https://www.sedar.com/GetFile.do?lang=EN&docClass=7&issuerNo=00026458&issuerType=03&projectNo=03122925&docId=4813488
  55. ^ https://ir.tetrabiopharma.com/newsroom/press-releases/news-details/2020/Tetra-Bio-Pharma-Targeted-Pharmaceutical--the-George-Mason-University-Partner-on-ARDS-003-to-Prevent--Treat-COVID-19/default.aspx
  56. ^ a b https://science.gmu.edu/directory/lance-liotta
  57. ^ https://tetrabiopharma.com/partners/
  58. ^ "SEDAR TBP Annual Report 17 Feb 2021". SEDAR. SEDAR Tetra Bio-Pharma. Retrieved 20 February 2021.
  59. ^ a b c https://ir.tetrabiopharma.com/newsroom/press-releases/news-details/2020/Tetra-Bio-Pharma-Completes-Major-Milestone-for-COVID-19-Therapeutic/default.aspx
  60. ^ Narayanan, Aarthi; Liotta, Lance. "GMU Grant Announcement: Narayanan and Liotta testing therapeutic efficacy of potential COVID-19 treatments". EurekAlert! operated by the nonprofit American Association for the Advancement of Science (AAAS). George Mason University. Retrieved 24 February 2021.
  61. ^ Cachapero, Joanne. "Cannabis and Coronavirus: Sales Surge as the Industry Carries On". MG Retailer. Retrieved 28 February 2021. Canadian cannabis pharmaceutical company Tetra Bio-Pharma recently contracted with Dalton Pharma Services to produce batches of its HU-308 and ARDS-003, which could help to treat severe cytokine reactions.
  62. ^ a b c d e f "Tetra Bio-Pharma 2020 Annual Report filed with SEDAR". SEDAR. Tetra Bio-Pharma. Retrieved 24 February 2021.
  63. ^ Smith, Damon; Baille, Wilms; Kujawa, Piotr. "Great Britain Patent GB2561009 Non-ionic block copolymers and pharmaceutical compositions derived therefrom". Google Patents. Tetra Bio-Pharma, Altus (by 50-50 JV:TALLC). Retrieved 23 February 2021. Abstract: There are provided PVP-PLA block copolymers as defined in Formula I: wherein, x is an initiator alcohol having a boiling point greater than 145°C, n is, on average, from 20 and 40, and m is, on average, from 10 and 40, wherein the block copolymers have a number average molecular weight (Ma) of at least 3000 Da. Polymers demonstrating flexibility in formulating multiple low-solubility active pharmaceutical ingredients (APIs) are described. Liquid and dry pharmaceutical formulations comprising an API are described, along with delivery methods, uses, and kits. APIs may include, e.g. flurbiprofen, celecoxib, acetaminophen, or propofol. Also provided is a method of synthesizing the PVP-PLA block copolymers by (i) initiating polymerization of D,L-Lactide from the initiator alcohol x to form poly(lactic acid), adding a xanthate, e.g Potassium O-Ethyl Xanthate, to form a PLA macroinitiator, and polymerizing NVP onto the PLA macroinitiator, by controlled polymerization, to form the block copolymer compound of Formula I.
  64. ^ 21 CFR — Schedules of controlled substances §1308.11 Schedule I.
  65. ^ Florida Statutes - Chapter 893 - Drug abuse prevention and control

See also[edit]