Reperfusion injury medical therapy: Difference between revisions

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*'''Therapeutic hypothermia'''
*'''Therapeutic hypothermia'''
** It has been shown in rats that [[Neuron|neurons]] sometimes die completely 24 hours after the [[blood flow]] returns.
** It has been shown in rats that [[Neuron|neurons]] sometimes die completely 24 hours after the [[blood flow]] returns<ref name="pmid14767591">{{cite journal |vauthors=Polderman KH |title=Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence |journal=Intensive Care Med |volume=30 |issue=4 |pages=556–75 |date=April 2004 |pmid=14767591 |doi=10.1007/s00134-003-2152-x |url=}}</ref>.
**This delayed reaction is the result of the multiple [[Inflammation|inflammatory]] [[immune responses]] that occur during [[reperfusion]].
**This delayed reaction is the result of the multiple [[Inflammation|inflammatory]] [[immune responses]] that occur during [[reperfusion]].
**Such inflammatory reactions cause increase in[[Intracranial pressure|ntracranial pressure]], a pressure that leads to [[Cell disruption|cell damage]] and [[cell death]] in some cases.
**Such inflammatory reactions cause increase in[[Intracranial pressure|ntracranial pressure]], a pressure that leads to [[Cell disruption|cell damage]] and [[cell death]] in some cases.
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*'''Hydrogen sulfide treatment'''
*'''Hydrogen sulfide treatment'''
** There are several preliminary studies in mice that seem to show that treatment with [[hydrogen sulfide]] ( H2S) could have a protective effect against [[reperfusion injury]]
** There are several preliminary studies in mice that seem to show that treatment with [[hydrogen sulfide]] ( H2S) could have a protective effect against [[reperfusion injury]].<ref>Elrod J.W., J.W. Calvert, M.R. Duranski, D.J. Lefer. "Hydrogen sulfide donor protects against acute myocardial ischemia-reperfusion injury." Circulation 114(18):II172, 2006</ref>


*'''Cyclosporine'''
*'''Cyclosporine'''
** In addition to its well-known [[Immunosuppression|immunosuppressive]] capabilities, the one-time administration of [[cyclosporine]] at the time of [[percutaneous coronary intervention]] (PCI) has been found to deliver a 40 percent reduction in [[infarct]] size in a small group proof of concept study of [[human]] patients with [[reperfusion injury]] published in The [[New England Journal of Medicine]] in 2008.
** In addition to its well-known [[Immunosuppression|immunosuppressive]] capabilities, the one-time administration of [[cyclosporine]]<ref name="pmid18669426">{{cite journal |vauthors=Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M |title=Effect of cyclosporine on reperfusion injury in acute myocardial infarction |journal=N. Engl. J. Med. |volume=359 |issue=5 |pages=473–81 |date=July 2008 |pmid=18669426 |doi=10.1056/NEJMoa071142 |url=}}</ref> at the time of [[percutaneous coronary intervention]] (PCI) has been found to deliver a 40 percent reduction in [[infarct]] size in a small group proof of concept study of [[human]] patients with [[reperfusion injury]] published in The [[New England Journal of Medicine]] in 2008.
**[[Cyclosporine]] works by inhibiting the action of [[Cyclophilin|Cyclophilin D]] which usually helps in opening [[Mitochondrial membrane transport protein]] ( MPT Pore). So once [[Cyclophilin|cyclophilin D]] action is inhibited, there is no more MPT pore opening and in turn, saves the [[mitochondria]] from getting damaged.
**[[Cyclosporine]] works by inhibiting the action of [[Cyclophilin|Cyclophilin D]] which usually helps in opening [[Mitochondrial membrane transport protein]]<ref name="pmid17595511">{{cite journal |vauthors=Javadov S, Karmazyn M |title=Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection |journal=Cell. Physiol. Biochem. |volume=20 |issue=1-4 |pages=1–22 |date=2007 |pmid=17595511 |doi=10.1159/000103747 |url=}}</ref><ref name="pmid18669431">{{cite journal |vauthors=Hausenloy DJ, Yellon DM |title=Time to take myocardial reperfusion injury seriously |journal=N. Engl. J. Med. |volume=359 |issue=5 |pages=518–20 |date=July 2008 |pmid=18669431 |doi=10.1056/NEJMe0803746 |url=}}</ref> ( MPT Pore). So once [[Cyclophilin|cyclophilin D]] action is inhibited, there is no more MPT pore opening and in turn, saves the [[mitochondria]] from getting damaged.
**The opening of [[Mitochondrial membrane transport protein|MTP Pore]] results in major [[cell]] destruction by causing the influx of water into [[mitochondria]], impairing its function and ultimately leading to the [[collapse]]. The strategy to protect [[mitochondria]] is the most important thing associated with the [[Treatment|treatment part]].
**The opening of [[Mitochondrial membrane transport protein|MTP Pore]] results in major [[cell]] destruction by causing the influx of water into [[mitochondria]], impairing its function and ultimately leading to the [[collapse]]. The strategy to protect [[mitochondria]] is the most important thing associated with the [[Treatment|treatment part]].


*'''TRO40303'''
*'''TRO40303'''
**TRO40303 is a new [[cardio]] protective compound that was shown to inhibit the [[Mitochondrial membrane transport protein|MP]][[Mitochondrial membrane transport protein|T pore]] and reduce [[infarct]] size after [[ischemia]]-[[reperfusion]].
**TRO40303 is a new [[cardio]] protective compound that was shown to inhibit the [[Mitochondrial membrane transport protein|MP]][[Mitochondrial membrane transport protein|T pore]] and reduce [[infarct]] size after [[ischemia]]-[[reperfusion]]<ref name="pmid24507657">{{cite journal |vauthors=Le Lamer S, Paradis S, Rahmouni H, Chaimbault C, Michaud M, Culcasi M, Afxantidis J, Latreille M, Berna P, Berdeaux A, Pietri S, Morin D, Donazzolo Y, Abitbol JL, Pruss RM, Schaller S |title=Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial |journal=J Transl Med |volume=12 |issue= |pages=38 |date=February 2014 |pmid=24507657 |pmc=3923730 |doi=10.1186/1479-5876-12-38 |url=}}</ref>.


*[[File: Ischemic Conditioning.png|thumb|357x357px|Ischemic Conditioning Flow chart- Ischemic Conditioning Mechanism- Role of ischemic conditioning in preventing and minimizing the damage associated with Reperfusion injury. [https://openi.nlm.nih.gov/detailedresult?img=PMC4386982_bph0172-2074-f1&query=preconditioning%20in%20ischemia%20reperfusion%20injury&it=xg&req=4&npos=82]]]'''Stem cell therapy'''
*[[File: Ischemic Conditioning.png|thumb|357x357px|Ischemic Conditioning Flow chart- Ischemic Conditioning Mechanism- Role of ischemic conditioning in preventing and minimizing the damage associated with Reperfusion injury. [https://openi.nlm.nih.gov/detailedresult?img=PMC4386982_bph0172-2074-f1&query=preconditioning%20in%20ischemia%20reperfusion%20injury&it=xg&req=4&npos=82]]]'''Stem cell therapy'''
** Recent investigations suggest a possible beneficial effect of [[Mesenchymal stem cell|mesenchymal stem cells]] on [[heart]] and [[kidney]] [[reperfusion injury]]
** Recent investigations suggest a possible beneficial effect of [[Mesenchymal stem cell|mesenchymal stem cells]]<ref name="pmid21498423">{{cite journal |vauthors=van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyöngyösi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA |title=Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease |journal=Cardiovasc. Res. |volume=91 |issue=4 |pages=649–58 |date=September 2011 |pmid=21498423 |doi=10.1093/cvr/cvr113 |url=}}</ref> on [[heart]] and [[kidney]] [[reperfusion injury]]<ref name="pmid24220681">{{cite journal |vauthors=Zhao JJ, Liu JL, Liu L, Jia HY |title=Protection of mesenchymal stem cells on acute kidney injury |journal=Mol Med Rep |volume=9 |issue=1 |pages=91–6 |date=January 2014 |pmid=24220681 |doi=10.3892/mmr.2013.1792 |url=}}</ref>


* '''Superoxide dismutase'''
* '''Superoxide dismutase'''
**[[Superoxide dismutase]] is an important [[antioxidant]] enzyme that transforms [[superoxide]] [[anions]] into water and [[hydrogen peroxide]]. Recent work has demonstrated important therapeutic effects on pre-clinical models of [[reperfusion]] damage following an [[ischemic stroke]]
**[[Superoxide dismutase]] is an important [[antioxidant]] enzyme that transforms [[superoxide]] [[anions]] into water and [[hydrogen peroxide]]. Recent work has demonstrated important therapeutic effects on pre-clinical models of [[reperfusion]] damage following an [[ischemic stroke]]<ref name="pmid26928528">{{cite journal |vauthors=Jiang Y, Arounleut P, Rheiner S, Bae Y, Kabanov AV, Milligan C, Manickam DS |title=SOD1 nanozyme with reduced toxicity and MPS accumulation |journal=J Control Release |volume=231 |issue= |pages=38–49 |date=June 2016 |pmid=26928528 |doi=10.1016/j.jconrel.2016.02.038 |url=}}</ref><ref name="pmid26093094">{{cite journal |vauthors=Jiang Y, Brynskikh AM, S-Manickam D, Kabanov AV |title=SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature |journal=J Control Release |volume=213 |issue= |pages=36–44 |date=September 2015 |pmid=26093094 |pmc=4684498 |doi=10.1016/j.jconrel.2015.06.021 |url=}}</ref>


*'''Metformin'''
*'''Metformin'''
**Some studies proved the role of [[metformin]] in preventing [[Ischemia-reperfusion injury|Ischemia-Reperfusion injury]] by inhibiting the opening of [[MPT Pore]] and [[Mitochondrial]] complex inhibition. Although the studies are done in [[rats]] only still the correlation can be derived [[clinically]] for humans as well.
**Some studies proved the role of [[metformin]] in preventing [[Ischemia-reperfusion injury|Ischemia-Reperfusion injury]] by inhibiting the opening of [[MPT Pore]] and [[Mitochondrial]] complex inhibition. Although the studies are done in [[rats]] only still the correlation can be derived [[clinically]] for humans as well.<ref name="pmid19295441">{{cite journal |vauthors=Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Gonçalves L, Providência L, Rongen GA, Smits P, Mocanu MM, Yellon DM |title=Metformin prevents myocardial reperfusion injury by activating the adenosine receptor |journal=J. Cardiovasc. Pharmacol. |volume=53 |issue=5 |pages=373–8 |date=May 2009 |pmid=19295441 |doi=10.1097/FJC.0b013e31819fd4e7 |url=}}</ref><ref name="pmid18080084">{{cite journal |vauthors=Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM |title=Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening |journal=Basic Res. Cardiol. |volume=103 |issue=3 |pages=274–84 |date=May 2008 |pmid=18080084 |doi=10.1007/s00395-007-0691-y |url=}}</ref>


*'''Cannabinoids'''
*'''Cannabinoids'''
** A [[synthetic]] analog of [[cannabis]] helps to prevent [[hepatic ischemia]] and [[injury]] by reducing the [[inflammation]] and [[oxidative stress]] occurring through [[CB2]] receptors. This in turn lowers the [[tissue]] [[damage]] and provides protective effects. The various [[synthetic]] analogs of [[phytocannabinoid]] that play major role are:
** A [[synthetic]] analog of [[cannabis]]<ref name="pmid21470208">{{cite journal |vauthors=Bátkai S, Mukhopadhyay P, Horváth B, Rajesh M, Gao RY, Mahadevan A, Amere M, Battista N, Lichtman AH, Gauson LA, Maccarrone M, Pertwee RG, Pacher P |title=Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors |journal=Br. J. Pharmacol. |volume=165 |issue=8 |pages=2450–61 |date=April 2012 |pmid=21470208 |pmc=3423240 |doi=10.1111/j.1476-5381.2011.01410.x |url=}}</ref> helps to prevent [[hepatic ischemia]] and [[injury]] by reducing the [[inflammation]] and [[oxidative stress]] occurring through [[CB2]] receptors<ref name="pmid21362471">{{cite journal |vauthors=Mukhopadhyay P, Rajesh M, Horváth B, Bátkai S, Park O, Tanchian G, Gao RY, Patel V, Wink DA, Liaudet L, Haskó G, Mechoulam R, Pacher P |title=Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death |journal=Free Radic. Biol. Med. |volume=50 |issue=10 |pages=1368–81 |date=May 2011 |pmid=21362471 |pmc=3081988 |doi=10.1016/j.freeradbiomed.2011.02.021 |url=}}</ref>. This in turn lowers the [[tissue]] [[damage]] and provides protective effects. The various [[synthetic]] analogs of [[phytocannabinoid]] that play major role are:
** THCV- [[Tetrahydrocannabivarin]]
** THCV- [[Tetrahydrocannabivarin]]
** 8-[[Tetrahydrocannabivarin]]
** 8-[[Tetrahydrocannabivarin]]

Revision as of 20:19, 22 August 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] Associate Editor(s)-in-Chief: Anjan K. Chakrabarti, M.D. [5] Shivam Singla, M.D.[6]

Overview

The most common myth about the ischemia-reperfusion injury is itself related to blood flow. One can easily think like if everything is happening due to ischemia and with the restoration of blood flow, the injury should heal. Here is the trick, reperfusion in turn further exacerbates the injury mainly due to the formation of free radicals. There are few approaches that are studied widely and do play a major role in controlling the injury related to ischemia-reperfusion injury

Hyperbaric oxygen therapy is also studied widely and best suited when used within 6 hrs of hypoxia as it helps in the reduction of local and systemic hypoxia and in turn, increases the survival of affected tissue.

Medical Therapy

Reperfusion injury treatment, shown at various steps the intermediates and the possible drugs and compounds that can help to inhibit those steps and in turn decresing the incidence of reperfusion injury at various steps. [1]

Various proposed medical managements studied are:

  • Hydrogen sulfide treatment
  • Ischemic Conditioning Flow chart- Ischemic Conditioning Mechanism- Role of ischemic conditioning in preventing and minimizing the damage associated with Reperfusion injury. [2]
    Stem cell therapy

Therapies Associated with Improved Clinical Outcomes

Pre-conditioning and Post-conditioning benefits in preventing severe damage to tissue during the ischemia-reperfusion injury. [3]

Therapies that have been associated with improved clinical outcomes include:

  1. "Preconditioning" - Preconditioning is basically an adaptive response in which ischemia is exposed for a brief period of time before the actual ischemia phase to the tissue. This phenomenon markedly increases the ability of the heart to withstand subsequent ischemic insults. In addition to that, the application of brief episodes of ischemia at the onset of reperfusion is termed as "postconditioning" which reduces the extent of injury that is supposed to happen.
  2. "Postconditioning" (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time).
  3. Inhibition of mitochondrial pore opening by cyclosporine.

Limitations to applying strategies that have demonstrated benefit in animal models are the fact that reperfusion therapy was administered prior to or at the time of reperfusion. In the management of STEMI patients, it is impossible to administer the agent before vessel occlusion (except during coronary artery bypass grafting). Given the time constraints and the goal of opening an occluded artery within 90 minutes, it is also difficult to administer experimental agents before reperfusion in STEMI.

Therapies Associated with Limited Success

Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include:

  1. Beta-blockade
  2. GIK (glucose-insulin-potassium infusion) (Studied in the Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II and other older studies
  3. Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN and EXPEDITION trials)
  4. Adenosine (Studied in the AMISTAD I and AMISTAD II trials as well as the ATTACC trial ). It should be noted that at high doses in anterior ST elevation myocardial infarction|ST elevation MI adenosine was effective in the AMISTAD trial. Likewise, intracoronary administration of adenosine prior to primary PCI has been associated with improved echocardiographic and clinical outcomes in one small study.
  5. Calcium-channel blockers
  6. Potassium–adenosine triphosphate channel openers
  7. Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial )
  8. Oxygen free radical scavengers/anti-oxidants, including Erythropoietin, estrogen, heme-oxygenase 1, and hypoxia induced factor-1 (HIF-1).
  9. Pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement (Studied in the Pexelizumab for ST elevation myocardial infarction|Acute ST-Elevation Myocardial Infarction in Patients Undergoing Primary Percutaneous Coronary Intervention (APEX AMI) trial )
  10. KAI-9803, a delta-protein kinase C inhibitor(Studied in the Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction trial or DELTA AMI trial).
  11. Human atrial natriuretic peptide (Studied in the Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomized trials.)
  12. FX06, an anti-inflammatory fibrin derivative that competes with fibrin fragments for binding with the vascular endothelial molecule VE-cadherin which deters migration of leukocytes across the endothelial cell monolayer (studied in the F.I.R.E. trial (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury)
  13. Magnesium, which was evaluated by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
  14. Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial).
  15. Bendavia studied in the EMBRACE STEMI trial

There are several explanations for why trials of experimental agents have failed in this area:

  1. The therapy was administered after reperfusion and after reperfusion injury had set in
  2. The greatest benefit is observed in anterior ST-elevation myocardial infarctions (as demonstrated in the AMISTAD study), and inclusion of non-anterior locations minimizes the potential benefit
  3. There are uninhibited redundant pathways mediating reperfusion injury
  4. Inadequate dosing of the agent

References

  1. ↑ Polderman KH (April 2004). "Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence". Intensive Care Med. 30 (4): 556–75. doi:10.1007/s00134-003-2152-x. PMID 14767591.
  2. ↑ Elrod J.W., J.W. Calvert, M.R. Duranski, D.J. Lefer. "Hydrogen sulfide donor protects against acute myocardial ischemia-reperfusion injury." Circulation 114(18):II172, 2006
  3. ↑ Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M (July 2008). "Effect of cyclosporine on reperfusion injury in acute myocardial infarction". N. Engl. J. Med. 359 (5): 473–81. doi:10.1056/NEJMoa071142. PMID 18669426.
  4. ↑ Javadov S, Karmazyn M (2007). "Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection". Cell. Physiol. Biochem. 20 (1–4): 1–22. doi:10.1159/000103747. PMID 17595511.
  5. ↑ Hausenloy DJ, Yellon DM (July 2008). "Time to take myocardial reperfusion injury seriously". N. Engl. J. Med. 359 (5): 518–20. doi:10.1056/NEJMe0803746. PMID 18669431.
  6. ↑ Le Lamer S, Paradis S, Rahmouni H, Chaimbault C, Michaud M, Culcasi M, Afxantidis J, Latreille M, Berna P, Berdeaux A, Pietri S, Morin D, Donazzolo Y, Abitbol JL, Pruss RM, Schaller S (February 2014). "Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial". J Transl Med. 12: 38. doi:10.1186/1479-5876-12-38. PMC 3923730. PMID 24507657.
  7. ↑ van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyöngyösi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA (September 2011). "Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease". Cardiovasc. Res. 91 (4): 649–58. doi:10.1093/cvr/cvr113. PMID 21498423.
  8. ↑ Zhao JJ, Liu JL, Liu L, Jia HY (January 2014). "Protection of mesenchymal stem cells on acute kidney injury". Mol Med Rep. 9 (1): 91–6. doi:10.3892/mmr.2013.1792. PMID 24220681.
  9. ↑ Jiang Y, Arounleut P, Rheiner S, Bae Y, Kabanov AV, Milligan C, Manickam DS (June 2016). "SOD1 nanozyme with reduced toxicity and MPS accumulation". J Control Release. 231: 38–49. doi:10.1016/j.jconrel.2016.02.038. PMID 26928528.
  10. ↑ Jiang Y, Brynskikh AM, S-Manickam D, Kabanov AV (September 2015). "SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature". J Control Release. 213: 36–44. doi:10.1016/j.jconrel.2015.06.021. PMC 4684498. PMID 26093094.
  11. ↑ Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Gonçalves L, Providência L, Rongen GA, Smits P, Mocanu MM, Yellon DM (May 2009). "Metformin prevents myocardial reperfusion injury by activating the adenosine receptor". J. Cardiovasc. Pharmacol. 53 (5): 373–8. doi:10.1097/FJC.0b013e31819fd4e7. PMID 19295441.
  12. ↑ Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM (May 2008). "Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening". Basic Res. Cardiol. 103 (3): 274–84. doi:10.1007/s00395-007-0691-y. PMID 18080084.
  13. ↑ Bátkai S, Mukhopadhyay P, Horváth B, Rajesh M, Gao RY, Mahadevan A, Amere M, Battista N, Lichtman AH, Gauson LA, Maccarrone M, Pertwee RG, Pacher P (April 2012). "Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors". Br. J. Pharmacol. 165 (8): 2450–61. doi:10.1111/j.1476-5381.2011.01410.x. PMC 3423240. PMID 21470208.
  14. ↑ Mukhopadhyay P, Rajesh M, Horváth B, Bátkai S, Park O, Tanchian G, Gao RY, Patel V, Wink DA, Liaudet L, Haskó G, Mechoulam R, Pacher P (May 2011). "Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death". Free Radic. Biol. Med. 50 (10): 1368–81. doi:10.1016/j.freeradbiomed.2011.02.021. PMC 3081988. PMID 21362471.
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