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Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety

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Abstract

Cationic arginine-rich peptides represent a novel class of peptides being developed as neuroprotective agents for stroke and other acute and chronic neurological disorders. As a group, cationic arginine-rich peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds. At present, while many neuroprotective cationic arginine-rich peptides have been examined in preclinical animal neuroprotection studies, few have been assessed in human safety studies. Despite this, the safety of the prototypical cationic arginine-rich peptide, protamine, which has been in clinical use for over 70 years to reverse the anticoagulant effects of heparin and as an excipient in certain insulin preparations, is well established. In addition, the poly-arginine peptide R9 (ALX40-4C) was developed as an anti-human inmmunodeficiency virus therapeutic in the mid-1990s, and more recently, the neuroprotective cationic arginine-rich peptides TAT-NR2B9c (NA-1), CN-105 and RD2 are being evaluated for the treatment of ischaemic stroke, haemorrhagic stroke and Alzheimer’s disease, respectively. Based on the available clinical data, cationic arginine-rich peptides as a group appear to be safe when administered at therapeutic doses by a slow intravenous infusion. While protamine, owing to its isolation from salmon milt and homology with human sperm protamine, can trigger anaphylactic and anaphylactoid reactions in a small proportion of patients previously exposed to the peptide (e.g. diabetic patients), who are allergic to fish or have undergone a vasectomy, such reactions are unlikely to be triggered in individuals exposed to non-protamine cationic arginine-rich peptides.

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References

  1. Meloni BP, Mastaglia FL, Knuckey NW. Cationic arginine-rich peptides (CARPs): a novel class of neuroprotective agents with a multimodal mechanism of action. Front Neurol. 2020;11:108.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mader JS, Hoskin DW. Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin Investig Drugs. 2006;15(8):933–46.

    Article  CAS  PubMed  Google Scholar 

  3. Schweizer F. Cationic amphiphilic peptides with cancer-selective toxicity. Eur J Pharmacol. 2009;625(1–3):190–4.

    Article  CAS  PubMed  Google Scholar 

  4. Felício MR, Silva ON, Gonçalves S, Santos NC, Franco OL. Peptides with dual antimicrobial and anticancer activities. Front Chem. 2017;5:5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Meloni B, et al. Neuroprotective peptides fused to arginine-rich cell penetrating peptides: neuroprotective mechanism likely mediated by peptide endocytic properties. Pharmacol Ther. 2015;153:36–54.

    Article  CAS  PubMed  Google Scholar 

  6. Meloni BP, et al. Poly-arginine and arginine-rich peptides are neuroprotective in stroke models. JCBFM. 2015;35:993–1004.

    CAS  Google Scholar 

  7. Meloni BP, et al. Assessment of the neuroprotective effects of arginine-rich protamine peptides, poly-arginine peptides (R12-cyclic, R22) and arginine–tryptophan-containing peptides following in vitro excitotoxicity and/or permanent middle cerebral artery occlusion in rats. Neuromol Med. 2017;19(2–3):271–85.

    Article  CAS  Google Scholar 

  8. Milani D, et al. Comparison of neuroprotective efficacy of poly-arginine R18 and R18D (D-enantiomer) peptides following permanent middle cerebral artery occlusion in the Wistar rat and in vitro toxicity studies. PLoS One. 2018;13(3):e0193884.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Milani D, Knuckey N, Anderton R, Cross J, Meloni B. The R18 polyarginine peptide is more effective than the TAT-NR2B9c (NA-1) peptide when administered 60 minutes after permanent middle cerebral artery occlusion in the rat. Stroke Res Treat. 2016;2016:2372710.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Milani D, Cross J, Anderton R, Blacker D, Knuckey N, Meloni B. Neuroprotective efficacy of poly-arginine R18 and NA-1 (TAT-NR2B9c) peptides following transient middle cerebral artery occlusion in the rat. Neurosci Res. 2017;114:9–15.

    Article  CAS  PubMed  Google Scholar 

  11. Meloni BP, et al. Poly-arginine peptide-18 (R18) reduces brain injury and improves functional outcomes in a nonhuman primate stroke model. Neurotherapeutics. 2020;17(2):627–34.

    Article  CAS  PubMed  Google Scholar 

  12. Edwards AB, Cross JL, Anderton RA, Knuckey NW, Meloni BP. Poly-arginine R18 and R18D (D-enantiomer) peptides reduce infarct volume and improves behavioural outcomes following perinatal hypoxic-ischaemic encephalopathy in the P7 rat. Mol Brain. 2018;11(1):8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Edwards AB, Anderton RA, Knuckey NW, Meloni BP. Assessment of therapeutic window for poly-arginine-18D (R18D) in a P7 rat model of perinatal hypoxic-ischaemic encephalopathy. J Neurosci Res. 2018;96(11):1816–26.

    Article  CAS  PubMed  Google Scholar 

  14. Marshall J, et al. Inhibition of N-methyl-d-aspartate-induced retinal neuronal death by polyarginine peptides is linked to the attenuation of stress-induced hyperpolarization of the inner mitochondrial membrane potential. J Biol Chem. 2015;290(36):22030–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sarko D, et al. The pharmacokinetics of cell-penetrating peptides. Mol Pharm. 2010;7(6):2224–31.

    Article  CAS  PubMed  Google Scholar 

  16. Stalmans S, et al. Cell-penetrating peptides selectively cross the blood-brain barrier in vivo. PLoS One. 2015;10(10):e0139652.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Dietz GPH, Dietz B, Bähr M. Bcl-xL protects cerebellar granule neurons against the late phase, but not against the early phase of glutamate-induced cell death. Brain Res. 2007;1164(1):136–41.

    Article  CAS  PubMed  Google Scholar 

  18. Horrow JC. Protamine: a review of its toxicity. Anesth Analg. 1985;64(3):348–61.

    Article  CAS  PubMed  Google Scholar 

  19. Morel DR, Costabella PM, Pittet JF. Adverse cardiopulmonary effects and increased plasma thromboxane concentrations following the neutralization of heparin with protamine in awake sheep are infusion rate-dependent. Anesthesiology. 1990;73(3):415–24.

    Article  CAS  PubMed  Google Scholar 

  20. Boer C, Meesters MI, Veerhoek D, Vonk ABA. Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review. Br J Anaesth. 2018;120(5):914–27.

    Article  CAS  PubMed  Google Scholar 

  21. Wakefield TW, Hantler CB, Wrobleski SK, Crider BA, Stanley JC. Effects of differing rates of protamine reversal of heparin anticoagulation. Surgery. 1996;119(2):123–8.

    Article  CAS  PubMed  Google Scholar 

  22. Yoshida H, Fujisawa H, Ohi Y. Influences of protamine on the Na+, K+-dependent ATPase and on the active transport processes of potassium and of l-DOPA into brain slices. Can J Biochem. 1965;43(7):841–9.

    Article  CAS  PubMed  Google Scholar 

  23. Diaz-Sylvester PL, Copello JA. Voltage-dependent modulation of cardiac ryanodine receptors (RyR2) by protamine. PLoS One. 2009;4(12):e8315.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Komatsu H, Enzan K, Matsuura S, Kurosawa S, Mitsuhata H. Systemic hypotensive response to protamine following chronic inhibition of nitric oxide synthase in rats. Can J Anaesth. 1998;45(12):1186–9.

    Article  CAS  PubMed  Google Scholar 

  25. Takakura K, Mizogami M, Fukuda S. Protamine sulfate causes endothelium-independent vasorelaxation via inducible nitric oxide synthase pathway. Can J Anaesth. 2006;53(2):162–7.

    Article  PubMed  Google Scholar 

  26. DeLucia A, et al. Tissue distribution, circulating half-life and excretion of intravenously administered protamine sulfate. ASAIOJ. 1993;39(3):715–8.

    Google Scholar 

  27. Butterworth J, Lin YA, Prielipp R, Bennett J, James R. The pharmacokinetics and cardiovascular effects of a single intravenous dose of protamine in normal volunteers. Anesth Analg. 2002;94(3):514–22.

    Article  CAS  PubMed  Google Scholar 

  28. Butterworth J, Lin YA, Prielipp RC, Bennett J, Hammon JW, James RL. Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg. 2002;74(5):1589–95.

    Article  PubMed  Google Scholar 

  29. Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. 2008;103(2):192–6.

    Article  CAS  PubMed  Google Scholar 

  30. Awotwe-Otoo D, et al. Physicochemical characterization of complex drug substances: evaluation of structural similarities and differences of protamine sulfate from various sources. AAPS J. 2012;14(3):619–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol. 2016;137(6):1674–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sokolowska E, Kalaska B, Miklosz J, Mogielnicki A. The toxicology of heparin reversal with protamine: past, present and future. Expert Opin Drug Metab Toxicol. 2016;12(8):897–909.

    Article  CAS  PubMed  Google Scholar 

  33. Tobin MC, Karns BK, Anselmino LM, Thomas LL. Potentiation of human basophil histamine release by protamine: a new role for a polycation recognition site. Mol Immunol. 1986;23(3):245–53.

    Article  CAS  PubMed  Google Scholar 

  34. Tainsh KR, Leung Liu W, Yung Lau H, Cohen J, Pearce FL. Mast cell heterogeneity in man: unique functional properties of skin mast cells in response to a range of polycationic stimuli. Immunopharmacology. 1992;24(3):171–80.

    Article  CAS  PubMed  Google Scholar 

  35. Schnitzler S, Renner H, Pfüller U. Histamine release from rat mast cells induced by protamine sulfate and polyethylene imine. Agents Actions. 1981;11(1–2):73–4.

    Article  CAS  PubMed  Google Scholar 

  36. Byun Y, Singh VK, Yang VC. Low molecular weight protamine: a potential nontoxic heparin antagonist. Thromb Res. 1999;94(1):53–61.

    Article  CAS  PubMed  Google Scholar 

  37. Li T, et al. New synthetic peptide with efficacy for heparin reversal and low toxicity and immunogenicity in comparison to protamine sulfate. Biochem Biophys Res Commun. 2015;467(3):497–502.

    Article  CAS  PubMed  Google Scholar 

  38. Liang JF, Zhen L, Chang LC, Yang VC. A less toxic heparin antagonist: low molecular weight protamine. Biochemistry. 2003;68(1):116–20.

    CAS  PubMed  Google Scholar 

  39. Chang L-C, Wrobleski S, Wakefield TW, Lee LM, Yang VC. Low molecular weight protamine as nontoxic heparin/low molecular weight heparin antidote (III): preliminary in vivo evaluation of efficacy and toxicity using a canine model. AAPS PharmSci. 2001;3(3):24–31.

    Article  PubMed Central  Google Scholar 

  40. Li MH, et al. Prevention and management of intraprocedural rupture of intracranial aneurysm with detachable coils during embolization. Neuroradiology. 2006;48(12):907–15.

    Article  PubMed  Google Scholar 

  41. Guptill JR, et al. Phase 1 randomized, double-blind, placebo-controlled study to determine the safety, tolerability, and pharmacokinetics of a single escalating dose and repeated doses of CN-105 in healthy adult subjects. J Clin Pharmacol. 2017;57(6):770–6.

    Article  CAS  PubMed  Google Scholar 

  42. Liddle L, et al. Poly-arginine-18 peptides do not exacerbate bleeding, or improve functional outcomes following collagenase-induced intracerebral hemorrhage in the rat. PLoS One. 2019;14(11):e0224870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miklosz J, et al. The inhibitory effect of protamine on platelets is attenuated by heparin without inducing thrombocytopenia in rodents. Drugs. 2019;17(9):539–57.

    CAS  Google Scholar 

  44. Coggin MH, Ahl R, Roland A, Beck D, Brecher AS. Protamine sulfate stimulates degradation of factor Xa and the factor Xa-antithrombin complex. Blood Coagul Fibrinolysis. 2011;22(4):247–53.

    Article  CAS  PubMed  Google Scholar 

  45. Ni Ainle F, et al. Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation. Blood. 2009;114(8):1658–65.

    Article  PubMed  CAS  Google Scholar 

  46. Dellagrammaticas D, Lewis SC, Gough MJ, GALA Trial Collaborators. Is heparin reversal with protamine after carotid endarterectomy dangerous? Eur J Vasc Endovasc Surg. 2008;36(1):41–4.

    Article  CAS  PubMed  Google Scholar 

  47. Stone DH, et al. Protamine reduces bleeding complications associated with carotid endarterectomy without increasing the risk of stroke. J Vasc Surg. 2010;51(3):559.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mazzalai F, Piatto G, Toniato A, Lorenzetti R, Baracchini C, Ballotta E. Using protamine can significantly reduce the incidence of bleeding complications after carotid endarterectomy without increasing the risk of ischemic cerebral events. World J Surg. 2014;38(5):1227–322.

    Article  PubMed  Google Scholar 

  49. Sumner-Smith M, Zheng Y, Zhang YP, Twist EM, Climie SC. Antiherpetic activities of N-alpha-acetyl-nona-d-arginine amide acetate. Drugs Exp Clin Res. 1995;21(1):1–6.

    CAS  PubMed  Google Scholar 

  50. Doranz BJ, et al. A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor. J Exp Med. 1997;186(8):1395–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Doranz BJ, et al. Safe use of the CXCR4 inhibitor ALX40-4C in humans. AIDS Res Hum Retroviruses. 2001;17(6):475–86.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang T, Gering I, Kutzsche J, Nagel-Steger L, Willbold D. Toward the mode of action of the clinical stage all-D-enantiomeric peptide RD2 on Aβ42 aggregation. ACS Chem Neurosci. 2019;10(12):4800–9.

    Article  CAS  PubMed  Google Scholar 

  53. Van Groen T, et al. The Aβ oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology. Sci Rep. 2017;7(1):16275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Schemmert S, et al. Aβ oligomer elimination restores cognition in transgenic Alzheimer’s mice with full-blown pathology. Mol Neurobiol. 2019;56(3):2211–23.

    Article  CAS  PubMed  Google Scholar 

  55. Leithold LHE, et al. Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer’s disease. Eur J Pharm Sci. 2016;89:31–8.

    Article  CAS  PubMed  Google Scholar 

  56. Elfgen A, et al. Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers. Sci Rep. 2019;9(1):5715.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Willbold D, Kutzsche J. Do we need anti-prion compounds to treat Alzheimer’s disease? Molecules. 2019;24(12):2237–47.

    Article  CAS  PubMed Central  Google Scholar 

  58. Kutzsche J, et al. Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: a single and multiple ascending dose phase I study. Alzheimer’s Dement Transl Res Clin Interv. 2020;6(1):e12001.

    Google Scholar 

  59. Aarts M, et al. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science. 2002;298(5594):846–50.

    Article  CAS  PubMed  Google Scholar 

  60. Sun HS, et al. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke. 2008;39(9):2544–53.

    Article  CAS  PubMed  Google Scholar 

  61. Bråtane BT, Cui H, Cook DJ, Bouley J, Tymianski M, Fisher M. Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor. Stroke. 2011;42(11):3265–70.

    Article  PubMed  CAS  Google Scholar 

  62. Teves LM, Cui H, Tymianski M. Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species. J Cereb Blood Flow Metab. 2016;36(3):555–61.

    Article  CAS  PubMed  Google Scholar 

  63. Cook FJ, Teves L, Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature. 2012;483(7388):213–7.

    Article  CAS  PubMed  Google Scholar 

  64. Hill MD, et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012;11(11):942–50.

    Article  CAS  PubMed  Google Scholar 

  65. Tymianski M, Garman J. Co-administration of an agent linked to an internalization peptide with an anti-inflammatory. EP2229185A2. 2008.

  66. Hill MD, et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet. 2020;395(10227):878–87.

    Article  CAS  PubMed  Google Scholar 

  67. Hankey GJ. Nerinetide before reperfusion in acute ischaemic stroke: déjà vu or new insights? Lancet. 2020;395(10227):843–4.

    Article  PubMed  Google Scholar 

  68. Rich JD, et al. QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension. Int J Cardiol. 2013;167(3):669–76.

    Article  PubMed  Google Scholar 

  69. Nagele P, Pal S, Brown F, Blood J, Miller JP, Johnston J. Postoperative QT interval prolongation in patients undergoing noncardiac surgery under general anesthesia. Anesthesiology. 2012;117(2):321–8.

    Article  PubMed  Google Scholar 

  70. Pugsley MK, Kalra V, Froebel-Wilson S. Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle. Life Sci. 2002;72(3):293–305.

    Article  CAS  PubMed  Google Scholar 

  71. Hoffman JA, Chance RE, Johnson MG. Purification andanalysis of the major components of chum salmon protaminecontained in insulin formulations using high-performanceliquid chromatography. Protein Expr Purif. 1990;1(2):127–35.

    Article  Google Scholar 

  72. Weiler JM, et al. A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery. J Allergy Clin Immunol. 1990;85(4):713–9.

    Article  CAS  PubMed  Google Scholar 

  73. Chilukuri K, et al. Incidence and outcomes of protamine reactions in patients undergoing catheter ablation of arterial fibrillation. J Interv Card Electrophysiol. 2009;25(3):175–81.

    Article  PubMed  Google Scholar 

  74. Gurses KM, et al. Safety and efficacy outcomes of protamineadministration for heparin reversal following cryoballoon-based pulmonary vein isolation. J Interv Card Electrophysiol. 2015;43(2):161–7.

    Article  PubMed  Google Scholar 

  75. Vehaskari VM, Root ER, Germuth FG, Robson AM. Glomerular charge and urinary protein excretion: efects of systemicand intrarenal polycation infusion in the rat. Kidney Int. 1982;22(2):127–35.

    Article  CAS  PubMed  Google Scholar 

  76. Strausbaugh LJ. Intracarotid infusions of protamine sulfate disruptthe blood-brain barrier of rabbits. Brain Res. 1987;409(2):221–6.

    Article  CAS  PubMed  Google Scholar 

  77. Raikar GV, Hisamochi K, Raikar BL, Schaf HV. Nitric oxideinhibition attenuates systemic hypotension produced by protamine. J Thorac Cardiovasc Surg. 1996;111(6):1240–6 (discussion1246–7).

    Article  CAS  PubMed  Google Scholar 

  78. Morgan MR, Monnet E, Gaynor JS. The effect of differingrates and injection sites on the amount of protamine deliveredbefore detection of hemodynamic alterations in dogs. Vet Surg. 2000;29(5):442–8.

    Article  CAS  PubMed  Google Scholar 

  79. Oguchi T, Doursout MF, Kashimoto S, Yan Liang Y, Hartley CJ, Chelly JE. Role of heparin and nitric oxide in the cardiac and regional hemodynamic properties of protamine in conscious chronically instrumented dogs. Anesthesiology. 2001;94(6):1016.

    Article  CAS  PubMed  Google Scholar 

  80. Satti SR. Vessel perforation during withdrawal of TrevoProVue stent retriever during mechanical thrombectomy for acute ischemic stroke. J Neurosurg. 2014;121(4):995–8.

    Article  PubMed  Google Scholar 

  81. Fontaine GV, Smith SM. Alteplase for acute ischemic stroke after heparin reversal with protamine: a case report and review. Pharmacotherapy. 2017;37(10):e103–e106106.

    Article  CAS  PubMed  Google Scholar 

  82. Guevara C, et al. Acute ischemic stroke after cardiac catheterization: the protamine low-dose recombinant tissue plasminogen activator pathway. Blood Coagul Fibrinolysis. 2017;28(3):261–3.

    Article  CAS  PubMed  Google Scholar 

  83. Danoun O, Sachar P, Rajamani K. Thrombolysis for acute ischemic stroke after protamine reversal of heparin. Am J Ther. 2018;25(5):e552–e55454.

    Article  PubMed  Google Scholar 

  84. Warner DS, et al. Thrombolysis after protamine reversal of heparin for acute ischemic stroke after cardiac catheterization: case report and literature review. Neurologist. 2018;23(6):194–6.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Perron Institute for Neurological and Translational Sciences, First Floor, RR Block, QEII Medical Centre, Nedlands, WA, Australia

    Adam B. Edwards, Frank L. Mastaglia, Neville W. Knuckey & Bruno P. Meloni

  2. Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, WA, Australia

    Adam B. Edwards, Neville W. Knuckey & Bruno P. Meloni

  3. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, Australia

    Adam B. Edwards, Frank L. Mastaglia, Neville W. Knuckey & Bruno P. Meloni

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This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of interest

Neville W. Knuckey and Bruno P. Meloni are named inventors on several patents for the use of CARPs as therapeutic agents. In addition, Neville W. Knuckey, Bruno P. Meloni and Adam B. Edwards are shareholders in Argenica Therapeutics, which is a company developing R18 as a stroke therapeutic. Frank L. Mastaglia has no conflicts of interest that are directly relevant to the content of this article.

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Edwards, A.B., Mastaglia, F.L., Knuckey, N.W. et al. Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety. Drug Saf 43, 957–969 (2020). https://doi.org/10.1007/s40264-020-00962-z

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