XG-102 administered to healthy male volunteers as a single intravenous infusion: A randomized, double-blind, placebo-controlled, dose-escalating study

Pharmacology Research and Perspectives

Volumn 2, Issue 1, 2014, Pages 1-12

  Deloche, Catherine ^a   Lopez Lazaro, Luis ^b   Mouz, Sébastien ^a   Perino, Julien ^a   Abadie, Claire ^a   Combette, Jean Marc ^a  

^a Solid Drug Development   (Switzerland)

^b Covance Clinical Research Unit ^*  (Switzerland)

Author keywords

PK; Clinical study; Healthy volunteers; Infusion; Intravenous; Phase I; Safety; Tolerability; XG 102

Indexed keywords

PLACEBO; STRESS ACTIVATED PROTEIN KINASE INHIBITOR; UNCLASSIFIED DRUG; XG 102;

ADULT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CONTUSION; DIARRHEA; DOUBLE BLIND PROCEDURE; DRUG DOSE ESCALATION; DRUG SAFETY; DRUG TOLERABILITY; ELECTROCARDIOGRAPHY; EVALUATION AND FOLLOW UP; FATIGUE; GEOMETRY; HEADACHE; HEMATOMA; HUMAN; HUMAN EXPERIMENT; INFLAMMATION; INTRAOCULAR PRESSURE; LACERATION; LIMIT OF QUANTITATION; MALE; MIDDLE AGED; NAUSEA; NORMAL HUMAN; OPHTHALMOSCOPY; OTITIS MEDIA; OUTCOME ASSESSMENT; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; SINGLE DRUG DOSE; SWELLING; THORAX PAIN; YOUNG ADULT;

EID: 85016074852     PISSN: None     EISSN: 20521707     Source Type: Journal    
DOI: 10.1002/prp2.20     Document Type: Article

References (45)

1. Andreasen AS, Kelly M, Berg RM, Møller K, Pedersen BK (2011). Type 2 diabetes is associated with altered NF-κB DNA binding activity, JNK phosphorylation, and AMPK phosphorylation in skeletal muscle after LPS. PLoS ONE 6: e23999.
2. Antoniou X, Falconi M, Di Marino D, Borsello T (2011). JNK3 as a therapeutic target for neurodegenerative diseases. J Alzheimers Dis 24: 633-642.
3. Armstead WM, Kiessling JW, Riley J, Cines DB, Higazi AA (2011). tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK. Neurol Res 33: 726-733.
4. Benakis C, Bonny C, Hirt L (2010). JNK inhibition and inflammation after cerebral ischemia. Brain Behav Immun 24: 800-811.
5. Bessero AC, Chiodini F, Rungger-Brändle E, Bonny C, Clarke PG (2010). Role of the c-Jun N-terminal kinase pathway in retinal excitotoxicity, and neuroprotection by its inhibition. J Neurochem 113: 1307-1318.
6. Bogoyevitch MA, Ngoei KR, Zhao TT, Yeap YY, Ng DC (2010). c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. Biochim Biophys Acta 1804: 463-475.
7. Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, et al. (2003). A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9: 1180-1186.
8. Braithwaite SP, Schmid RS, He DN, Sung ML, Cho S, Resnick L, et al. (2010). Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease. Neurobiol Dis 39: 311-317.
9. Chen L, Harrison SD (2007). Cell-penetrating peptides in drug development: enabling intracellular targets. Biochem Soc Trans 35: 821-825.
10. Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, et al. (2009). JNK regulates APP cleavage and degradation in a model of Alzheimer's disease. Neurobiol Dis 33: 518-525.
11. Davies C, Tournier C (2012). Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies. Biochem Soc Trans 40: 85-89.
12. Eshraghi AA, He J, Mou CH, Polak M, Zine A, Bonny C, et al. (2006). D-JNKI-1 treatment prevents the progression of hearing loss in a model of cochlear implantation trauma. Otol Neurotol 27:504-511.
13. Esneault E, Castagne V, Moser P, Bonny C, Bernaudin M (2008). D-JNKi, a peptide inhibitor of c-Jun N-terminal kinase, promotes functional recovery after transient focal cerebral ischemia in rats. Neuroscience 152: 308-320.
14. Gibaldi M (1991). Drug Disposition. - Distribution. Chapter 11. Pp. 187-202 in M. Gibaldi, ed. Biopharmaceutics and clinical pharmacokinetics 4th ed. Lea & Febiger, Philadelphia-London.
15. Gow WR, Campbell K, Meade AJ, Watt PM, Milech N, Knuckey NW, et al. (2011). Lack of neuroprotection of inhibitory peptides targeting Jun/JNK after transient focal cerebral ischemia in spontaneously hypertensive rats. J Cereb Blood Flow Metab 31: e1-e8. doi: 10.1038/jcbfm.2011.140
16. Guma M, Ronacher LM, Firestein GS, Karin M, Corr M (2011). JNK-1 deficiency limits macrophage-mediated antigen-induced arthritis. Arthritis Rheum 63: 1603-1612.
17. Han Z, Boyle DL, Aupperle KR, Bennett B, Manning AM, Firestein GS (1999). Jun N-terminal kinase in rheumatoid arthritis. J Pharmacol Exp Ther 291: 124-130.
18. Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, et al. (2001). c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108: 73-81.
19. Han D, Shinohara M, Ybanez MD, Saberi B, Kaplowitz N (2010). Signal transduction pathways involved in drug-induced liver injury. Handb Exp Pharmacol 196: 267-310.
20. Keshet Y, Seger R (2010). The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol Biol 661: 3-38.
21. Kim EK, Choi EJ (2010). Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802: 396-405.
22. Liu JR, Zhao Y, Patzer A, Staak N, Boehm R, Deuschl G, et al. (2010). The c-Jun N-terminal kinase (JNK) inhibitor XG-102 enhances the neuroprotection of hyperbaric oxygen after cerebral ischaemia in adult rats. Neuropathol Appl Neurobiol 36: 211-224.
23. Manning AM, Davis RJ (2003). Targeting JNK for therapeutic benefit: from junk to gold? Nat Rev Drug Discov 2: 554-565.
24. Mehan S, Meena H, Sharma D, Sankhla R (2011). JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer's and various neurodegenerative abnormalities. J Mol Neurosci 43: 376-390.
25. Michel-Monigadon D, Bonny C, Hirt L (2010). c-Jun N-terminal kinase pathway inhibition in intracerebral hemorrhage. Cerebrovasc Dis 29: 564-570.
26. Milano G, Morel S, Bonny C, Samaja M, von Segesser LK, Nicod P, et al. (2007). A peptide inhibitor of c-Jun NH2-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo. Am J Physiol Heart Circ Physiol 292: H1828-H1835.
27. Navon H, Bromberg Y, Sperling O, Shani E (2012). Neuroprotection by NMDA preconditioning against glutamate cytotoxicity is mediated through activation of ERK 1/2, inactivation of JNK, and by prevention of glutamate-induced CREB inactivation. J Mol Neurosci 46: 100-108.
28. Nijboer CH, van der Kooij MA, van Bel F, Ohl F, Heijnen CJ, Kavelaars A (2010). Inhibition of the JNK/AP-1 pathway reduces neuronal death and improves behavioral outcome after neonatal hypoxic-ischemic brain injury. Brain Behav Immun 24: 812-821.
29. Omotehara Y, Hakuba N, Hato N, Okada M, Gyo K (2011). Protection against ischemic cochlear damage by intratympanic administration of AM-111. Otol Neurotol 32: 1422-1427.
30. Ortolano F, Colombo A, Zanier ER, Sclip A, Longhi L, Perego C, et al. (2009). c-Jun N-terminal kinase pathway activation in human and experimental cerebral contusion. J Neuropathol Exp Neurol 68: 964-971.
31. Reinecke K, Eminel S, Dierck F, Roessner W, Kersting S, Chromik AM, et al. (2012). The JNK inhibitor XG-102 protects against TNBS-induced colitis. PLoS ONE 7: e30985.
32. Relja B, Schwestka B, Lee VS, Henrich D, Czerny C, Borsello T, et al. (2009). Inhibition of c-Jun N-terminal kinase after hemorrhage but before resuscitation mitigates hepatic damage and inflammatory response in male rats. Shock 32: 509-516.
33. Repici M, Chen X, Morel MP, Doulazmi M, Sclip A, Cannaya V, et al. (2012). Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury. Neurobiol Dis 46: 710-721.
34. Sabapathy K (2012). Role of the JNK pathway in human diseases. Prog Mol Biol Transl Sci 106: 145-169.
35. Savage MJ, Lin YG, Ciallella JR, Flood DG, Scott RW (2002). Activation of c-Jun N-terminal kinase and p38 in an Alzheimer's disease model is associated with amyloid deposition. J Neurosci 22: 3376-3385.
36. Sclip A, Antoniou X, Colombo A, Camici GG, Pozzi L, Cardinetti D, et al. (2011). c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model. J Biol Chem 286: 43871-43880.
37. Seki E, Brenner DA, Karin M (2012). A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology 143: 307-320.
38. Shoji M, Iwakami N, Takeuchi S, Waragai M, Suzuki M, Kanazawa I, et al. (2000). JNK activation is associated with intracellular beta-amyloid accumulation. Brain Res Mol Brain Res 85: 221-233.
39. Spigolon G, Veronesi C, Bonny C, Vercelli A (2010). c-Jun N-terminal kinase signaling pathway in excitotoxic cell death following kainic acid-induced status epilepticus. Eur J Neurosci 31: 1261-1272.
40. Suckfuell M, Canis M, Strieth S, Scherer H, Haisch A (2007). Intratympanic treatment of acute acoustic trauma with a cell-permeable JNK ligand: a prospective randomized phase I/II study. Acta Otolaryngol 127: 938-942.
41. Touchard E, Omri S, Naud MC, Berdugo M, Deloche C, Abadie C, et al. (2010). A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 51: 4683-4693.
42. Wang J, Van De Water TR, Bonny C, de Ribaupierre F, Puel JL, Zine A (2003). A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci 23:8596-8607.
43. Zhao Y, Spigolon G, Bonny C, Culman J, Vercelli A, Herdegen T (2012). The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria. Mol Cell Neurosci 49: 300-310.
44. Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, et al. (2001). Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J Neurochem 76: 435-441.
45. Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, et al. (2006). A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26: 3551-3560.