Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

Heij, Lara; Niesters, Marieke; Swartjes, Maarten; Hoitsma, Elske; Drent, Marjolein; Dunne, Ann; Grutters, Jan C.; Vogels, O.J.M.; Brines, Michael; Cerami, Anthony; Dahan, Albert

doi:10.2119/molmed.2012.00332

Cited by 87 publications

(59 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, recent clinical trials of ARA 290 in patients with neuropathy have shown benefit [11], [12]. Similar observations have been made following treatment of patients with NP with ketamine, which has shown to have potent and long-lasting analgesic effects on NP [13]–[15].…”

Section: Introductionmentioning

confidence: 54%

Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

et al. 2013

Self Cite

View full text Add to dashboard Cite

Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the β-common receptor (βcR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 µg/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the βcR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine’s analgesic and side effects.

show abstract

Section: Introductionmentioning

confidence: 54%

Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…ARA 290 (Cibinetide), an erythropoietin derivative that activates the innate repair receptor and initiates anti-inflammation, cytoprotection, and healing, has been well tolerated and showed benefit in treating sarcoidosis associated neuropathic pain in two phase II clinical trials 18249…”

Section: Emerging Disease Specific Treatmentsmentioning

confidence: 99%

Diagnosis and management of sensory polyneuropathy

Gwathmey

Pearson

2019

BMJ

View full text Add to dashboard Cite

Sensory polyneuropathies, which are caused by dysfunction of peripheral sensory nerve fibers, are a heterogeneous group of disorders that range from the common diabetic neuropathy to the rare sensory neuronopathies. The presenting symptoms, acuity, time course, severity, and subsequent morbidity vary and depend on the type of fiber that is affected and the underlying cause. Damage to small thinly myelinated and unmyelinated nerve fibers results in neuropathic pain, whereas damage to large myelinated sensory afferents results in proprioceptive deficits and ataxia. The causes of these disorders are diverse and include metabolic, toxic, infectious, inflammatory, autoimmune, and genetic conditions. Idiopathic sensory polyneuropathies are common although they should be considered a diagnosis of exclusion. The diagnostic evaluation involves electrophysiologic testing including nerve conduction studies, histopathologic analysis of nerve tissue, serum studies, and sometimes autonomic testing and cerebrospinal fluid analysis. The treatment of these diseases depends on the underlying cause and may include immunotherapy, mitigation of risk factors, symptomatic treatment, and gene therapy, such as the recently developed RNA interference and antisense oligonucleotide therapies for transthyretin familial amyloid polyneuropathy. Many of these disorders have no directed treatment, in which case management remains symptomatic and supportive. More research is needed into the underlying pathophysiology of nerve damage in these polyneuropathies to guide advances in treatment.

show abstract

“…Similarly, in diabetic patients the treatment resulted in a reduction in pain scores of 30% until at least day 8. The second trial was aimed to assess whether pHBSP produces analgesia greater than placebo in sarcoidosis-related neuropathic pain (Heij et al, 2012). This double-blind, randomized, placebocontrolled trial was performed with 22 sarcoidosis patients, of which 12 received a 4-week pHBSP treatment (2 mg IV with 3 injections/ week); the others received normal saline instead of pHBSP.…”

Section: Clinical Studiesmentioning

confidence: 99%

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

Collino

Thiemermann

Cerami

et al. 2015

Pharmacology & Therapeutics

Self Cite

View full text Add to dashboard Cite

Many disease processes activate a cellular stress response that initiates a cascade of inflammation and damage. However, this process also triggers a tissue protection and repair system mediated by locally-produced hyposialated erythropoietin (hsEPO). Although recombinant EPO is used widely for treating anemia, potential use of recombinant EPO for tissue-protection is limited by rises in hematocrit, platelet activation, and selectin expression resulting in a high risk of thrombosis. Importantly, the erythropoietic and tissue-protective effects of EPO are mediated by different receptors. Whereas EPO stimulates red cell progenitors by binding to an EPO receptor (EPOR) homodimer, a heterodimer receptor complex composed of EPOR and β common receptor (βcR) subunits, termed the innate repair receptor (IRR), activates tissue protection and repair. The IRR is typically not expressed by normal tissues, but instead is rapidly induced by injury or inflammation. Based on this understanding, EPO derivatives have been developed which selectively activate the IRR without interacting with the EPOR homodimer. The latest generation of specific ligands of the IRR includes an 11 amino acid peptide modeled from the three dimensional structure of the EPO in the region of helix B called pyroglutamate helix B surface peptide (pHBSP; ARA-290). Despite a short plasma half-life (~2min), pHBSP activates a molecular switch that triggers sustained biological effects that have been observed in a number of experimental animal models of disease and in clinical trials. This review summarizes pharmacokinetic and pharmacodynamic data and discusses the molecular mechanisms underlying the long-lasting effects of this short-lived peptide.

show abstract

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

Cited by 87 publications

References 30 publications

Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

Diagnosis and management of sensory polyneuropathy

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

Contact Info

Product

Resources

About