Clinical evaluation of the efficacy of the P2X<sub>7</sub>purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine

Keystone, Edward; Wang, Millie M; Layton, Mark; Hollis, Sally; McInnes, Iain B.

doi:10.1136/annrheumdis-2011-143578

Cited by 271 publications

(177 citation statements)

References 9 publications

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“…P2X3, P2X2/3, P2X4, and P2X7 receptors have received a lot of recent attention as potential targets to treat a variety of conditions that include chronic pain and arthritis [44]. Clinically the P2X7 receptor antagonists CE-224535 and AZD9056 have not demonstrated efficacy in rheumatoid arthritis and it is unknown whether they may be useful in pain indications [45,46]. P2X3 receptor expression changes in animal pain models of P2X3 knock-out mice have shown the development of reduced mechanical allodynia [47] and neuronal P2X3 receptor activation predisposing afferent neurons to inflammatory hyperalgesia [48].…”

Section: Introductionmentioning

confidence: 99%

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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Introduction: Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain.Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC. They review repurposed and new pharmacological treatments. Several meta-analyses were performed to compare the efficacy of treatments where possible.Expert opinion: Repurposed pain medications such as gabapentin and pregabalin reduce the frequency of cough and improve quality of life. Along with speech pathology, they are important and alternate treatments for refractory CC. However, more treatments are needed and the P2X3 ion channel receptor antagonists show the most promise. With a better understanding of neuronal activation and sensitisation and their signal processing in the brain, improved animal models of cough, and the use of validated cough measurement tools, more effective treatments will develop.

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Section: Introductionmentioning

confidence: 99%

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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“…It has been reported that inhibition of the expression of inflammatory cytokines prevents the decomposition of cartilage tissues [15]. The characteristic features of OA include knee joint edema, decomposition of cartilage, hyperplasia of synovium and degradation of sub-chondral bones [16].…”

Section: Discussionmentioning

confidence: 99%

Benzoxime inhibits matrix metalloproteinase-13 activation and cartilage damage in osteoarthritis rats via inhibition of NF-κB pathway

He¹,

Li²,

Li³

et al. 2018

Trop. J. Pharm Res

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“…Block of P2X7 receptor signalling in the collagen-induced arthritis animal model of RA inhibited peripheral inflammatory tissue destruction and the autoreactive humoral response, supporting the view that P2X7 receptor antagonists may cure inflammatory autoimmune diseases, such as RAs [389]. However, a later study claimed that AZD9056, a P2X7 receptor antagonist, did not appear to be a therapeutically useful target for RA [390]. P2X7 receptor antagonists are also being explored for the treatment of inflammatory pain in joints [391].…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Purinergic signalling in the musculoskeletal system

Burnstock

Arnett

Orriss

2013

Purinergic Signalling

111

114

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It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y 1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone-destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors.

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Clinical evaluation of the efficacy of the P2X₇purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine

Abstract: ClinicalTrials.gov NCT00520572.

Cited by 271 publications

References 9 publications

An update and systematic review on drug therapies for the treatment of refractory chronic cough

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Benzoxime inhibits matrix metalloproteinase-13 activation and cartilage damage in osteoarthritis rats via inhibition of NF-κB pathway

Purinergic signalling in the musculoskeletal system

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Clinical evaluation of the efficacy of the P2X7purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine

Abstract: ClinicalTrials.gov NCT00520572.

Cited by 271 publications

References 9 publications

An update and systematic review on drug therapies for the treatment of refractory chronic cough

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Benzoxime inhibits matrix metalloproteinase-13 activation and cartilage damage in osteoarthritis rats via inhibition of NF-κB pathway

Purinergic signalling in the musculoskeletal system

Contact Info

Product

Resources

About

Clinical evaluation of the efficacy of the P2X₇purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine