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Jan M Keppel Hesselink, Michael E Schatman
EMA401 is an old molecule, synthesized by Parke-Davis in the last century and characterized at that time as an AT2R antagonist. Professor Maree Smith and her group from the University of Queensland (Australia) patented the drug and many related derivatives and other compounds with high affinity for the AT2R for the indication neuropathic pain in 2004, an example of drug repositioning. After some years of university work, the Australian biotech company Spinifex Pharmaceuticals took over further research and development and characterized the S-enantiomer, code name EMA401, and related compounds in a variety of animal models for neuropathic and cancer pain...
2017: Journal of Pain Research
Osvaldo J M Nascimento, Bruno L Pessoa, Marco Orsini, Pedro Ribeiro, Eduardo Davidovich, Camila Pupe, Pedro Moreira Filho, Ricardo Menezes Dornas, Lucas Masiero, Juliana Bittencourt, Victor Hugo Bastos
Neuropathic pain (NP) is the result of a series of conditions caused by diseases or lesions to the somatosensory system. Due to the better understanding of NP pathophysiology previously unexplored therapies have been used with encouraging results. In this group, acetyl-L-carnitine, alpha-lipoic-acid, cannabinoids, clonidine, EMA401, botulinum toxin type A and new voltage-gated sodium channel blockers, can be included. Besides, changing paradigms may occur with the advent of optogenetics and a better understanding of epigenetic regulation...
June 15, 2016: Neurology International
U Anand, M Sinisi, M Fox, A MacQuillan, T Quick, Y Korchev, C Bountra, T McCarthy, P Anand
BACKGROUND: Mycolactone is a polyketide toxin secreted by the mycobacterium Mycobacterium ulcerans, responsible for the extensive hypoalgesic skin lesions characteristic of patients with Buruli ulcer. A recent pre-clinical study proposed that mycolactone may produce analgesia via activation of the angiotensin II type 2 receptor (AT2R). In contrast, AT2R antagonist EMA401 has shown analgesic efficacy in animal models and clinical trials for neuropathic pain. We therefore investigated the morphological and functional effects of mycolactone in cultured human and rat dorsal root ganglia (DRG) neurons and the role of AT2R using EMA401...
2016: Molecular Pain
Maree T Smith, Praveen Anand, Andrew S C Rice
Neuropathic pain affects up to 10% of the general population, but drug treatments recommended for the treatment of neuropathic pain are associated with modest efficacy and/or produce dose-limiting side effects. Hence, neuropathic pain is an unmet medical need. In the past 2 decades, research on the pathobiology of neuropathic pain has revealed many novel pain targets for use in analgesic drug discovery programs. However, these efforts have been largely unsuccessful as molecules that showed promising pain relief in rodent models of neuropathic pain generally failed to produce analgesia in early phase clinical trials in patients with neuropathic pain...
February 2016: Pain
Bruno L Pessoa, Gabriel Escudeiro, Osvaldo J M Nascimento
Neuropathic pain is a series of well-known conditions caused by diseases or lesions to the somatosensory system. Due to the better understanding of the pathophysiology of neuropathic pain, previously unexplored therapies have been used with encouraging results. As such, Acetyl-L-carnitine (ALC), Alpha-lipoic-acid (ALA), cannabinoids, Clonidine, EMA401, Botulinum Toxin type A, and new voltage-gated sodium channel blockers, can be cited. Furthermore, new modalities in neuromodulation such as high-frequency spinal cord stimulation, burst stimulation, dorsal root ganglion stimulation, transcranial direct current stimulation, and many others have been showing exciting results...
December 2015: Current Pain and Headache Reports
Uma Anand, Yiangos Yiangou, Marco Sinisi, Michael Fox, Anthony MacQuillan, Tom Quick, Yuri E Korchev, Chas Bountra, Tom McCarthy, Praveen Anand
BACKGROUND: The clinical efficacy of the Angiotensin II (AngII) receptor AT2R antagonist EMA401, a novel peripherally-restricted analgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT2R is expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRG neurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, and their signalling pathways, require investigation...
June 26, 2015: Molecular Pain
A S C Rice, M T Smith
Neuropathic pain is a large unmet medical need. The angiotensin II type 2 (AT2 ) receptor is a target with promising data in rodent models of peripheral neuropathic pain. The AT2 receptor has attracted attention on the basis of human data from a proof-of-concept clinical trial showing that oral EMA401, a highly selective, peripherally restricted, small molecule AT2 receptor antagonist, at 100 mg twice-daily for 4 weeks, alleviated postherpetic neuralgia, an often intractable type of peripheral neuropathic pain...
February 2015: Clinical Pharmacology and Therapeutics
Maree T Smith, Arjun Muralidharan
INTRODUCTION: Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous 'pain targets' have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT2R) antagonist. AREAS COVERED: Herein, angiotensin II/AT2R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT2R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed...
January 2015: Expert Opinion on Therapeutic Targets
T McCarthy
No abstract text is available yet for this article.
October 2014: Journal of the Peripheral Nervous System: JPNS
(no author information available yet)
Neuropathic pain, including post-herpetic neuralgia after shingles, is not well controlled by existing treatments. EMA401 is an angiotensin II type 2 receptor antagonist developed in the search for antihypertensive drugs. The renin-angiotensin system has roles outside the cardiovascular system, including in the central and peripheral nervous systems.
August 2014: Nursing Older People
Kinga Sałat, Paula Kowalczyk, Beata Gryzło, Anna Jakubowska, Katarzyna Kulig
INTRODUCTION: Neuropathic pain (NP) is a chronic condition that arises from a lesion or dysfunction of the somatosensory nervous system. However, there are several new targets and novel technologies in the pipeline to address this unmet medical need. AREAS COVERED: In this review, the authors briefly discuss a direction of the development of agents that could be potentially used in NP treatment. Special attention is paid to 1.7-selective voltage-gated sodium channels, N-type voltage-gated calcium channels, angiotensin II (Ang II) AT₂ receptors and nerve growth factor (NGF) as promising targets for new drugs...
August 2014: Expert Opinion on Investigational Drugs
Andrew S C Rice, Robert H Dworkin, Tom D McCarthy, Praveen Anand, Chas Bountra, Philip I McCloud, Julie Hill, Gary Cutter, Geoff Kitson, Nuket Desem, Milton Raff
BACKGROUND: Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. METHODS: In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries...
May 10, 2014: Lancet
Maree T Smith, Bruce D Wyse, Stephen R Edwards
OBJECTIVE: Neuropathic pain is an area of unmet clinical need. The objective of this study was to define the pharmacokinetics, oral bioavailability, and efficacy in rats of small molecule antagonists of the angiotensin II type 2 receptor (AT₂R) for the relief of neuropathic pain. DESIGN AND METHODS: Adult male Sprague-Dawley (SD) rats received single intravenous (1-10 mg/kg) or oral (5-10 mg/kg) bolus doses of EMA200, EMA300, EMA400 or EMA401 (S-enantiomer of EMA400)...
May 2013: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
U Anand, P Facer, Y Yiangou, M Sinisi, M Fox, T McCarthy, C Bountra, Y E Korchev, P Anand
BACKGROUND: The angiotensin II (AngII) receptor subtype 2 (AT2 R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration. METHODS: We used immunostaining with characterized antibodies to study the localization of AT2 R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2 R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence...
August 2013: European Journal of Pain: EJP
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