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Ford A.P.,Afferent Pharmaceuticals
Purinergic Signalling | Year: 2012

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention. © 2011 The Author(s). Source

Kablinger A.S.,Virginia Polytechnic Institute and State University | Lindner M.A.,BioAdvance | Casso S.,University of Texas Health Science Center at San Antonio | Hefti F.,Embera NeuroTherapeutics | And 6 more authors.
Journal of Psychopharmacology | Year: 2012

Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted. © The Author(s) 2012. Source

Ford A.P.,Afferent Pharmaceuticals | Birder L.A.,University of Pittsburgh | Grundy D.,University of Sheffield | Pijacka W.,University of Bristol | Paton J.F.R.,University of Bristol
Autonomic Neuroscience: Basic and Clinical | Year: 2015

A great deal of basic and applied physiology and pharmacology in sensory and autonomic neuroscience has teased apart mechanisms that drive normal perception of mechanical, thermal and chemical signals and convey them to CNS, the distinction of fiber types and receptors and channels that mediate them, and how they may become dysfunctional or maladaptive in disease. Likewise, regulation of efferent autonomic traffic to control organ reflexes has been well studied. In both afferent and efferent limbs, a wide array of potential therapeutic mechanisms has surfaced, some of which have progressed into clinic, if not full regrastration. One conversation that has been less well progressed relates to how the afferent limb and its sensitization shapes the efferent outputs, and where modulation may offer new therapeutic avenues, especially for poorly addressed and common signs and symptoms of disease.Therapeutics for CV disease (HF, hypertension), respiratory disease (asthma, COPD), urological disease (OAB), GI disease (IBS), and inter alia, have largely focused on the efferent control of effector cells to modulate movement, contraction and secretion; medicinal needs remain with limits to efficacy, AEs and treatment resistance being common. We now must turn, in the quest for improved therapeutics, to understand how sensation from these organs becomes maladapted and sensitized in disease, and what opportunities may arise for improved therapeutics given the abundance of targets, many pharmacologically untapped, on the afferent side. One might look at the treatment resistant hypertension and the emerging benefit of renal denervation; or urinary bladder overactivity / neurogenic bladder and the emergence of neuromodulation, capsaicin instillation or botox injections to attenuate sensitized reflexes, as examples of merely the start of such progress. This review examines this topic more deeply, as applies to four major organ systems all sharing a great need from unsatisfied patients. © 2015 Elsevier B.V. Source

Munoz A.,Baylor College of Medicine | Somogyi G.T.,Baylor College of Medicine | Boone T.B.,Michael bakey Va Medical Center | Ford A.P.,Afferent Pharmaceuticals | Smith C.P.,Baylor College of Medicine
BJU International | Year: 2012

OBJECTIVE: To evaluate the role of bladder sensory purinergic P2X3 and P2X2/3 receptors on modulating the activity of lumbosacral neurones and urinary bladder contractions in vivo in normal or spinal cord-injured (SCI) rats with neurogenic bladder overactivity. MATERIALS AND METHODS: SCI was induced in female rats by complete transection at T8-T9 and experiments were performed 4 weeks later, when bladder overactivity developed. Non-transected rats were used as controls (normal rats). Neural activity was recorded in the dorsal horn of the spinal cord and field potentials were acquired in response to intravesical pressure steps via a suprapubic catheter. Field potentials were recorded under control conditions, after stimulation of bladder mucosal purinergic receptors with intravesical ATP (1mm), and after intravenous injection of the P2X3/P2X2/3 antagonist AF-353 (10mg/kg and 20mg/kg). Cystometry was performed in urethane-anaesthetised rats intravesically infused with saline. AF-353 (10mg/kg) was systemically applied after baseline recordings; the rats also received a second dose of AF-353 (20mg/kg). Changes in the frequency of voiding (VC) and non-voiding (NVC) contractions were evaluated. RESULTS: SCI rats had significantly higher frequencies for field potentials and NVC than NL rats. Intravesical ATP increased field potential frequency in control but not SCI rats, while systemic AF-353 significantly reduced this parameter in both groups. AF-353 also reduced the inter-contractile interval in control but not in SCI rats; however, the frequency of NVC in SCI rats was significantly reduced. CONCLUSION: The P2X3/P2X2/3 receptors on bladder afferent nerves positively regulate sensory activity and NVCs in overactive bladders. © 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL. Source

Weigand L.A.,Johns Hopkins University | Ford A.P.,Afferent Pharmaceuticals | Undem B.J.,Johns Hopkins University
Journal of Physiology | Year: 2012

Activation of vagal afferent sensory C-fibres in the lungs leads to reflex responses that produce many of the symptoms associated with airway allergy. There are two subtypes of respiratory C-fibres whose cell bodies reside within two distinct ganglia, the nodose and jugular, and whose properties allow for differing responses to stimuli. We here used extracellular recording of action potentials in an ex vivo isolated, perfused lung-nerve preparation to study the electrical activity of nodose C-fibres in response to bronchoconstriction. We found that treatment with both histamine and methacholine caused strong increases in tracheal perfusion pressure that were accompanied by action potential discharge in nodose, but not in jugular C-fibres. Both the increase in tracheal perfusion pressure and action potential discharge in response to histamine were significantly reduced by functionally antagonizing the smooth muscle contraction with isoproterenol, or by blocking myosin light chain kinase with ML-7. We further found that pretreatment with AF-353 or 2',3'-O-(2,4,6-Trinitrophenyl)-adenosine-5'-triphosphate (TNP-ATP), structurally distinct P2X3 and P2X2/3 purinoceptor antagonists, blocked the bronchoconstriction-induced nodose C-fibre discharge. Likewise, treatment with the ATPase apyrase, in the presence of the adenosine A1 and A2 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and SCH 58261, blocked the C-fibre response to histamine, without inhibiting the bronchoconstriction. These results suggest that ATP released within the tissues in response to bronchoconstriction plays a pivotal role in the mechanical activation of nodose C-fibres. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society. Source

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