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Key Points The detection of noxious stimuli by nociceptors is mediated by high-threshold transducers expressed on their peripheral terminal membranes. These transducers are receptor/ion channels that convert thermal, mechanical and chemical stimuli into ion fluxes that excite the neuron to produce a sensory inflow. Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins and encode thermal and chemical stimuli. Among the TRP channels expressed by nociceptors, TRPV1 and TRPA1 have been the most extensively investigated, and represent validated targets for the development of novel analgesics. In addition to detecting noxious stimuli, the density, threshold and kinetics of TRPV1 and TRPA1 are modulated by inflammatory mediators, and in this way sensitize nociceptors to increase pain sensitivity after tissue damage or on exposure to inflammation. TRPV1 and TRPA1 are also expressed on the central terminals of sensory neurons where they seem to act as synaptic modulators. Antagonists acting at these two channels are promising candidates as analgesics by virtue of blocking the activation of the channels in response to noxious stimuli or inflammation. TRP nociceptive transducer proteins may have adaptive actions beyond simply detecting noxious stimuli, including body temperature control, synaptic plasticity, and respiratory and cardiovascular function, which may produce adverse effects when blocked. TRP channel agonists can also produce analgesia by either desensitizing the receptors or, at high doses, ablating them. TRP channels can be used as a drug delivery system to target small cationic drugs selectively into nociceptors. Overall, targeting nociceptive TRP channels, where the pain-pathway begins, represents a promising opportunity for the development of novel analgesics. Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting compounds and looks at recent clinical trials with TRP-channel-acting drugs. Pain results from the complex processing of neural signals at different levels of the central nervous system, with each signal potentially offering multiple opportunities for pharmacological intervention. A logical strategy for developing novel analgesics is to target the beginning of the pain pathway, and aim potential treatments directly at the nociceptors — the high-threshold primary sensory neurons that detect noxious stimuli. The largest group of receptors that function as noxious stimuli detectors in nociceptors is the transient receptor potential (TRP) channel family. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting drugs, and discusses the development pathways needed to test candidates as analgesics in humans.

Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study. We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18–80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov (NCT01540630) and EudraCT (2010-023963-16). The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 [19%] of 67 patients), followed by dizziness (in six [9%] patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one [7%] of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one [7%] of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication. The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials. Convergence Pharmaceuticals.

Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human pain disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (Na V 1.7, Na V 1.8 and Na V 1.9). Gain-of-function mutations in Na V 1.6, which is expressed in myelinated and unmyelinated central nervous system (CNS) and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in Na V 1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglia (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel Na V 1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function Na V 1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN.

Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs. Two double-blind randomized withdrawal studies are planned to evaluate the efficacy and safety of vixotrigine compared with placebo in participants with TN (NCT03070132 and NCT03637387). Participant criteria include ≥18 years old who have classical, purely paroxysmal TN diagnosed ≥3 months prior to study entry, who experience ≥3 paroxysms of pain/day. The two studies will include a screening period, 7-day run-in period, a 4- or 6-week single-dose-blind dose-optimization period (Study 1) or 4-week open-label period (Study 2), and 14-week double-blind period. Participants will receive vixotrigine 150 mg orally three times daily in the dose-optimization and open-label periods. The primary endpoint of both studies is the proportion of participants classified as responders at Week 12 of the double-blind period. Secondary endpoints include safety measures, quality of life, and evaluation of vixotrigine population pharmacokinetics. There is a need for an effective, well-tolerated, noninvasive treatment for the neuropathic pain associated with TN. The proposed studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with TN.

Background This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia. Methods This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n  = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N  = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics. Results Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change. Conclusions Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges. Trial registration ClinicalTrials.gov, NCT01540630 . EudraCT, 2010-023963-16. 07 Aug 2015.

We have cloned a second tetrodotoxin-resistant (TTX-R) sodium channel α subunit, SNS2, with the same amino-acid sequence as a putative sodium channel α subunit NaN (ref. 1 ). SNS2 expression in HEK293T cells produced a TTX-R voltage-gated sodium current with faster kinetics and a lower TTX IC 50 than the previously cloned sensory-neuron-specific sodium channel, SNS/PN3 (Refs 2 , 3 ). SNS2 was co-expressed with SNS/PN3 in small DRG neurons.

In this work molecular modeling was applied to generate homology models of the pore region of the Na(v)1.2 and Na(v)1.8 isoforms of human voltage-gated sodium channels. The models represent the channels in the resting, open, and fast-inactivated states. The transmembrane portions of the channels were based on the equivalent domains of the closed and open conformation potassium channels KcsA and MthK, respectively. The critical selectivity loops were modeled using a structural template identified by a novel 3D-search technique and subsequently merged with the transmembrane portions. The resulting draft models were used to study the differences of tetrodotoxin binding to the tetrodotoxin-sensitive Na(v)1.2 (EC50: 0.012 microM) and -insensitive Na(v)1.8 (EC50: 60 microM) isoforms, respectively. Furthermore, we investigated binding of the local anesthetic tetracaine to Na(v)1.8 (EC50: 12.5 microM) in resting, conducting, and fast-inactivated state. In accordance with experimental mutagenesis studies, computational docking of tetrodotoxin and tetracaine provided (1) a description of site 1 toxin and local anesthetic binding sites in voltage-gated sodium channels. (2) A rationale for site 1 toxin-sensitivity versus -insensitivity in atomic detail involving interactions of the Na(v)1.2 residues F385-I and W943-II. (3) A working hypothesis of interactions between Na(v)1.8 in different conformational states and the local anesthetic tetracaine.

The future of the Ottoman Empire was an important issue in international politics during the early years of the Twentieth Century. As more and more of its territory was chipped away, the events caused by this this process of disintegration became central to Great Power relations in the period before the First World War. These developments were particularly significant from the British perspective, not only because the Young Turk revolution of 1908 seemed to promise a brighter future for Anglo-Turkish relations, but because the British interest in maintaining the Ottoman Empire for as long as possible, for fear of what came next, directly conflicted with the more aggressive designs of Russia, one of the two Powers with which Britain had recently become aligned. Much of the literature on Anglo-Turkish relations of the period has tended to argue that a 'golden opportunity' existed for Britain to improve her relations with the Ottoman Empire following the coming to power of the 'Young Turks', who were, both at the time and in more recent scholarship, asserted to have possessed Anglophile tendencies. In the literature on Britain's Great Power relations of the period more widely, meanwhile, a discernible trend has emerged suggesting that Sir Edward Grey, the British Foreign Minister, was wedded to a policy of ententes, which blinded him to the wider realities of Great Power relations. In understanding how historical events took place, it is important to view events through the eyes of those experiencing them. Through means of an analytical narrative, this work will reconstruct contemporary worldviews and decision-making processes within the British Foreign Office to examine these two conclusions critically, and demonstrate both that Grey was not fixated on a policy of ententes and that a 'golden opportunity' was no more than illusion.

Drawing upon ideas from critical geopolitics, this paper compares the role that the British government plays within the contemporary transatlantic alliance with that played by Churchill's government during the Second World War. It argues that the Blair government's approach to foreign policy has parallels with Churchill's - that it should act as a bridge between the US and European governments. From this basis the paper reflects upon geopolitical change since 1945, re-evaluating the reasons for foreign policy failures during the Iraq War. Belying the assumption that these were caused by Blair's failures at diplomacy, it argues that failure was the result of an outdated geopolitical strategy.