Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers.

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

Associations among domains of self-disturbance in schizophrenia.

Self-disturbances are increasingly recognized as important, possibly even central, features of schizophrenia. However, little is known about the associations among different manifestations of self-disturbances. The aims of the current study were threefold. We aimed to (1) replicate previous findings of increased self-disturbances in schizophrenia, (2) correlate manifestations of self-disturbances in schizophrenia across three domains, and (3) correlate self-disturbances with five symptoms domains of schizophrenia, including positive, negative, disorganized symptoms, excitement, and emotional distress. We examined three domains of self-experience, including somatosensation, anomalous self-experiences, and self-concept clarity. Participants included 48 individuals with schizophrenia and 36 non-psychiatric controls. The results of this study replicate previous findings of significantly higher levels of self-disturbances in people with schizophrenia. The results also indicate positive correlations between the domains of anomalous self-experiences and self-concept clarity, but not somatosensation, in individuals with schizophrenia. As well, anomalous self-experiences were positively correlated with positive symptoms, disorganized symptoms, and emotional distress and self-concept clarity was negatively correlated with disorganized symptoms and emotional distress.

Microneedles: A versatile strategy for transdermal delivery of biological molecules.

Human skin is made up of multiple layers and is designed to protect the human body. The stratum corneum (SC), specifically, is a keratinized layer of skin through which molecules heavier than 500 Da cannot penetrate. Traditional methods of transdermal drug delivery through the SC, such as hypodermic needles, are less than ideal because their size and appearance can cause fear and pain, creating hesitation, limiting self-administration, and preventing their use in some patients altogether. A new technology has been developed to address these limitations, in which an array of needles, each microns in diameter and length, called microneedles, are able to pierce the skin's SC to deliver therapeutic agents without stimulating the proprioceptive pain nerves. These needles provide a strong advantage because they are capable of being incorporated into patches that can be conveniently self-administered by patients, while also offering the same bioabsorption and bioavailability currently provided by hypodermic needles. There have been many advancements in microneedle fabrication, and there are currently many variations of microneedle technology. Therefore, the purpose of this review is to provide a broad, introductory summary of current microneedle technology.

Does Dexamethasone Facilitate Neurosensory Function Regeneration After Zygomatic Fracture? A Randomized Controlled Trial.

PURPOSE: This study sought to clarify the rate of neurosensory disturbance (NSD) after zygomatic complex fractures in general, as well as the effect of perioperatively administered dexamethasone on neurosensory recovery. PATIENTS AND METHODS: This was a single-blinded randomized study aiming to clarify the benefits of perioperative dexamethasone after surgery. The patients were randomly assigned either to receive dexamethasone (up to a total dose of 10 or 30 mg) or to act as control patients (no glucocorticoid treatment). The outcome variable was NSD, the presence of which was established when patients had any sensory disturbance of the infraorbital nerve. Other predictor variables included in the analysis were age, gender, time span from accident to surgery, surgical approach to the fracture line, and relation of the fracture to the infraorbital foramen. The statistical significance of associations was evaluated with χ2 tests. RESULTS: We included 64 patients in the analyses. Of the patients in the dexamethasone group (either 10 or 30 mg), 58.3% had NSD at 6 months postoperatively, whereas in the control group, 66.7% of the patients had NSD. This finding was not statistically significant (P = .565). At the 1-month interval, the patients without a fracture through the infraorbital foramen had less NSD (P = .009); this finding was not significant at 3 and 6 months postoperatively. Age, gender, injury mechanism, surgical approach, and time span from accident to surgery were not significant predictors of NSD. In total, 64.4% of the patients still had NSD at 6 months postoperatively. CONCLUSIONS: This study showed no benefits of short-term, high-dose dexamethasone administration in the neurosensory recovery of patients with zygomatic complex fractures. The type of primary trauma is the main cause of NSD, but the precise predictors remain unknown.

Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat.

BACKGROUND: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI. METHODS: The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). RESULTS: Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α. CONCLUSIONS: Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.

Corticosteroids for treating nerve damage in leprosy.

BACKGROUND: Leprosy causes nerve damage that can result in nerve function impairment and disability. Corticosteroids are commonly used for treating nerve damage, although their long-term effect is uncertain. This is an update of a review first published in 2007, and previously updated in 2009 and 2011. OBJECTIVES: To assess the effects of corticosteroids on nerve damage in leprosy. SEARCH METHODS: On 16 June 2015, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL Plus, and LILACS. We also checked clinical trials registers and contacted trial authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of corticosteroids for nerve damage in leprosy. The comparators were no treatment, placebo treatment, or a different corticosteroid regimen. DATA COLLECTION AND ANALYSIS: The primary outcome was improvement in nerve function after one year. Secondary outcomes were change in nerve pain, limitations in activities of daily living, limitations in participation, and adverse events. Two review authors independently extracted data and assessed trial quality. When data were lacking, we contacted trial authors for additional information. MAIN RESULTS: We included five RCTs involving 576 people. The trials were largely at low risk of bias, but we considered the quality of the evidence from these trials as moderate to low, largely due to imprecision from small sample sizes. Two out of the five trials reported on improvement in nerve function at one year. These two trials compared prednisolone with placebo. One trial, with 84 participants, treated mild sensory impairment of less than six months' duration, and the other, with 95 participants, treated nerve function impairment of 6 to 24 months' duration. There was no significant difference in nerve function improvement after 12 months between people treated with prednisolone and those treated with placebo. Adverse events were not reported significantly more often with corticosteroids than with placebo. The other three trials did not report on the primary outcome measure. One (334 participants) compared three corticosteroid regimens for severe type 1 reactions. No serious side effects of steroids were reported in any participant during the follow-up period. Another trial (21 participants) compared low-dose prednisone with high-dose prednisone for ulnar neuropathy. Two participants on the higher dose of prednisone reported adverse effects. The last (42 participants) compared intravenous methylprednisolone and oral prednisolone with intravenous normal saline and oral prednisolone. The trial found no significant differences between the groups in the occurrence of adverse events. AUTHORS' CONCLUSIONS: Corticosteroids are used for treating acute nerve damage in leprosy, but moderate-quality evidence from two RCTs treating either longstanding or mild nerve function impairment did not show corticosteroids to have a superior effect to placebo on nerve function improvement. A third trial showed significant benefit from a five-month steroid regimen over a three-month regimen in terms of response to treatment (need for additional corticosteroids). Further RCTs are needed to establish optimal corticosteroid regimens and to examine the efficacy and safety of adjuvant or new therapies for treating nerve damage in leprosy. Future trials should address non-clinical aspects, such as costs and impact on quality of life, which are highly relevant indicators for both policymakers and participants.

Tanezumab Reduces Pain in Women with Interstitial Cystitis/Bladder Pain Syndrome and Patients with Nonurological Associated Somatic Syndromes.

PURPOSE: We performed pooled analyses from 3 small, clinical trials of tanezumab in patients with urological chronic pelvic pain, including chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/bladder pain syndrome, to identify patient subpopulations more likely to benefit from tanezumab treatment. MATERIALS AND METHODS: Pooled analyses included data from 208 patients with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome randomized to placebo (104, 65 [62.5%] female) or tanezumab (104, 63 [60.6%] female) who received 1 dose or more of study medication. Data on tanezumab were from study A4091010 (interstitial cystitis/bladder pain syndrome) on 200 µg/kg intravenous, study A4091019 (chronic prostatitis/chronic pelvic pain syndrome) on 20 mg intravenous and study A4091035 (interstitial cystitis/bladder pain syndrome) on 20 mg subcutaneous. Primary study end points were evaluated using analysis of covariance with gender, study and baseline pain as covariates. RESULTS: For pooled analyses least squares mean (SE) change from baseline in 24-hour pain intensity vs placebo was -0.60 (0.24, 90% CI -0.99, -0.20) overall and -0.99 (0.32, p=0.002) and -0.17 (0.36, p=0.650) for females and males, respectively. The improvement in pain intensity was significant (p=0.011) for patients with symptoms suggesting the concomitant presence of nonurological associated somatic syndromes but not for those with pelvic pain symptoms only (p=0.507). CONCLUSIONS: Women with interstitial cystitis/bladder pain syndrome and patients with symptoms suggesting the concomitant presence of nonurological associated somatic syndromes were more likely to experience significant pain reduction with tanezumab than with placebo therapy. In contrast, no difference was reported in response between tanezumab and placebo therapy for men with chronic prostatitis/chronic pelvic pain syndrome symptoms only.

Thermo-sensitive TRP channels in peripheral nerve injury: a review of their role in cold intolerance.

One of the sensory complications of traumatic peripheral nerve injury is thermal intolerance, which manifests in humans mainly as cold intolerance. It has a major effect on the quality of life, and adequate therapy is not yet available. In order to better understand the pathophysiological background of thermal intolerance, we focus first on the various transient receptor potential (TRP) channels that are involved in temperature sensation, including their presence in peripheral nerves and in keratinocytes. Second, the role of thermo-sensitive TRP channels in cold and heat intolerance is described showing three different mechanisms that contribute to thermal intolerance in the skin: (a) an increased expression of TRP channels on nerve fibres and on keratinocytes, (b) a lower activation threshold of TRP channels and (c) the sprouting of non-injured nerve fibres. Finally, the data that are available on the effects of TRP channel agonists and antagonists and their clinical use are discussed. In conclusion, TRP channels play a major role in temperature sensation and in cold and heat intolerance. Unfortunately, the available pharmaceutical agents that successfully target TRP channels and counteract thermal intolerance are still very limited. Yet, our focus should remain on TRP channels since it is difficult to imagine a reliable treatment for thermal intolerance that will not involve TRP channels.

High concentration capsaicin for treatment of peripheral neuropathic pain: effect on somatosensory symptoms and identification of treatment responders.

BACKGROUND: Pain is usually assessed by spontaneous pain ratings. Time-dependent (brief attacks) or evoked (allodynia) phenomena, common in neuropathic pain, are not captured. To evaluate the overall effectiveness of a treatment, improvement of all sensory symptoms should be measured. Since the pattern of sensory abnormalities might hint at the underlying mechanisms of pain, this baseline information may aid in predicting the treatment effect. Data on sensory neuropathic abnormalities (painDETECT questionnaire) were analyzed aiming to (1) evaluate the frequency of neuropathic symptoms in different peripheral neuropathic pain syndromes, (2) assess the effect of capsaicin 8% patch on neuropathic symptoms and (3) identify treatment responders based on baseline values. METHODS: Data analysis of a prospective 12 week non-interventional trial in peripheral neuropathic pain treated with capsaicin 8% cutaneous patch. Average pain intensity during the past 24 hours, pain descriptors and qualities of neuropathic pain were assessed to characterize the patients' sensory symptoms at baseline and to document changes. RESULTS: (1) Characteristic symptoms of neuropathic pain were present in all peripheral neuropathic pain syndromes, but frequencies varied in the individual syndromes. (2) Topical capsaicin 8% treatment significantly reduced the overall pain intensity and resulted in a reduction of sensory abnormalities. (3) Short disease duration predicted a better treatment effect. High painDETECT scores, the presence of burning and pressure-evoked pain were weakly associated with treatment response. CONCLUSIONS: Topical capsaicin 8% treatment effectively reduced sensory abnormalities in peripheral neuropathic pain. The association of sensory symptoms and treatment response aids in understanding the mechanism of action of high concentration capsaicin. It is, however, not possible to use sensory symptom patterns to predict treatment response to capsaicin on an individual level. LIMITATIONS: Completion of painDETECT was optional and therefore data was not available for all patients. Further studies for confirmation of these results are needed.

Psychopharmacological therapies in dermatology.

When patients with psychodermatologic disorders present in clinic, the dermatologist can refer them to psychiatrists or other mental health care professionals. However, it is often the case that these patients will refuse a psychiatric referral because they either do not believe they have a disorder of psychiatric nature or they feel there is societal stigma associated with psychiatric illness. Therefore, it is essential for dermatologists to understand the common classifications for psychodermatological cases and to know how to optimally treat these patients with pharmacotherapy. The intent of this article is to help guide physicians in understanding the classifications of psychodermatological cases and in managing these conditions with pharmacotherapies. In this article, two classifications for psychodermatological cases are presented, followed by a discussion of medical therapies used to treat the main categories of psychopathologies that are more frequently encountered in dermatology. These include depression, anxiety, delusions, and obsessive-compulsive disorder.

Principles of brain plasticity in improving sensorimotor function of the knee and leg in patients with anterior cruciate ligament injury: a double-blind randomized exploratory trial.

BACKGROUND: Severe traumatic knee injury, including injury to the anterior cruciate ligament (ACL), leads to impaired sensorimotor function. Although improvements are achieved by training, impairment often persists. Because good sensorimotor function is associated with better patient-reported function and a potential lower risk of future joint problems, more effective treatment is warranted. Temporary cutaneous anesthesia of adjacent body parts was successfully used on the hand and foot to improve sensorimotor function. The aim of this study was to test whether this principle of brain plasticity could be used on the knee. The hypothesis was that temporary anesthesia of the skin area above and below the knee would improve sensorimotor function of the ipsilateral knee and leg in subjects with ACL injury. METHODS: In this double-blind exploratory study, 39 subjects with ACL injury (mean age 24 years, SD 5.2, 49% women, mean 52 weeks after injury or reconstruction) and self-reported functional limitations and lack of trust in the knee were randomized to temporary local cutaneous application of anesthetic (EMLA®) (n = 20) or placebo cream (n = 19). Fifty grams of EMLA®, or placebo, was applied on the leg 10 cm above and 10 cm below the center of patella, leaving the area around the knee without cream. Measures of sensory function (perception of touch, vibration sense, knee kinesthesia) and motor function (knee muscle strength, hop test) were assessed before and after 90 minutes of treatment with EMLA® or placebo. The paired t-test was used for comparisons within groups and analysis of variance between groups, except for ordinal data where the Wilcoxon signed rank test, or Mann-Whitney test, was used. The number of subjects needed was determined by an a priori sample size calculation. RESULTS: No statistically significant or clinically relevant differences were seen over time (before vs. after) in the measures of sensory or motor functions in the EMLA® group or in the placebo group. There were no differences between the groups due to treatment effect (EMLA® vs. placebo). CONCLUSIONS: Temporary cutaneous anesthesia of adjacent body parts had no effect in improving sensorimotor function of the knee and leg in subjects with severe traumatic knee ligament injury.

Somatosensory cortical activation in cervical dystonia and its modulation with botulinum toxin: an fMRI study.

Converging data on focal dystonias suggest a widespread disorder of somatosensory processing. The aims of our study were, first, to assess somatosensory activation patterns in cervical dystonia (CD) beyond the representation of the affected body parts and, second, to search for task-related activation changes induced by botulinum toxin type-A (BoNT-A) therapy. Functional magnetic resonance imaging (MRI) during electrical median nerve stimulation was employed in seven CD patients and nine controls; the examination was repeated 4 weeks after BoNT-A application to dystonic neck muscles. The pretreatment activation map of patients showed activation in the contralateral primary somatosensory cortex, but missing activation in the secondary somatosensory cortex and insula, in contrast to controls and patients after treatment. Clinically significant effect of BoNT-A therapy was associated with a significant increase of BOLD response in the contralateral secondary somatosensory, insular, and inferior parietal cortices. The posttreatment somatosensory maps of patients did not significantly differ from controls. This study has brought evidence of widespread disruption of somatosensory processing in CD and its modification with BoNT-A therapy.

Protective effect of hydrogen gas therapy after germinal matrix hemorrhage in neonatal rats.

BACKGROUND: Germinal matrix hemorrhage (GMH) is a neurological disease of very low birth weight premature infants leading to post-hemorrhagic hydrocephalus, cerebral palsy, and mental retardation. Hydrogen (H2) is a potent antioxidant shown to selectively reverse cytotoxic oxygen-radical injury in the brain. This study investigated the therapeutic effect of hydrogen gas after neonatal GMH injury. METHODS: Neonatal rats underwent stereotaxic infusion of clostridial collagenase into the right germinal matrix brain region. Cognitive function was assessed at 3 weeks, and then sensorimotor function, cerebral, cardiac and splenic growths were measured 1 week thereafter. RESULTS: Hydrogen gas inhalation markedly suppressed mental retardation and cerebral palsy outcomes in rats at the juvenile developmental stage. The administration of H2 gas, early after neonatal GMH, also normalized the brain atrophy, splenomegaly and cardiac hypertrophy 1 month after injury. CONCLUSION: This study supports the role of cytotoxic oxygen-radical injury in early neonatal GMH. Hydrogen gas inhalation is an effective strategy to help protect the infant brain from the post-hemorrhagic consequences of brain atrophy, mental retardation and cerebral palsy. Further studies are necessary to determine the mechanistic basis of these protective effects.

The effect of dopamine replacement therapy on haptic sensitivity in Parkinson's disease.

Increasing evidence indicates that processing of proprioceptive information is altered in Parkinson's disease (PD), leading to reduced kinaesthetic and haptic sensitivity. However, there is inconclusive evidence whether dopamine replacement therapy (DRT) ameliorates or worsens kinaesthetic and haptic function in PD. For assessing perceptual function, we employed a task that did not require active motion or stressed working memory function, which may become impaired in PD. A group of mild to moderate stage PD patients (n = 9) and a group of age-matched healthy controls participated in this study. Without vision, a subject's hand was moved by a robotic manipulandum along the contours of a small "virtual box" (5 × 15 cm). At the end of each trial, they indicated whether the contour was "curved" or "straight". PD patients were tested ON and OFF antiparkinsonian medication. Psychophysical detection thresholds were determined (curvature at which subjects correctly perceived a curved contour at the 75% level). Compared to the control group, thresholds were elevated by 55% in the PD patient group. During the ON medication state, the mean detection threshold of the patient group was reduced by 15% (ON: 4.71 m(-1); OFF: 5.42 m(-1)). Increases in curvature sensitivity were highly correlated with improved clinical scores of motor function (r = 0.74) with more affected patients showing higher gains in sensitivity as the result of DRT (r = 0.80). This report documents that DRT can ameliorate haptic and kinaesthetic function in patients with mild to moderate PD, suggesting that DRT can have beneficial effects on perceptual function.

[Association of immunization and thermal latencies in rats with chronic constriction injury].

OBJECTIVE: To observe the change of thermal latencies, spinal cord morphology and quantity of microglia following the treatment of lipopolysaccharide (LPS) or cyclosporin A (CsA) in rats with established neuropathic pain through chronic constriction injury (CCI). METHODS: A total of 36 male SD rats with CCI of sciatic nerve were randomly divided into LPS group, CsA group and NS group, and injected with LPS (1 mg/kg), CsA (6 mg/kg), and NS (2 mL) per day respectively since the 3rd day post operation. The thermal latencies and mechanical thresholds of the rats were measured preoperatively and on the 3rd, 5th, 7th, 10th, 13th and 14th day post operation. The rats were sacrificed on the 14th day and the L4 of spinal cords were harvested for CD11b IHC examination of microglia. RESULTS: The thermal latencies went down steadily in rats treated with LPS, but went up in rats treated with CsA since the 3rd day after nerve injury. More active microglia were found in the white and grey matter of the spinal cord L4 in rats treated with LPS and NS than in rats treated with CsA. The majority of microglia were inactive in rats treated with CsA. CONCLUSION: Immunomodulator might affect the thermal latencies of CCI rat model, perhaps through microglia in the central nerve system.

Efficacy of keishibukuryogan, a traditional Japanese herbal medicine, in treating cold sensation and numbness after stroke: clinical improvement and skin temperature normalization in 22 stroke patients.

Cold sensation and numbness have been reported as post-stroke sensory sequelae attributable to distal axonopathy, which is caused by chronic ischemia of diseased limbs resulting from dysfunction of vasomotor regulatory systems. Keishibukuryogan is a traditional herbal medicine used to treat symptoms of peripheral ischemia such as cold extremities. This study investigated clinical improvement and skin temperature in peripheral ischemia patients to determine the efficacy of keishibukuryogan in alleviating post-stroke cold sensation and numbness. Twenty-two stroke patients with cold sensation and/or numbness were enrolled in this study. Subjective cold sensation and numbness, evaluated using the visual analogue scale, were found in 21 and 31 limbs, respectively. The skin temperature of diseased and healthy limbs was recorded. We observed all patients for 4 weeks and 17 patients for 8 weeks after administration of keishibukuryogan. The skin temperature of diseased limbs was significantly higher than baseline at 4 weeks and 8 weeks, whereas that of healthy limbs did not change significantly. Cold sensation and numbness were significantly improved at 4 weeks and 8 weeks compared to baseline. Keishibukuryogan administration resulted in warming of diseased limbs and improved cold sensation and numbness, probably by increasing peripheral blood flow.