Anti-nerve Growth Factor Antibody Research Articles

Measuring the effect of the anti-nerve growth factor antibodies bedinvetmab and frunevetmab on quality of life in dogs and cats with osteoarthritis using a validated health-related quality of life outcome measure: an observational real-world study.

Osteoarthritis causes chronic pain, impaired joint function, decreased mobility and negatively impacts quality of life (QOL). Anti-nerve growth factor antibodies bedinvetmab for dogs and frunevetmab for cats are licensed for the alleviation of osteoarthritis pain but their QOL impact is unreported. Our aim was to determine if these therapeutics improve QOL using a validated health-related QOL measure that generates scores in four domains of QOL-energetic and enthusiastic (E/E), happy and content (H/C), active and comfortable (A/C) and calm and relaxed (C/R)-in the dog and three in the cat-vitality, comfort and emotional wellbeing (EWB). Summary scores for physical wellbeing (PWB) and emotional wellbeing (EWB) for dogs and PWB for cats are calculated from the domain scores. Animals received bedinvetmab (dogs) at 0.5-1 mg/kg or frunevetmab (cats) at 1-2.8 mg/kg by subcutaneous injection on days 0, 28 and 56 and owners completed QOL assessments within 48 hours of day 0 and on days 14, 28, 56, 63 and 70 using a study-specific app. Assessments were completed by 75 dog and 56 cat owners. By day 14 there was a statistically significant improvement (p ≤ 0.001) in PWB, EWB and all domains except C/R (p = 0.005) in dogs and in all domains and PWB in the cat. Subsequently there was a continued improvement in all domains and summary scores (p ≤ 0.001) except for H/C in the dog and EWB in the cat, which were excluded from the statistical model. The overall improvement in all domain scores in the cat and E/E and A/C in the dog exceeded the previously reported minimum important difference scores for the QOL measure, indicating a clinically significant change. Treatment with bedinvetmab and frunevetmab produced a significant improvement in the QOL of dogs and cats. This latest evidence for the use of these OA pain medications could be helpful in the clinical management of osteoarthritis and post-marketing clinical trials.

Effect of the novel anti-NGF monoclonal antibody DS002 on the metabolomics of pain mediators, cartilage and bone.

The anti-nerve growth factor antibody class of drugs interrupts signaling by blocking NGF binding to TrkA receptors for the treatment of pain; however, this target class of drugs has been associated with serious adverse effects in the joints during clinical trials. DS002 is a novel anti-nerve growth factor antibody drug independently developed by Guangdong Dashi Pharmaceuticals. The main purpose of this study is to explore the correlation between DS002 and pain as well as cartilage and bone metabolism with the help of metabolomics technology and the principle of enzyme-linked reaction, and to examine whether DS002 will produce serious adverse effects in joints caused by its same target class of drugs, in order to provide more scientific basis for the safety and efficacy of DS002. Our results showed that DS002 mainly affected the metabolism of aromatic amino acids and other metabolites, of which six metabolites, l -phenylalanine, 5-hydroxytryptophan, 5-hydroxytryptamine hydrochloride, 3-indolepropionic acid, kynuric acid, and kynurenine, were significantly altered, which may be related to the effectiveness of DS002 in treating pain. In addition, there were no significant changes in biological indicators related to cartilage and bone metabolism in vivo, suggesting that DS002 would not have a significant effect on cartilage and bone metabolism, so we hypothesize that DS002 may not produce the serious adverse effects in joints caused by its fellow target analogs. Therefore, the Anti-NGF analgesic drug DS002 has the potential to become a promising drug in the field of analgesia, providing pain patients with an efficient treatment option without adverse effects.

Phase 2 Randomized, Double-blind, Placebo-controlled Study of the Anti-nerve Growth Factor (NGF) Antibody Tanezumab in Subjects with Moderate to Severe Pain Due to Schwannomatosis (P6-13.001)

Phase 2 Randomized, Double-blind, Placebo-controlled Study of the Anti-nerve Growth Factor (NGF) Antibody Tanezumab in Subjects with Moderate to Severe Pain Due to Schwannomatosis (P6-13.001)

Peripheral Nerve Safety of Nerve Growth Factor Inhibition by Tanezumab: Pooled Analyses of Phase III Clinical Studies in Over 5000 Patients with Osteoarthritis.

Tanezumab, a humanized anti-nerve growth factor antibody, was developed for the treatment of pain associated with osteoarthritis. Due to its mechanism of action, peripheral nerve safety was assessed in all clinical studies. To summarize the neurological safety of intravenous (IV) and subcutaneous (SC) tanezumab versus placebo in patients with osteoarthritis. Data were pooled from 3389 patients across seven studies that investigated IV administration, and from 1840 patients across three studies that investigated SC administration. The treatment period of each study ranged from 16 to 24weeks, and follow-up periods ranged from 8 to 24weeks. Neurological safety evaluations focused on adverse events (AEs) of abnormal peripheral sensation (APS), neurologic examinations, and consultations. Across datasets, the incidence of AEs of APS was higher in tanezumab groups versus placebo. Paresthesia and hypoesthesia were the most frequently reported AEs in tanezumab-treated patients, compared with placebo. In both datasets, most AEs were of mild severity, resolved, and rarely resulted in discontinuation. In all treatment groups in both IV and SC studies, over 90% of patients had no new or worsened neurological examination abnormalities at the last study visit. Across datasets, mononeuropathy was diagnosed more frequently in tanezumab groups compared with placebo. Polyneuropathy was diagnosed in ≤ 0.9% of patients in tanezumab and placebo groups. Tanezumab IV or SC had an increased incidence of AEs of APS, such as paresthesia and hypoesthesia, and diagnoses of mononeuropathy compared with placebo. However, tanezumab was not associated with generalized peripheral neuropathy. NCT00733902, NCT00744471, NCT00830063, NCT00863304, NCT00863772, NCT01089725, NCT00985621, NCT02697773, and NCT02709486.

Anti-NGF treatment worsens subchondral bone and cartilage measures while improving symptoms in floor-housed rabbits with osteoarthritis.

Objective: Osteoarthritis (OA) is a common joint disorder often affecting the knee. It is characterized by alterations of various joint tissues including subchondral bone and by chronic pain. Anti-nerve growth factor (NGF) antibodies have demonstrated improvement in pain associated with OA in phase 3 clinical trials but have not been approved due to an increased risk of developing rapidly progressive OA. The aim of this study was to investigate effects of systemic anti-NGF-treatment on structure and symptoms in rabbits with surgically induced joint instability. Methods: This was elicited by anterior cruciate ligament transection and partial resection of the medial meniscus in right knee of 63 female rabbits, housed altogether in a 56m2 floor husbandry. Rabbits received either 0.1, 1 or 3mg/kg anti-NGF antibody intra-venously at weeks 1, 5 and 14 after surgery or vehicle. During in-life phase, static incapacitance tests were performed and joint diameter was measured. Following necropsy, gross morphological scoring and micro-computed tomography analysis of subchondral bone and cartilage were performed. Results: After surgery, rabbits unloaded operated joints, which was improved with 0.3 and 3mg/kg anti-NGF compared to vehicle injection during the first half of the study. The diameter of operated knee joints increased over contralateral measures. This increase was bigger in anti-NGF treated rabbits beginning 2weeks after the first IV injection and became dose-dependent and more pronounced with time. In the 3mg/kg anti-NGF group, the bone volume fraction and trabecular thickness increased in the medio-femoral region of operated joints compared to contralateral and to vehicle-treated animals, while cartilage volume and to a lesser extent thickness decreased. Enlarged bony areas were found in right medio-femoral cartilage surfaces of animals receiving 1 and 3mg/kg anti-NGF. Alterations of all structural parameters were particularly distinct in a subgroup of three rabbits, which also exhibited more prominent symptomatic improvement. Conclusion: This study showed that anti-NGF administration exerted negative impact on structure in destabilized joints of rabbits, while pain-induced unloading of joints was improved. Our findings open up the possibility to better understand the effects of systemic anti-NGF, particularly on subchondral bone, and thus the occurrence of rapidly progressive OA in patients.

Barriers to participation in a prospective clinical trial for schwannomatosis-related pain (P7-13.003)

Barriers to participation in a prospective clinical trial for schwannomatosis-related pain (P7-13.003)

Management of pain in patients with bone metastases.

Cancer-induced bone pain (CIBP) has a considerable impact on patients' quality of life as well as physical and mental health. At present, patients with CIBP are managed according to the three-step analgesic therapy algorithm proposed by the World Health Organization. Opioids are commonly used as the first-line treatment for moderate-to-severe cancer pain but are limited due to addiction, nausea, vomiting and other gastrointestinal side effects. Moreover, opioids have a limited analgesic effect in some patients. In order to optimize the management of CIBP, we must first identify the underlying mechanisms. In some patients, surgery, or surgery combined with radiotherapy or radiofrequency ablation is the first step in the management of CIBP. Various clinical studies have shown that anti-nerve growth factor (NGF) antibodies, bisphosphonates, or RANKL inhibitors can reduce the incidence and improve the management of cancer pain. Herein, we review the mechanisms of cancer pain and potential therapeutic strategies to provide insights for optimizing the management of CIBP.

Efficacy and Safety of Anti-Nerve Growth Factor Antibody Therapy for Hip and Knee Osteoarthritis: A Meta-analysis.

Background:The efficacy and safety of anti–nerve growth factor (NGF) antibody therapy used for osteoarthritis (OA) pain are controversial.Purpose:To evaluate the efficacy and safety of anti-NGF antibody therapy via a meta-analysis of randomized controlled trials (RCTs).Study Design:Systematic review; Level of evidence, 1.Methods:PubMed, the Cochrane Central Register of Controlled Trials, Embase, and the Web of Science databases were searched for RCTs assessing anti-NGF antibody treatments for hip and knee OA. A total of 623 records were retrieved from the databases. A random-effects model was used to assess primary and secondary outcomes. Bias was assessed using the Cochrane Collaboration tool, funnel plots, and the Egger test. Subgroup analyses were used to assess the efficacy and safety of the independent variables. Sensitivity analysis was conducted to evaluate the effectiveness of tanezumab and the effectiveness of anti-NGF antibodies compared to active comparator drugs. We present the effects of dose, administration mode, and treatment duration on the efficacy and safety of anti-NGF antibody therapy.Results:There were 19 RCTs included in our meta-analysis. Anti-NGF antibody treatment showed significant improvements on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for pain, physical function, and stiffness as well as on a patient global assessment (PGA). The overall standardized mean differences were as follows: WOMAC pain (–0.31 [95% CI, –0.36 to –0.26]; Z = 11.75; P < .001; I 2 = 38%), WOMAC physical function (−0.36 [95% CI, –0.41 to –0.30]; Z = 12.67; P < .001; I 2 = 44%), WOMAC stiffness (–3.59 [95% CI, –4.87 to –2.30]; Z = 5.47; P < .001; I 2 = 98%), and PGA (−0.28 [95% CI, –0.34 to –0.22]; Z = 9.39; P < .001; I 2 = 50%). Anti-NGF antibody treatment resulted in a greater incidence of adverse events (risk ratio, 1.09 [95% CI, 1.06 to 1.12]; Z = 5.60; P < .001; I 2 = 0%). The incidence of serious adverse events was similar between the treatment and control groups (risk ratio, 1.15 [95% CI, 0.98 to 1.34]; Z = 1.71; P = .09; I 2 = 0%).Conclusion:Anti-NGF antibody treatment significantly relieved pain and improved function in patients with hip and knee OA. However, no conclusion could be drawn regarding the optimal treatment plan for anti-NGF antibodies when all 3 variables (dose, administration mode, and treatment duration) were combined in the analyses.

Efficacy and Safety of an Anti-nerve Growth Factor Antibody (Frunevetmab) for the Treatment of Degenerative Joint Disease-Associated Chronic Pain in Cats: A Multisite Pilot Field Study.

Background: Pain management for cats with degenerative joint disease (DJD) remains a critical unmet need. Recent work has shown promise for a feline-specific anti-nerve growth factor monoclonal antibody (frunevetmab) to deliver safe and effective pain management. Our objectives were to evaluate the efficacy and safety of frunevetmab administered twice using two administration routes (subcutaneous and intravenous) compared to placebo.Methods: This was a randomized placebo-controlled, double-masked study. After a week-long pain and activity baseline, 126 cats were randomized to receive injections of frunevetmab (IV then SC; n = 42 or SC then SC; n = 43) or placebo (IV then SC; n = 41) on Days 0 and 28. Owners completed questionnaires on Days 14, 28, 42, and 56. Accelerometry data were collected continuously throughout.Results: Owner questionnaire results showed significant improvement in frunevetmab-treated cats [compared to placebo; (p < 0.05)] at Days 42 and 56; no difference was found between routes of administration for frunevetmab. All groups had decreased objectively measured weekly activity from baseline; frunevetmab-treated cats had a mean decrease of 0.9%, while placebo-treated cats had a mean decrease of 9.3%. Treatments were generally well-tolerated. The majority of adverse events included dermatitis/alopecia related to activity-monitor collars; these occurred in a higher percentage of frunevetmab, compared to placebo, treated cats.Conclusions and Clinical Relevance: Treatment with frunevetmab provided improvements in owner ratings of mobility over treatment with placebo; these results were supported by objectively measured accelerometry. Frunevetmab has the potential to address a critical gap in the treatment of chronic pain in cats.

Comparative safety review of current treatment options for chronic low back pain and unmet needs: a narrative review

ABSTRACT Introduction: The healthcare expenditures in the United States are substantial for the management of refractory, chronic low back pain (CLBP). The objective of this review is to summarize and evaluate the safety profiles of different pharmacological treatment options used in the management of CLBP. Areas covered: The authors conducted a search of randomized controlled trials (RCTs) assessing the safety profiles of different pharmacological agents used in the management of CLBP. This narrative review covered corticosteroids, opioids, antidepressants, gabapentinoids, nonsteroidal anti-inflammatory drugs, muscle relaxants, anti-nerve growth factor antibodies and topical agents, as monotherapy or in combination. Expert opinion: The risk-benefit ratio of a particular treatment is a subject driving the ongoing development of pharmaceuticals. The most commonly reported AEs across all drug classes are of gastrointestinal nature, followed by neurological and skin-related. These AEs include nausea, dizziness, constipation, arthralgia, headache, dry mouth, pruritus, etc. The majority of the AEs reported are not life-threatening, although they may lower patients’ quality of life, thus, affecting their compliance. One of the biggest limitations of our review stems from the paucity of safety assessments in published RCTs. Advances in our understanding of the neurobiology of pain will promote development of new therapeutic strategies.

P108 Anti-nerve growth factor (anti-NGF) antibodies as analgesia in the management of osteoarthritis

Abstract Background/Aims Osteoarthritis is a major cause of morbidity and disability. Much of this comes from joint pain, which is exacerbated by movement and exercise. Pharmacological analgesia therefore not only has the obvious benefit of alleviating pain, but in doing so, it also facilitates exercise (a pillar of conservative management). Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are currently the main analgesics used in this context. However, these agents can cause unwanted side effects and are contraindicated in some patients. We thus conducted a systematic review and meta-analysis using the Cochrane collaboration criteria to evaluate the efficacy of anti-nerve growth factor (anti-NGF) antibodies as potential alternative analgesics in osteoarthritis of the hip and/or knee. Whilst tanezumab has been studied extensively and monoclonal anti-NGF antibodies have been reviewed in other pain states, this is the first systematic review of three key anti-NGF antibodies: tanezumab, fulranumab and fasinumab in symptomatic hip and/or knee osteoarthritis. Methods An interdisciplinary work group conducted a literature search across seven electronic databases for the use of anti-NGF antibodies in osteoarthritis. All hip/knee osteoarthritis studies investigating anti-NGF antibodies regardless of dose regimen or phase of trial were included. Studies in which participants received NSAIDs or analgesics other than anti-NGF antibodies, or studies in which the only intervention was the administration of anti-NGF antibodies in combination with NSAIDs or other analgesics were excluded. The Jadad Scale score was used to assess the quality of each study. Results Thirteen studies involving 8,145 patients with a diagnosis of hip and/or knee osteoarthritis were analysed. Demographic information including duration of disease and Kellgren-Lawrence grades were also extracted. Anti-NGF antibodies showed significant improvements compared to placebo as rated on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scales for pain (SMD= -0.50, 95% CI -0.71 to -0.28, P &amp;lt; 0.00001; I2 = 88%), physical function (SMD= -0.82, 95% CI -1.09 to -0.55, P &amp;lt; 0.00001; I2 = 94%) and stiffness (SMD= -0.88, 95% CI -1.22 to -0.54, P &amp;lt; 0.00001; I2 = 95%). These agents were not associated with a significant increase in serious adverse events but were associated with a significant increase in discontinuation due to adverse events, abnormal peripheral sensations and peripheral neuropathy. Conclusion Anti-NGF antibodies appear very promising with regard to alleviating osteoarthritic hip/knee pain but more studies are needed to determine the optimal dosage and the overall risk-to benefit ratio, particularly with long-term use. Disclosure J. Rammanohar: None. J. Sutton: None. K. Seah: None. W.S. Khan: None. K. To: None.

Receptor and Molecular Targets for the Development of Novel Opioid and Non-Opioid Analgesic Therapies

Although conventional pain relief therapeutics have centered around mu-opioid agonists, these drugs are limited by adverse side effects, including respiratory depression and addiction potential. The ongoing opioid epidemic has galvanized research into novel analgesic therapies with more favorable profiles. New pharmacologic agents have been developed to target neuronal pathways involved in pain sensation. Certain receptors have been recognized to mediate nociceptive transmission, central sensitization, and the development of chronic pain states. We conducted a literature review to identify potential targets for novel analgesic therapies. This study is a narrative review of potential analgesic targets. We characterize their antinociceptive mechanisms of action and evaluate their therapeutic potential. A systemized search of available literature on novel analgesics was performed. A search was performed through the PubMed database to identify articles with key words of "novel analgesics," "novel non-opioid analgesics," "novel pain targets," and "non-opioid analgesics." Potential drug classes were identified and researched through corresponding keywords, with an emphasis on publications from 2018 to 2020. Older articles were included if frequently referenced by current literature. Potential novel analgesic targets include Nav1.7, Nav1.8, CaV2.2, and transient receptor potential vanilloid-1 (TRPV1) cation channel receptors in the peripheral nervous system. Other approaches disrupt the synthesis of pronociceptive signaling molecules such as nitric oxide, prostaglandin E2, and interleukin-6 (IL-6). Within central pain pathways, modification of kappa-opioid, delta-opioid, N-methyl-D-aspartate, and cannabinoid receptors have been investigated in chronic pain and hyperalgesia models. Recent advances in molecular technology have also presented opportunities to modify protein expression or the cellular genome altogether. Several analgesic targets have only demonstrated efficacy in preclinical trials. There are limited data evaluating the long-term safety profiles of therapies further on in development. We provide an overview of potential analgesic therapies in various stages of development, which may become clinically relevant in the near future. Some drugs such as TRPV1 agonists, anti-IL-6, and anti-nerve growth factor antibodies have demonstrated analgesic effect in specific clinical pain states.

Nebulized Inhalation of Anti-Nerve Growth Factor Microspheres Inhibits Airway Remodeling in an Ovalbumin-Induced Rat Asthma Model.

Airway remodeling is considered an important factor in refractory and uncontrollable asthma. Previous studies have confirmed that anti-nerve growth factor (NGF) antibody can ameliorate airway remodeling. However, whether nebulized inhalation of anti-NGF microspheres (NANM) can inhibit airway remodeling is not clear. The purpose of this study was to investigate the effects of NANM on ovalbumin (OVA)-induced airway remodeling, and the mechanisms involved. Anti-NGF microspheres were produced using a polymer alloy method. OVA was used to establish a rat model of asthma airway remodeling. Rats were treated with inhalation atomized anti-NGF antibody or NANM. Airway inflammation, airway reactivity, and airway remodeling were measured. Lung tissue P-Smad3 and tumor growth factor (TGF)-β1 mRNA and protein expression were also measured. The anti-NGF antibody microsphere encapsulation rate was high, and the release time was long. NANM markedly attenuated OVA-induced airway remodeling, such as collagen deposition, average pulmonary resistance, the WAm/Pbm, WAt/Pbm, and Wcol/Pbm ratios (WAt, bronchial wall area; Pbm, perimeter of basement membrane; WAm, smooth muscle wall area; Wcol, airway collagen fiber area). Compared with the anti-NGF antibody group and the OVA group, the expression of TGF-β1 mRNA, TGF-β1 protein, and P-Smad3 in the NANM group were markedly decreased. NANM ameliorated OVA-induced airway remodeling, partly through regulation of the TGF-β1/Smad3 pathway.

Contribution of synovial macrophages to rat advanced osteoarthritis pain resistant to cyclooxygenase inhibitors.

Most advanced knee osteoarthritis (OA) patients experience chronic pain resistant to cyclooxygenase (COX) inhibitors. However, the cells and molecules involved in this advanced OA pain remain poorly understood. In this study, we developed a rat model of advanced knee OA by modification of the monoiodoacetate-induced OA pain model and examined involvement of synovial macrophages in advanced OA pain. Cyclooxygenase inhibitors, such as celecoxib and naproxen, and a steroid were ineffective, but an opioid and anti-nerve growth factor (NGF) antibody was effective for pain management in the advanced OA model. Similar to advanced OA patients, histological analysis indicated severe bone marrow damages, synovitis, and cartilage damage and an increase of macrophages with high expression of interleukin-1β, NGF, nitric oxide synthase (NOS) 1, NOS2, and COX-2 in the knee joint of the advanced OA model. Intravenous injection of clodronate liposomes depleted synovial macrophages, which decreased the level of not only proinflammatory mediator interleukin-1β but also NGF in the knee joint, leading to pain suppression in the advanced OA model. These data suggest the involvement of synovial macrophages in advanced knee OA pain resistant to COX inhibitors by increasing proinflammatory mediators, and that drugs targeting synovial macrophages might have potent analgesic effects.

Effects of Monoclonal Antibodies against Nerve Growth Factor on Healthy Bone and Joint Tissues in Mice, Rats, and Monkeys: Histopathologic, Biomarker, and Microcomputed Tomographic Assessments.

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article-related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.

Trace element levels are associated with neuroinflammatory markers in children with autistic spectrum disorder

The objective of the present study was to estimate the association between brain inflammatory markers and serum trace element levels as assessed by inductively coupled plasma mass spectrometry at NexION 300D. Leukocyte elastase (LE), α1-proteinase inhibitor (α1-PI) activity, anti-nerve growth factor-antibodies (anti-NGF-Ab), and anti-myelin basic protein-antibodies (anti-MBP-Ab) levels were assessed as inflammatory markers. The obtained data demonstrate that the increase in LE and α1-PI activity is associated with higher serum Cr and Cu levels, respectively. The increase in Anti-NGF-Ab levels was associated with a nearly significant 16% increase in serum Mn levels. Autistic children with high MBP-Ab levels were characterized by 28% higher serum Mn and lower Mg concentration. The results of correlation analysis were generally in agreement with the outcome of group comparisons. Regression analysis demonstrated that serum Mg was significantly negatively associated with LE activity, whereas both serum Fe and V concentrations were characterized by a positive influence on the parameter. In turn, serum Cu was a significant predictor of α1-PI, as well as Cr levels. At the same time, the serum concentrations of Cd and Fe were found to be inversely associated with α1-PI levels. Serum Cd and Mn levels were significant positive predictors of anti-MBP-Ab levels, whereas Mg levels had a negative impact on anti-MBP-Ab values. Generally, the obtained data demonstrate the interrelationship between trace element homeostasis and neuroinflammation in autism. Hypothetically, modulation of trace element status may be used for reduction of neuroinflammatory response, although further studies are required to reveal the underlying mechanisms of the observed associations.

Anti-nerve growth factor antibody improves airway hyperresponsiveness by down-regulating RhoA

ABSTRACTBackground: The pathogenesis of asthma is complex and continues to be considered as a challenging subject. Some studies have shown that nerve growth factor (NGF) participates in the pathogenesis of asthma, but the mechanism of airway contraction caused by NGF is still unclear. Objective: Our aim was to discuss the effect of anti-NGF antibody on RhoA expression, and further explore the role of NGF in airway hyperresponsiveness (AHR). Methods: Thirty female BALB/c mice were divided into three groups randomly: control group (group C, n = 10), asthma group (group A, n = 10) and anti-NGF antibody intervention group (group N, n = 10). The asthmatic mice were stimulated by OVA suspension, the intervention mice were given nasal instillation of anti-NGF antibody before the stimulation. Airway responsiveness, eosinophils, IL-13, IFN-γ were measured. The protein expression and mRNA level of NGF and RhoA were detected by immunohistochemical and Real Time-PCR (RT-PCR) analyses. Results: Airway responsiveness, eosinophils and IL-13 levels in group A were significantly increased compare with the other groups, and significantly decreased in group N than those in group A. IFN-γ level was significantly reduced in group A and increased in group N. Immunohistochemistry and RT-PCR analyses showed that the protein expression and mRNA level of NGF and RhoA were significantly increased in group A and significantly decreased in group N. Conclusion: NGF participates in the pathogenesis of asthma in mice. Anti-NGF antibody can inhibit airway inflammation and alleviate AHR by down-regulating the protein expression and mRNA level of RhoA.

What is new in pain modification in osteoarthritis?

There is a big need for the development of novel therapies for the safe management of chronic pain associated with OA. Here we reviewed PubMed (2015 onward) and ClinicalTrials.gov for ongoing and recently completed trials where pain in OA is the primary outcome measure. Three broad categories were identified: biological therapies, small molecules and cryoneurolysis. The most promising new strategy is blockade of nerve growth factor with antibodies. Two anti-nerve growth factor antibodies, tanuzemab and fasinumab, are in active development after the 2010 hold on trials was lifted in 2015. In addition, several active clinical trials are testing distinct mechanism-based interventions, including cytokine inhibition, selective μ, δ or κ opioid receptor agonists, zoledronate and intra-articular capsaicin. In addition to pharmacological approaches, cryoneurolytic strategies that directly target peripheral nerves may play a role in OA pain management, but efficacy profiles and long-term effects of such treatments need more study. Clearly, the therapeutic landscape for OA pain is rapidly expanding. Since symptomatic OA is a heterogeneous disease, the challenge will be to identify patients that will benefit the most from specific approaches.

Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models?

Anti-nerve growth factor (NGF) antibodies hold tremendous potential for the management of osteoarthritis pain, but clinical trials have revealed serious adverse effects that are incompletely understood. This review discusses clinical trial results along with preclinical studies that have assessed NGF blockade in experimental osteoarthritis, in order to provide insight for future studies. Systematic reviews have revealed that anti-NGF therapy, including tanezumab, is efficacious in improving pain and function, but serious adverse events, including rapidly progressive osteoarthritis and osteonecrosis, resulted in a moratorium on trials that was only recently lifted. Within the past year, preclinical testing has revealed effects of NGF blockade on both pain behaviors and joint structure in experimental models of osteoarthritis. Similar to clinical trial results, these studies in laboratory animals demonstrated analgesic efficacy of NGF blockade. Interestingly, several animal studies have suggested detrimental effects on joint integrity as a result of treatment, particularly when treatment is started early in the disease, when joint damage is mild to moderate. NGF blockade continues to represent a promising new approach for the treatment of osteoarthritis pain, but the actual benefits and risks remain to be fully elucidated. Preclinical models may suggest patient populations that could be best served while limiting side-effects, but future work should further investigate the mechanisms of benefits and unwanted side-effects.

Evaluation of Clinical Metrology Instrument in Dogs with Osteoarthritis.

BackgroundIn veterinary clinical pain studies, there is a paucity of data on test‐retest variability in Clinical Metrology Instruments (CMIs), and it is unknown whether CMIs should be administered using independent (respondents not permitted to see previous answers) or dependent (respondents shown previous answers) interviewing.ObjectivesTo compare baseline variability in CMIs designed to assess pain in dogs with osteoarthritis, and compare CMI scores using independent (InD) and dependent interviewing (DI) for the Canine Brief Pain Inventory (CBPI) and the Client‐Specific Outcome Measures (CSOM).AnimalsFifty‐one client‐owned dogs with radiographic evidence of osteoarthritis and associated pain.MethodsClinical Metrology Instruments data were collected during 2 randomized, double‐masked, placebo‐controlled, proof of principle pilot studies with parallel treatment groups. Enrolled dogs received either placebo or antinerve growth factor antibody (NV‐01).ResultsAgreement between baseline CMI scores was good (CBPI Pain P = .29, CBPI Interference P = .32, CSOM P = .036, LOAD P = .67, HCPI P = .27), being best for the LOAD (ICC = 0.89). CMI responses collected during independent and dependent interviewing were not statistically different (CBPI Pain P = .33, CBPI Interference P = .28, CSOM P = .42) and showed good agreement. Additionally, dependent interviewing resulted in increased treatment effect sizes.Conclusions and Clinical ImportanceThere is little difference between independent and dependent interviewing, however, dependent interviewing resulted in increased treatment effect sizes. By using dependent interviewing, investigators could increase clinical trial power through minimal change to study design. Further research is warranted to investigate the use of dependent interviewing.