Increased expression of nerve growth factor in injured or inflamed tissue is associated with increased pain. This proof-of-concept study was designed to investigate the safety and analgesic efficacy ...of tanezumab, a humanized monoclonal antibody that binds and inhibits nerve growth factor.
We randomly assigned 450 patients with osteoarthritis of the knee to receive tanezumab (administered at a dose of 10, 25, 50, 100, or 200 μg per kilogram of body weight) or placebo on days 1 and 56. The primary efficacy measures were knee pain while walking and the patient's global assessment of response to therapy. We also assessed pain, stiffness, and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); the rate of response using the criteria of the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI); and safety.
When averaged over weeks 1 through 16, the mean reductions from baseline in knee pain while walking ranged from 45 to 62% with various doses of tanezumab, as compared with 22% with placebo (P<0.001). Tanezumab, as compared with placebo, was also associated with significantly greater improvements in the response to therapy as assessed with the use of the patients' global assessment measure (mean increases in score of 29 to 47% with various doses of tanezumab, as compared with 19% with placebo; P≤0.001). The rate of response according to the OMERACT-OARSI criteria ranged from 74 to 93% with tanezumab treatment, as compared with 44% with placebo (P<0.001). The rates of adverse events were 68% and 55% in the tanezumab and placebo groups, respectively. The most common adverse events among tanezumab-treated patients were headache (9% of the patients), upper respiratory tract infection (7%), and paresthesia (7%).
In this proof-of-concept study, treatment with tanezumab was associated with a reduction in joint pain and improvement in function, with mild and moderate adverse events, among patients with moderate-to-severe osteoarthritis of the knee. (Funded by Rinat Neuroscience; ClinicalTrials.gov number, NCT00394563.).
Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized ...anti-nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 μg/kg plus oral placebo (n=88), intravenous placebo plus oral naproxen 500 mg twice a day (n=88), or intravenous placebo plus oral placebo (n=41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland-Morris Disability Questionnaire and Brief Pain Inventory-short form scores, Patients' Global Assessment of LBP, Patients' Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P=0.004) and placebo (P<0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P≤0.013) and placebo (P<0.001), and greater improvements in Roland-Morris Disability Questionnaire (P<0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab-treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.
MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition ...occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEβ mutations.
► Treatment-emergent mutations in NAEβ confer resistance to MLN4924 ► Amino acid substitution A171T in the adenylate binding site is the most frequent mutation ► NAEβ mutants reduce inhibitor potency and decrease affinity of NEDD8-MLN4924 adduct ► A tight-binding pan-E1 inhibitor overcomes resistance in NAEβ mutant cells
Abstract
Objective
To evaluate the analgesic efficacy and safety of ASP8477 in patients with peripheral neuropathic pain (PNP).
Design
Enriched enrollment randomized withdrawal.
Setting
Centers in ...Poland (four), Czech Republic (six), and the United Kingdom (two).
Subjects
Patients aged 18 years or older with PNP resulting from painful diabetic peripheral neuropathy or postherpetic neuralgia.
Methods
A four-week screening period followed by a single-blind period (six-day dose titration and three-week maintenance period with ASP8477 20/30 mg BID). Treatment responders (defined as a ≥30% decrease in the mean average daily pain intensity during the last three days of the single-blind period) were stratified by disease and randomized to receive placebo or continue ASP8477 during a three-week, double-blind, randomized withdrawal period. The primary end point was change in mean 24-hour average numeric pain rating scale (NPRS) from baseline to end of double-blind period.
Results
Among 132 patients who enrolled, 116 entered the single-blind period and 63 (ASP8477, N = 31; placebo, N = 32) completed the double-blind period. There was no difference in mean 24-hour average NPRS score (P = 0.644) or in time-to-treatment failure (P = 0.485) between ASP8477 and placebo. During the single-blind period, 57.8% of patients were treatment responders. ASP8477 was well tolerated. During the single-blind period, 22% of patients experienced at least one treatment-related adverse event (TEAE); during the double-blind period, 8% in the ASP8477 arm and 18% in the placebo arm experienced at least one TEAE.
Conclusions
ASP8477 was well tolerated in patients with PNP; however, ASP8477 did not demonstrate a significant treatment difference compared with placebo.
Moraxella bovoculi is a recently described bacterium that is associated with infectious bovine keratoconjunctivitis (IBK) or "pinkeye" in cattle. In this study, closed circularized genomes were ...generated for seven M. bovoculi isolates: three that originated from the eyes of clinical IBK bovine cases and four from the deep nasopharynx of asymptomatic cattle. Isolates that originated from the eyes of IBK cases profoundly differed from those that originated from the nasopharynx of asymptomatic cattle in genome structure, gene content and polymorphism diversity and consequently placed into two distinct phylogenetic groups. These results suggest that there are genetically distinct strains of M. bovoculi that may not associate with IBK.
The successful re‐introduction of grey wolves to the western United States is an impressive accomplishment for conservation science. However, the degree to which subpopulations are genetically ...structured and connected, along with the preservation of genetic variation, is an important concern for the continued viability of the metapopulation. We analysed DNA samples from 555 Northern Rocky Mountain wolves from the three recovery areas (Greater Yellowstone Area, Montana, and Idaho), including all 66 re‐introduced founders, for variation in 26 microsatellite loci over the initial 10‐year recovery period (1995–2004). The population maintained high levels of variation (HO = 0.64–0.72; allelic diversity k = 7.0–10.3) with low levels of inbreeding (FIS < 0.03) and throughout this period, the population expanded rapidly (n1995 = 101; n2004 = 846). Individual‐based Bayesian analyses revealed significant population genetic structure and identified three subpopulations coinciding with designated recovery areas. Population assignment and migrant detection were difficult because of the presence of related founders among different recovery areas and required a novel approach to determine genetically effective migration and admixture. However, by combining assignment tests, private alleles, sibship reconstruction, and field observations, we detected genetically effective dispersal among the three recovery areas. Successful conservation of Northern Rocky Mountain wolves will rely on management decisions that promote natural dispersal dynamics and minimize anthropogenic factors that reduce genetic connectivity.
Synapses are fundamental components of brain circuits and are disrupted in over 100 neurological and psychiatric diseases. The synapse proteome is physically organized into multiprotein complexes and ...polygenic mutations converge on postsynaptic complexes in schizophrenia, autism and intellectual disability. Directly characterising human synapses and their multiprotein complexes from post-mortem tissue is essential to understanding disease mechanisms. However, multiprotein complexes have not been directly isolated from human synapses and the feasibility of their isolation from post-mortem tissue is unknown.
Here we establish a screening assay and criteria to identify post-mortem brain samples containing well-preserved synapse proteomes, revealing that neocortex samples are best preserved. We also develop a rapid method for the isolation of synapse proteomes from human brain, allowing large numbers of post-mortem samples to be processed in a short time frame. We perform the first purification and proteomic mass spectrometry analysis of MAGUK Associated Signalling Complexes (MASC) from neurosurgical and post-mortem tissue and find genetic evidence for their involvement in over seventy human brain diseases.
We have demonstrated that synaptic proteome integrity can be rapidly assessed from human post-mortem brain samples prior to its analysis with sophisticated proteomic methods. We have also shown that proteomics of synapse multiprotein complexes from well preserved post-mortem tissue is possible, obtaining structures highly similar to those isolated from biopsy tissue. Finally we have shown that MASC from human synapses are involved with over seventy brain disorders. These findings should have wide application in understanding the synaptic basis of psychiatric and other mental disorders.
Abstract Objective To test the accuracy of a multi-sensor activity monitor (SWM) in detecting slow walking speeds in patients with chronic obstructive pulmonary disease (COPD). Background Concerns ...have been expressed regarding the use of pedometers in patient populations. Although activity monitors are more sophisticated devices, their accuracy at detecting slow walking speeds common in patients with COPD has yet to be proven. Methods A prospective observational study design was employed. An incremental shuttle walk test (ISWT) was completed by 57 patients with COPD wearing an SWM. The ISWT was repeated by 20 patients wearing the same SWM. Results Differences were identified between metabolic equivalents (METS) and between step-count across five levels of the ISWT ( p < 0.001). Good within monitor reproducibility between two ISWT was identified for total energy expenditure and step-count ( p < 0.001). Conclusions The SWM is able to detect slow (standardized) speeds of walking and is an acceptable method for measuring physical activity in individuals disabled by COPD.
To better elucidate the ecological effects of naphthenic acids and major ions liberated in oil sands development, the summer-time composition of phytoplankton communities in ten water bodies near ...Fort McMurray (northeastern Alberta) was studied in 1997. The water bodies varied in degree of process water influence, and in age, size and ancillary chemical characteristics. Community biomass of phytoplankton was not systematically related to naphthenic acid or major ion concentrations, even though the higher naphthenate concentrations exceeded published EC50's for acute effects on several different aquatic species. Chlorophyta were frequently dominant, particularly where naphthenate and major ion concentrations were highest. Canonical Correspondence Analysis (CCA) revealed gradients in taxonomic composition at a finer (genus and species) taxonomic level. Despite the simultaneous and uncontrolled variation of other environmental factors, naphthenate and major ion concentrations (as indexed by conductivity) explained a highly-significant 40% of the variation in taxonomic composition. Systems with naphthenates <6.5 mg l
−1 and conductivity <800 ΦS cm
−1 were clustered together near the origin of the CCA plots, suggesting little ecological effect at such concentrations. Taxa associated with elevated naphthenate and/or major ion concentrations were derived from six different algal divisions and included many that were identified as tolerant in previous bioassay experiments. Over the range of concentrations encountered (1.5–45 and 100–3000 mg l
−1 for naphthenates and ions, respectively), CCA indicated that the ecological effect of major ions appeared to be at least as great as that of naphthenates.
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