Obesity dysregulates the pulmonary antiviral immune response.

Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.

Improving the Prevention, Detection, and Management of Delirium in Adult Inpatients; an Interprofessional Consultative Team Pilot Project.

Delirium is a common, often preventable fluctuating state of cognition associated with increased morbidity and mortality. This report describes the implementation of an interprofessional consultative Delirium Team formed to improve the prevention, detection, and management of delirium in a community hospital. Team members consulted refered inpatients with delirium to establish a care plan and provide recommendations for pharmacological and non-pharmacological management. The team also offered delirium-related education to unit staff, patients, and caregivers. Consultations were initially completed by the team Nurse Practitioner or Occupational Therapist, and complex patients were discussed with the team Geriatrician and Psychiatrist at rounds to optimize specialist input. Of the 160 patients managed by the team over the 8-month study period, two-thirds of referred patients did not require specialist consultation for their delirium management. Strategies most often recommended by experts for managing delirium were related to medical management, social/cognitive engagement, and functional mobility. Two-thirds of all recommendations made by the team were implemented. Barriers and facilitators to implementation and improving unit staff adherence are further described. The consultative Delirium Team is a promising model that should be further explored for managing an aging population in a capacity-limited medical system.

Cost-effectiveness and efficacy of fluoride varnish for caries prevention in South African children: A cluster-randomized controlled community trial.

OBJECTIVES: This cluster-randomized controlled community trial aimed to assess the efficacy and costs of fluoride varnish (FV) application for caries prevention in a high-risk population in South Africa. METHODS: 513 children aged 4-8 years from two schools in a township in South Africa were randomly allocated by class to the FV or Control (CO) groups. In addition to supervised toothbrushing with fluoridated toothpaste in both groups, FV was applied in 3-month intervals by trained local non-professional assistants. Intraoral examinations were conducted at baseline, 12, 21 and 24 months. Primary outcome was the increment of teeth with cavitated lesions (i.e. newly developed or progressed, formerly non-cavitated lesions), requiring restoration or extraction over the study period. Additionally, treatment and re-treatment costs were analyzed. RESULTS: 513 children (d1-4 mft 5.9 ± 4.3 (mean ± SD)) were randomly allocated to FV (n = 287) or CO (n = 226). 10.2% FV and CO teeth received or required a restoration; 3.9% FV and 4.1% CO teeth were extracted, without significant differences between groups. While FV generated high initial costs, follow-up costs were comparable in both groups, resulting in FV being significantly more expensive than CO (1667 ± 1055 ZAR vs. 950 ± 943 ZAR, p < .001). CONCLUSIONS: Regular FV application, in addition to daily supervised toothbrushing, had no significant caries-preventive effect and was not cost-effective in a primary school setting within a peri-urban, high-risk community in South Africa. Alternative interventions on community or public health level should be considered to reduce the caries burden in high-risk communities.

Control of measles in a juvenile custodial setting in the wake of the recent US outbreak.

The recent US measles outbreak is the largest since 1992. It is just a matter of time before measles is introduced into a juvenile custodial setting. Are we prepared? Should we be prepared? This short article addresses steps institutional settings should take to prevent the spread of measles in a contained setting.

Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients.

In order to improve targeted therapeutic approaches for asthma patients, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as obese asthmatics or severe asthmatics, are required. Here we report immunological and microbiome alterations in obese asthmatics (n = 50, mean age = 45), non-obese asthmatics (n = 53, mean age = 40), obese non-asthmatics (n = 51, mean age = 44) and their healthy counterparts (n = 48, mean age = 39). Obesity is associated with elevated proinflammatory signatures, which are enhanced in the presence of asthma. Similarly, obesity or asthma induced changes in the composition of the microbiota, while an additive effect is observed in obese asthma patients. Asthma disease severity is negatively correlated with fecal Akkermansia muciniphila levels. Administration of A. muciniphila to murine models significantly reduces airway hyper-reactivity and airway inflammation. Changes in immunological processes and microbiota composition are accentuated in obese asthma patients due to the additive effects of both disease states, while A. muciniphila may play a non-redundant role in patients with a severe asthma phenotype.

A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.

Background and Objectives: Codeine requires biotransformation by the CYP2D6 enzyme, encoded by the polymorphic CYP2D6 gene, to morphine for therapeutic efficacy. CYP2D6 phenotypes of poor, intermediate, and ultra-rapid metabolisers are at risk of codeine non-response and adverse drug reactions due to altered CYP2D6 function. The aim of this study was to determine whether genotype, inferred phenotype, and urinary and oral fluid codeine O-demethylation metabolites could predict codeine non-response following a short course of codeine. Materials and Methods: There were 131 Caucasians with persistent pain enrolled. Baseline assessments were recorded, prohibited medications ceased, and DNA sampling completed before commencing codeine 30 mg QDS for 5 days. Day 4 urine samples were collected 1-2 h post morning dose for codeine O-demethylation metabolites analysis. Final pain assessments were conducted on day 5. Results: None of the poor, intermediate, ultra-rapid metabolisers and only 24.5% of normal metabolisers responded to codeine. A simple scoring system to predict analgesic response from day 4 urinary metabolites was devised with overall prediction success of 79% (sensitivity 0.8, specificity 0.78) for morphine and 79% (sensitivity 0.76, specificity 0.83) for morphine:creatinine ratio. Conclusions: In conclusion, this study provides tentative evidence that day 4 urinary codeine O-demethylation metabolites could predict non-response following a short course of codeine and could be utilised in the clinical assessment of codeine response at the point of care to improve analgesic efficacy and safety in codeine therapy. We offer a scoring system to predict codeine response from urinary morphine and urinary morphine:creatinine ratio collected on the morning of day 4 of codeine 30 mg QDS, but this requires validation before it could be considered for use to assess codeine response in clinical practice.

Analysis of HIV testing refusal among patients aged less than 21 years in the Pediatric Emergency Department.

HIV testing in the Pediatric Emergency Department (PED) is a novel concept as adolescents, and young adults, use the PED as point of care or first point of contact with the health care system. Our objective was to study the HIV nontesting data and factors that influenced testing decision among patients receiving care in our PED. We designed a survey that inquired about testing acceptance, reasons for rejection, satisfaction with testing conditions, and understanding of the consequence of HIV test results. We approached 500 patients across all shifts in the PED; for analysis, categorical variables were created using demographic data (race, age, ethnicity, marital status, level of education). Forward conditional binary logistic regression was used to explore the effect of various independent predictors on HIV testing rejection with the strength of association measured with adjusted odds ratio (OR), and their 95% CIs. We conducted model fitting by plotting residuals, Hosmer and Lemeshow test statistic, and area under the curve completed using predicted probabilities. We used SPSS Version 25™, Microsoft Excel 2016™ for data preparation and analysis. Of the 500 patients approached, 423 (84.6%) completed the survey, median (interquartile) age of survey participants was 19 (17-20) years, 158 (37.4%) rejected HIV testing, 284 (67.1%) were older than 18 years of age, 200 (47.3%) were males, 154 (36.4%) were white, and 127 (30%) were of Hispanic origin. The most common reason for rejecting HIV was low risk perception declared by 79 (50%) respondents. In multivariate analysis, age <18 years (OR, 3.5; 95% CI, 2.3-5.5, P<0.00) and being Hispanic (OR, 2.5; 95% CI, 1.6-3.8, P<0.00) were significant predictors for respondent nontesting. Hosmer and Lemeshow test was not significant, P=0.42, and area under the curve was 0.67 (95% CI, 0.61-0.76). Respondents, <18 years were more likely to reject HIV testing because of low perception of risk. Program addressing risk perception which emphasizes safe health practices should be developed to reduce HIV transmission.

The effects of repeated Toll-like receptors 2 and 4 stimulation in COPD alveolar macrophages.

Background: COPD is a progressive inflammatory airway disease characterized by increased numbers of alveolar macrophages in the lungs. Bacterial colonization of the lungs is a common feature in COPD and can promote inflammation through continual and repeated Toll-like receptor (TLR) stimulation. We have studied the response of COPD alveolar macrophages to repetitive stimulation with TLR2 and TLR4 ligands. We investigated the effect of sequential stimulation with different ligands to determine whether this results in tolerance or amplification of the immune response. Methods: We stimulated alveolar macrophages from COPD patients (n=9) and smokers (n=8) with the TLR4 agonist lipopolysaccharide (LPS) or the TLR2 agonist Pam3CSK4 for 24 hours before restimulating again for 24 hours. Cytokine protein release and gene expression were investigated. Results: Repetitive stimulation of COPD and smokers macrophages with LPS for both 24-hour periods caused a reduction in tumor necrosis factor α, CCL5, and IL-10 production compared to cells that were not exposed initially to LPS. IL-6 and CXCL8 production were not significantly altered following repetitive LPS stimulation. The same pattern was observed for repeated stimulation with Pam3CSK4. Using COPD macrophages, LPS followed by Pam3CSK4 stimulation increased the levels of all cytokines compared to media followed by Pam3CSK4. Conclusion: TLR tolerance in COPD alveolar macrophages occurs after repetitive stimulation with the same TLR ligand, but this only occurs for selected cytokines. CXCL8 production is not reduced after repetitive TLR stimulation with the same ligand; this may be an important mechanism for the increased CXCL8 levels that have been observed in COPD. We showed that TLR4 stimulation followed by TLR2 stimulation does not cause tolerance, but enhances cytokine production. This may be a relevant mechanism by which bacteria cause excessive inflammation in COPD patients.

Ampicillin resistance in Haemophilus influenzae from COPD patients in the UK.

BACKGROUND: Haemophilus influenzae is commonly isolated from the airways of COPD patients. Antibiotic treatment may cause the emergence of resistant H. influenzae strains, particularly ampicillin-resistant strains, including ß-lactamase-negative ampicillin resistance (BLNAR) strains. Genetic identification using ftsI sequencing is the optimum method for identifying mutations within BLNAR strains. The prevalence of BLNAR in COPD patients during the stable state has not been reported. We investigated the antibiotic resistance patterns of H. influenzae present in the sputum of stable COPD patients, focusing on ampicillin resistance; the prevalence of enzyme and non-enzyme-mediated ampicillin resistance was determined. A subset of patients was followed up longitudinally to study H. influenzae strain switching and antibiotic sensitivity changes. PATIENTS AND METHODS: Sputum sampling was performed in 61 COPD patients, with 42 samples obtained at baseline; H. influenzae was detected by polymerase chain reaction in 28 samples. In all, 45 patients completed the follow-up for 2 years; 24 H. influenzae isolates were obtained. RESULTS: Disk diffusion showed the highest antibiotic resistance in the penicillin antibiotic group (eg, 67% for ampicillin) and macrolides (eg, 46% for erythromycin), whereas all isolates were susceptible to quinolones. Of the 16 isolates resistant to ampicillin, 9 (56%) were ß-lactamase positive. The ß-lactamase-negative isolates were further investigated; none of these fulfilled the phenotypic BLNAR classification criteria of ampicillin minimum inhibitory concentration >1 µg/mL, and only one demonstrated an ftsI mutation. Frequent H. influenzae strain switching was confirmed using multilocus sequence typing and was associated with changes in the antibiotic sensitivity pattern. CONCLUSION: We observed an overidentification of ampicillin resistance by disk diffusion. The majority of ampicillin resistance was due to enzyme production. H. influenzae strain changes during the stable state may be associated with a change in antibiotic sensitivity; this has implications for empirical antibiotic prescribing.

Advancing methods for research on household water insecurity: Studying entitlements and capabilities, socio-cultural dynamics, and political processes, institutions and governance.

Household water insecurity has serious implications for the health, livelihoods and wellbeing of people around the world. Existing methods to assess the state of household water insecurity focus largely on water quality, quantity or adequacy, source or reliability, and affordability. These methods have significant advantages in terms of their simplicity and comparability, but are widely recognized to oversimplify and underestimate the global burden of household water insecurity. In contrast, a broader definition of household water insecurity should include entitlements and human capabilities, sociocultural dynamics, and political institutions and processes. This paper proposes a mix of qualitative and quantitative methods that can be widely adopted across cultural, geographic, and demographic contexts to assess hard-to-measure dimensions of household water insecurity. In doing so, it critically evaluates existing methods for assessing household water insecurity and suggests ways in which methodological innovations advance a broader definition of household water insecurity.

The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD.

INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. METHODS: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. RESULTS: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. CONCLUSION: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.

The role of CRAC channel in asthma.

Asthma is increasing globally and current treatments only manage a proportion of patients. There is an urgent need to develop new therapies. Lymphocytes are thought to play a central role in the pathophysiology of asthma through the production of inflammatory mediators. This is thought to be via the transcription factor NFAT which in turn can be activated through Ca(2+) release-activated Ca(2+) (CRAC) channels. The aim of this work was to investigate the role of CRAC in clinical and pre-clinical models of allergic asthma. Initial data demonstrated that the NFAT pathway is increased in stimulated lymphocytes from asthmatics. To confirm a role for the channel we showed that a selective inhibitor, Synta 66, blocked mediator production from lymphocytes. Synta 66 inhibited CD2/3/28 induced IL-2, IL-7, IL-13 & IFNΥ in a concentration-dependent manner in healthy and severe asthma donors, with over 60% inhibition observed for all cytokines. NFAT pathway was also increased in a pre-clinical asthma model. In this model we have demonstrated that CRAC played a central role in the airway inflammation and late asthmatic response (LAR). In conclusion, our data provides evidence that suggests targeting CRAC channels could be of therapeutic benefit for asthma sufferers.

New Formulation of Sustained Release Naloxone Can Reverse Opioid Induced Constipation Without Compromising the Desired Opioid Effects.

UNLABELLED: An international double-blind randomized placebo controlled study evaluated the safety and efficacy of four doses of a new sustained release naloxone capsule to treat Opioid Induced Constipation (OIC). METHODS: Forty patients taking opioids for noncancer related pain, and experiencing OIC, were randomized into 4 cohorts of 10 patients. A multiple ascending dose design was used to evaluate the safety and efficacy of 2.5 mg, 5 mg, 10 mg, and 20 mg naloxone sustained release (NSR) capsules vs placebo. Drug was given once-daily for 3 weeks followed by twice daily (bid) dosing between weeks 4 and 6. RESULTS: The incidence of treatment emergent adverse events was highest in the placebo group. The incidence of adverse events among the four active treatment groups were similar. There were no serious adverse events. The number of severe events was low overall but highest in the placebo group. Significant improvements were seen in Spontaneous Bowel Movements with 5 mg, 10 mg, and 20 mg NSR capsules. Mean change in SBMs from baseline of 2.21 (P = 0.052), 2.37 (P = 0.032); 4.11 (P = 0.0005); 5.19 (<0.0001) was noted with NSR 2.5 mg, 5 mg, 10 mg, and 20 mg, respectively, when taken once daily, compared with 1.38 (P = 0.2) for patients on placebo therapy. No changes in subjective or objective measures of opioid withdrawal as measured by the Subjective Opioid Withdrawal Scale or Clinical Opioid Withdrawal Scale were observed. There was no increase in patient reported pain as measured daily using a visual analogue scale. CONCLUSIONS: This Phase II study has shown that using a new sustained release formulation to deliver oral naloxone to the colon allows successful treatment of OIC without comprising the desired opioid effects.

The effects of corticosteroids on cytokine production from asthma lung lymphocytes.

BACKGROUND: Lymphocytes play a central role in the pathophysiology of asthma. Corticosteroids have a limited effect in severe asthma and we hypothesise that lymphocytes play a central role in corticosteroid insensitivity. We investigated the effects of corticosteroids on cytokine production from lung lymphocytes obtained from patients with moderate severe asthma (MSA) compared to mild asthma (MA) and healthy non-smokers (HNS). METHODS: Bronchoalveolar lavage (BAL) cells obtained by bronchoscopy from patients with MSA and MA (n = 11 and n = 14 respectively) and HNS (n = 7) were stimulated with CD2/3/28 beads to activate the lymphocytes, in the presence or absence of dexamethasone (0.01-1 µM). Supernatants were assayed for IL-2, IFNγ, IL-17, IL-13 and IL-10 production. RESULTS: Dexamethasone caused variable inhibition of cytokines; 1 µM inhibited IL-10 and IL-17 by 50% or lower, while inhibition > 50% was observed for IL-2, IL-13 and IFNγ. The effect of dexamethasone on IL-13 production was reduced in MSA. CONCLUSION: These findings suggest that the production of specific lymphocyte derived cytokines is poorly suppressed by corticosteroids in MSA, which may be responsible for persistent airway inflammation in these patients

Fixed ratio (2:1) prolonged-release oxycodone/naloxone combination improves bowel function in patients with moderate-to-severe pain and opioid-induced constipation refractory to at least two classes of laxatives.

OBJECTIVE: The effects of combined oxycodone/naloxone prolonged release tablets (OXN PR) were investigated in patients with moderate-to-severe chronic cancer-related or non-cancer pain. All patients had opioid-induced constipation (OIC) which persisted despite substantial laxative therapy. RESEARCH DESIGN AND METHODS: This pooled analysis included 75 patients with OIC at study entry that was refractory to at least two laxatives with different modes of action. Patients completed randomized, double-blind treatment with OXN PR 20-120 mg/day for either 12 weeks (OXN 9001: non-cancer pain study) or 4 weeks (OXN 2001: cancer-related pain study). Analgesia and bowel function were assessed using the Brief Pain Inventory Short Form and Bowel Function Index (BFI), respectively. Use of laxative medication and safety were assessed throughout the studies. CLINICAL TRIAL REGISTRATION: NCT00513656, EudraCT 2005-002398-57, EudraCT 2005-003510-15. RESULTS: Statistically and clinically significant improvements in bowel function were observed following double-blind treatment with OXN PR. Mean (SD) reduction in BFI score was 21.2 (28.8) and comparable in patients with cancer-related (19.0 [28.9]) and non-cancer pain (23.3.[29.0]; P ≤ 0.0002). Furthermore, the proportion of patients with a BFI score within normal range (≤28.8) increased from 9.5% at screening to 43.1% at Day 15 of OXN PR. While all patients used ≥2 laxatives of different classes at screening, during study treatment 36% stopped using laxatives (P < 0.001). OXN PR provided effective analgesia, evidenced by stable pain scores during study treatment, and there were no unanticipated adverse events. CONCLUSIONS: OXN PR significantly improved bowel function and reduced the use of laxatives in patients with OIC, previously unresponsive to at least two different classes of laxatives. OXN also provided effective analgesia for patients with moderate-to-severe cancer-related pain and non-cancer-related pain.

Spinal cord stimulation for visceral pain--a novel approach.

BACKGROUND: Spinal cord stimulation and dorsal column stimulation have been used successfully in the management of visceral pain for many years. A novel technique of ventral column stimulation has been used in our institute with good outcomes since 2007. We describe a retrospective series of 26 patients with visceral neuropathic pain who were treated with neuromodulation. METHODS: Patients with either dermatomal hyperalgesia or sympathetically mediated neuropathic abdominal pain who had been treated with spinal cord stimulation were assessed. An independent observer conducted a face-to-face interview with each patient to collect data including demography, electrode placement, electrode mapping, and outcomes. RESULTS: There was significant reduction in visual analog pain scores from a median 9 at baseline to 4 at 26 months (p ≤ 0.05). Reduction in opioid consumption was very significant from a baseline median oral morphine equivalent of 160 mg to 26 mg (p < 0.001). In addition, quality of life, activities of daily living, and patient global impression of change improved. CONCLUSION: There is a need to further investigate the use of ventral stimulation for visceral pain syndromes. This would need multicenter trials to collect adequate numbers of patients to allow hypothesis testing to underpin recommendations for future evidence-based therapies.

The role of the liver X receptor in chronic obstructive pulmonary disease.

BACKGROUND: There is a need for novel anti-inflammatory therapies to treat COPD. The liver X receptor (LXR) is a nuclear hormone receptor with anti-inflammatory properties. METHODS: We investigated LXR gene and protein expression levels in alveolar macrophages and whole lung tissue from COPD patients and controls, the effect of LXR activation on the suppression of inflammatory mediators from LPS stimulated COPD alveolar macrophages, and the effect of LXR activation on the induction of genes associated with alternative macrophage polarisation. RESULTS: The levels of LXR mRNA were significantly increased in whole lung tissue extracts in COPD patients and smokers compared to non-smokers. The expression of LXR protein was significantly increased in small airway epithelium and alveolar epithelium in COPD patients compared to controls. No differences in LXR mRNA and protein levels were observed in alveolar macrophages between patient groups. The LXR agonist GW3965 significantly induced the expression of the LXR dependent genes ABCA1 and ABCG1 in alveolar macrophage cultures. In LPS stimulated alveolar macrophages, GW3965 suppressed the production of CXCL10 and CCL5, whilst stimulating IL-10 production. CONCLUSIONS: GW3965 did not significantly suppress the production of TNFα, IL-1ß, or CXCL8. Our major finding is that LXR activation has anti-inflammatory effects on CXC10, CCL5 and IL-10 production from alveolar macrophages.

Opioid therapy in non-cancer chronic pain patients: Trends and efficacy in different types of pain, patients age and gender.

BACKGROUND: In both developing and developed countries, chronic pain remains a real issue and a true disease that affects up to 42% of the population in some areas. Opioids are widely used for the management of chronic pain with variations in prescribing practices, indications and observed efficacy. AIM: to analyze trends in opioids prescribing and patient response in chronic non-cancer pain conditions. METHODS: Retrospective study of 1500 casenotes of patients suffering variable non-cancer chronic pain conditions. Detailed review of those cases who were managed using opioids. Statistical analysis using "SOFA" software set. RESULTS: The prevalence of opioids prescribing in patients suffering this condition was thus around 35% (n=526). Women older than 50 years were more likely than men to have a chronic pain condition and to be given opioid therapy for 1 year or more. Opioid efficacy on neuropathic and mixed types of pain was found to be significant with relatively low rate of drop-out and limited side-effects that are not life threatening. Overall, patients stopped or changed their opioid medication due to inefficacy in only 12.7% of cases. CONCLUSIONS: The simple fact of having pain is itself a source of self-reported disability regardless of the actual physiological or pathological mechanism. Policy makers should be aware of the huge impact of chronic pain disease and of its serious effects on social and economical well-being. In developing countries, chronic pain could represent a real challenge for all parties. Multimodal management, including opioids, appears crucial for the approach of this disease.

A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function.

The ubiquitously expressed glucocorticoid receptor (GR) is a major drug target for inflammatory disease, but issues of specificity and target tissue sensitivity remain. We now identify high potency, non-steroidal GR ligands, GSK47867A and GSK47869A, which induce a novel conformation of the GR ligand-binding domain (LBD) and augment the efficacy of cellular action. Despite their high potency, GSK47867A and GSK47869A both induce surprisingly slow GR nuclear translocation, followed by prolonged nuclear GR retention, and transcriptional activity following washout. We reveal that GSK47867A and GSK47869A specifically alter the GR LBD structure at the HSP90-binding site. The alteration in the HSP90-binding site was accompanied by resistance to HSP90 antagonism, with persisting transactivation seen after geldanamycin treatment. Taken together, our studies reveal a new mechanism governing GR intracellular trafficking regulated by ligand binding that relies on a specific surface charge patch within the LBD. This conformational change permits extended GR action, probably because of altered GR-HSP90 interaction. This chemical series may offer anti-inflammatory drugs with prolonged duration of action due to altered pharmacodynamics rather than altered pharmacokinetics.