Performance Analysis of the National Early Warning Score and Modified Early Warning Score in the Adaptive COVID-19 Treatment Trial Cohort.

We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN: We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING: A multisite international inpatient trial. PATIENTS: A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS: Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS: For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60-0.68), and improved with addition of age (c-index, 0.66-0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65-0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68-0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59-0.69) and improved with addition of age (c-index, 0.63-0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS: In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

Non-pharmacological sleep interventions for pediatric cancer patients and survivors: a systematic review protocol.

BACKGROUND: Sleep disturbances constitute a common complication in pediatric cancer patients and survivors and are frequently severe enough to warrant treatment. Suboptimal sleep has been associated with decreased emotional well-being and cognitive functioning and increased behavioral problems. Standardized guidelines for non-pharmacological sleep interventions for adults with cancer exist, but no standard of care intervention or standard guidelines are available to guide such intervention in pediatric cancer patients and survivors. Therefore, effective behavioral interventions for improving sleep quality need to be identified. The objective of the review is to evaluate the effect of non-pharmacological sleep interventions on sleep quality in pediatric cancer patients and survivors. METHODS: The review will consider studies that include children and adolescents between 0 and 18 years diagnosed with cancer or who have a history of cancer who have non-respiratory sleep disturbance. We will include experimental and quasi-experimental studies evaluating non-pharmacological interventions such as psychological interventions, technical/device interventions, interventions targeting physical activity, and complementary and alternative medicine interventions (e.g., yoga, massage, music). Interventions involving medications, ingestible supplements, products purported to work through absorption, and medical devices will be excluded. Primary outcome will be sleep quality as measured by methods including retrospective ratings, daily sleep diary, and validated questionnaires. Secondary outcomes will include total sleep time, sleep onset latency, wake after sleep onset, daytime sleepiness, and daytime sleep duration (naps) as measured by retrospective ratings, daily sleep diary, validated questionnaires, and/or actigraphy. Databases will include MEDLINE (Ovid), EMBASE (Ovid), Cochrane Library, CINAHL (Ebsco), and PsycINFO (Ovid) and will be queried from database inception to present. Two reviewers will independently screen all citations, full-text articles, and extract data. The study methodological quality will be assessed using Joanna Briggs Institute (JBI) critical appraisal tools. Data will be extracted and findings pooled and synthesized using a meta-aggregation approach via the JBI System for the Unified Management, Assessment, and Review of Information (SUMARI). If feasible, we will conduct random effects meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., methodological quality, study design, outcome measures). DISCUSSION: This systematic review will synthesize and consolidate evidence on existing non-pharmacological interventions to improve sleep in pediatric cancer patients and survivors. Findings may help inform practitioners working with pediatric cancer patients and survivors experiencing sleep disturbances and is intended to identify gaps and opportunities to improve methodical quality of further non-pharmacological sleep intervention research in this population toward developing an eventual standard of care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020200397 .

How hospital-based health care providers perceive clinical librarian services: a qualitative review protocol.

OBJECTIVE: The objective of the review is to evaluate how health care providers working in hospitals perceive clinical librarian services. INTRODUCTION: Clinical librarianship programs existed as early as 1971; however, there is a lack of evidence on their effectiveness in impacting health care outcomes. Studies report primarily on programs supporting medicine, although these programs also support other health care providers. In order to affect outcomes, particularly those focused on patient-centered, evidence-based care, clinical librarians need insight into how hospital health care providers perceive clinical librarian services. INCLUSION CRITERIA: The review will consider studies that include any health care provider who works within a hospital, including surgical, clinical, and inpatient units. Studies that focus on qualitative data about clinical librarian services, published from 1971 onward, will be eligible for inclusion. METHODS: The primary databases to be searched are PubMed, CINAHL, Embase, PsycINFO, Library Literature & Information Science, LISTA (Library, Information Science & Technology Abstracts), and Web of Science. Studies will be selected based on their assessment against the inclusion criteria by two independent reviewers. Eligible studies will be critically appraised for methodological quality. Data will be extracted using a standardized tool, and findings pooled and synthesized using a meta-aggregation approach.

Intracranial Pressure Monitoring via External Ventricular Drain: Are We Waiting Long Enough Before Recording the Real Value?

BACKGROUND: External ventricular drain (EVD) is a standard approach for both monitoring intracranial pressure (ICP) and draining cerebrospinal fluid (CSF) for patients with subarachnoid hemorrhage. Documenting an accurate ICP value is important to assess the status of the brain, which would require the EVD system to be leveled properly and closed to CSF drainage for an adequate period. It is suggested that a minimum period of 5-minute EVD closure is needed before documenting a true ICP; however, there is no commonly agreed upon standard for documenting ICP. To obtain an insight into how well the intermittent EVD clamping procedure is performed for ICP documentation, we conducted a retrospective analysis of ICP recordings obtained through EVD from 107 patients with subarachnoid hemorrhage. METHODS: The EVD was kept open for continuous CSF drainage and then intermittently closed for ICP documentation. For each EVD closure, mean ICP, standard deviation of ICP, duration of EVD closure, and time interval between 2 adjacent EVD closures were studied. The total number of EVD closures was calculated for each patient. We developed an algorithm to evaluate whether ICP reached a new equilibrium before the EVD was reopened to drainage. The percentage of EVD closures that reach the equilibrium was calculated. RESULTS: The 107 patients had 32 755 EVD closures in total, among which 65.9% instances lasted less than 1 minute and only 16.3% of all the EVD closure episodes lasted longer than 5 minutes. The median duration of each EVD closure was 25 seconds (interquartile range, 10.2 seconds to 2.33 minutes). Only 22.9% of the EVD closures reached ICP equilibrium before EVD reopening. CONCLUSION: A standard guideline and proper training are needed for bedside nurses, and a potential tool that can render ICP trend at a proper scale at bedside would help clinicians correctly document ICP.

Nurse-facilitated reflective exercise post patient death in the ICU: a best practice implementation project.

INTRODUCTION: ICUs are stressful environments where patient care is complex and demanding; death is not an unusual outcome. Nurses can become emotionally distressed from experiencing multiple, unexpected, or traumatic patient deaths. Performing a reflective exercise immediately post death is one coping strategy which encourages healthcare staff and family to debrief their feelings in a timelier manner. OBJECTIVES: The aim of this project was to educate the nurses in the ICU with emotional coping skills pertaining to the effects of patient deaths. The objective was to implement a nurse-guided reflective exercise following each patient death in three adult ICUs in a quaternary academic medical center. METHODS: The current change project used the Joanna Briggs Institute's Getting Research into Practice and Practical Application of Clinical Evidence Systems for auditing and strategy development. After standardizing the reflective exercise procedure, teaching methods were employed to support implementation. One follow-up audit measured compliance with completing a reflective exercise for all deaths occurring in the three ICUs. Contextual data were collected for completed exercises including type of death and words to describe nurses' emotions. RESULTS: The reflective exercise script was revised and the standard procedure posted to the intranet for easy access. All ICU nurses received education on the use of this reflective exercise. For each of the two ICUs where this practice was new, compliance with nurses initiating and completing a reflective exercise was at a rate of 17 and 2%, respectively. For the ICU where reflective exercise was reintroduced, compliance was 30%. All deaths included in this study were anticipated (e.g., patient on comfort care) and calm, with the exception of one post cardiac arrest death. CONCLUSION: Despite multipronged teaching for why, when, and how to use reflective exercise, there was minimal success in completing reflective exercises in the two units where the practice was new. This outcome was most likely due to higher than anticipated levels of needed support or the unpredictability of frequency of deaths on each unit. However, the main achievement was having the Minute of Silence procedure with a standardized script readily available at all times for nursing staff. Reimplementation success in the other ICU was attributed to more recently established reflective practices. Further exploration of barriers, such as type of death, and re-education are essential strategies to bolster and sustain practice and to provide support for our nursing staff to prevent emotional distress.

Actionable Real-World Evidence to Improve Health Outcomes and Reduce Medical Spending Among Risk-Stratified Patients with Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic condition with a high economic burden as well as drug treatments that have not all demonstrated effects on longevity. Managed care organizations want to improve health outcomes in these complex patients but lack actionable evidence to make informed decisions on which therapies are most effective among their members and may also control total health care spending. OBJECTIVE: To produce actionable evidence by identifying antidiabetic treatments that are effective and may reduce total cost of care in various risk groups of patients with T2DM, using insurance claims data that includes medical claims and pharmacy dispensing data among members of Horizon Blue Cross Blue Shield of New Jersey with T2DM. METHODS: We identified patients with T2DM in longitudinal claims data from Horizon between 2014 and 2017 with demographic and enrollment information, inpatient and outpatient diagnoses and procedures, and pharmacy dispensing. Outcomes included myocardial infarction, heart failure (HF), stroke, percutaneous revascularization, health care services utilization, and plan costs (i.e., medical, pharmacy, and total cost of care). After propensity score decile adjustment on over 20 covariates, we evaluated the effectiveness and safety of second-line antidiabetic treatment that included sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas (SUs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. RESULTS: Among 115,308 members with T2DM, the most common comorbidities were cardiovascular risk factors, including hyperlipidemia (56%), hypertension (50%), and existing cardiovascular disease (CVD; 55%). Among members receiving dual antidiabetic treatment (n = 20,204), the most prevalent treatments were metformin plus the following second-line medications: SUs (42%), DPP-4 inhibitors (29%), SGLT-2 inhibitors (10%), or GLP-1 receptor agonists (3%). Approximately 20% of members accounted for 79% of total cost of care, with an average of $9,605 per member per year (PMPY). Compared with SU initiation and after propensity score decile adjustment, new users of SGLT-2 inhibitors had a reduced risk for HF hospitalization (HR = 0.35, 95% CI = 0.13-0.89), hypoglycemia, albuminuria, microvascular disease, and metabolic failure. Among SGLT-2 inhibitor initiators with established CVD, the savings in total cost of care compared with SU initiators was $5,520 per member over an average treatment duration of 6 months and an approximate savings of $11,000 PMPY if patients persisted on treatment for 12 months. CONCLUSIONS: In the Horizon membership, we confirmed that SGLT-2 inhibitors reduce HF hospitalizations, resulting in reduced medical spending and savings in total cost of care. Regulatory-grade analytics of local data provided the confidence to encourage increased SGLT-2 inhibitor use to produce better outcomes and save total cost of care despite higher pharmacy spending. DISCLOSURES: This research did not receive outside funding; however, Aetion has since begun a contractual relationship with Horizon Blue Cross Blue Shield of New Jersey. Garry, Petruski-Ivleva, Cheever, and Rajan are employees of and have stock options in Aetion, a company that makes software for the analysis of real-world data. Eapen was an employee of Aetion during the implementation of this study. Rassen is an employee of and has ownership interest in Aetion. Murk is a consultant to Aetion of which he owns equity. Schneeweiss is a consultant to WHISCON and to Aetion, of which he also owns equity. He is the principal investigator of investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Genentech, Boehringer Ingelheim, and Vertex. Gambino is an employee and officer at Horizon Blue Cross and Blue Shield of New Jersey. He was recently appointed to a board observer position at Aetion, as Horizon has small equity interest in Aetion. Jan is an employee of Rutgers State University and Horizon Blue Cross Blue Shield of New Jersey and has no conflict of interest or association with Aetion or any pharmaceutical company. Jang and Rubin are employees of Horizon Blue Cross and Blue Shield of New Jersey and have no conflict of interest or association with Aetion. This work was presented as a poster at AMCP Nexus 2018, October 22-25, 2018, in Orlando, FL; as part of a continuing education session at the AMCP Managed Care & Specialty Pharmacy 2019 Annual Meeting in San Diego, CA, March 25-28, 2019; as invited podium presenter at the Blue Cross Blue Shield 2019 National Summit conference in Grapevine, TX, April 29-May 2, 2019; and was accepted for a podium presentation at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2019 annual conference in New Orleans, LA, May 18-22, 2019, where it won an award for Best Podium Presentation.

Interventions to Reduce Unhealthy Alcohol Use among Primary Care Patients with HIV: the Health and Motivation Randomized Clinical Trial.

BACKGROUND: Unhealthy alcohol use has adverse effects on HIV treatment. Screening, brief intervention, and referral to treatment (SBIRT) has some evidence of efficacy but may not be sufficient for those with low motivation or comorbid substance use. OBJECTIVE: To examine the effectiveness of motivational interviewing (MI) and emailed feedback (EF) among primary care HIV-positive patients, compared with treatment as usual care (UC) only, which included SBIRT. DESIGN: Randomized clinical trial. PARTICIPANTS: Six hundred fourteen adult HIV-positive patients in Kaiser Permanente Northern California who reported prior-year unhealthy alcohol use. INTERVENTION: Participants were randomized to either three sessions of MI (one in person and two by phone), information regarding alcohol risks via EF through a patient portal, or UC alone. MI and EF participants who reported unhealthy alcohol use at 6 months were offered additional MI and EF treatment, respectively. MAIN MEASURES: Participant-reported unhealthy alcohol use (defined as ≥ 4/≥ 5 drinks per day for women/men), alcohol problems at 12 months, based on blinded telephone interviews. Secondary outcomes included drug use and antiretroviral (ART) adherence. KEY RESULTS: At 12 months, there were no overall group differences, but in all three arms, there were declines in unhealthy alcohol use and alcohol-related problems (p < 0.001). Participants reporting low motivation to reduce drinking at baseline were less likely to report unhealthy alcohol use if they received MI vs. EF and UC (p = 0.013). At 6 months, reported illegal drug use/misuse of prescription drugs other than marijuana was lower in the MI arm than EF or UC (p = 0.012). There were no differences in ART adherence between groups. CONCLUSIONS: In a randomized trial of HIV-positive patients using two behavioral interventions compared with SBIRT alone, participants in all three conditions reduced unhealthy alcohol use. MI may provide added benefit for patients with low motivation or who report illegal drug use/misuse of prescription drugs. TRIAL REGISTRATION: NCT01671501 ( ClinicalTrials.gov ).

Mental and Physical Quality of Life by Age Groups in People Living With HIV.

Quality of life (QoL) is relevant to people living with HIV (PLWH) with increased life expectancy because of antiretroviral therapy. Our cross-sectional study examined associations between sociodemographic, HIV-related and psychological variables, and QoL, overall and by age. PLWH (n = 614) completed questionnaires at enrollment in an alcohol treatment study. QoL was assessed by the 12-item Short Form Survey, which includes physical and mental domains. Linear regression models evaluated the association of age and other factors with mental and physical QoL. PLWH younger than 50 years (n = 310) reported poorer mental QoL but better physical QoL compared to older PLWH (n = 304). Poorer mental QoL was associated with substance use, depression, and anxiety. Poorer physical QoL was associated with depression and history of injection drug use. We identified age-group differences in QoL for this primary care-based sample. Health care providers can use our findings to guide patient-centered care.

Nursing Partnerships in Research and Quality Improvement Within a Large Integrated Health Care System.

Within a large integrated health care system that includes local, regional, and national medical centers and offices, quality and patient safety teams, and research institutes, more than 58 000 nurses are employed, with the vast majority providing point-of-care service to patients and members. A small but increasingly important number of nurses are involved in quality improvement and research teams to improve patient care. Within this environment, a number of developments point to a growing need for nursing leadership in systems-level and delivery science policies and research. This article describes a partnership between clinical operations leaders and researchers (nurse scientists) to determine and utilize evidence-based practices to meet a system goal. The first objective of this article is to describe the barriers and potential solutions in combining practice, quality improvement, and research efforts across regions within a large integrated health care system. The second objective is to describe the uniqueness and importance of nurse leaders across interdisciplinary teams to simultaneously pursue research, quality improvement, and operational goals for the organization.

Factors associated with hazardous alcohol use and motivation to reduce drinking among HIV primary care patients: Baseline findings from the Health & Motivation study.

BACKGROUND: Limited primary care-based research has examined hazardous drinking risk factors and motivation to reduce use in persons with HIV (PWH). METHODS: We computed prevalence ratios (PR) for factors associated with recent (<30 days) hazardous alcohol use (i.e., 4+/5+ drinks in a single day for women/men), elevated Alcohol Use Disorders Identification Test (AUDIT) scores, and importance and confidence (1-10 Likert scales) to reduce drinking among PWH in primary care. RESULTS: Of 614 participants, 48% reported recent hazardous drinking and 12% reported high alcohol use severity (i.e., AUDIT zone 3 or higher). Factors associated with greater alcohol severity included moderate/severe anxiety (PR: 2.07; 95% CI: 1.18, 3.63), tobacco use (PR: 1.79; 1.11, 2.88), and other substance use (PR: 1.72; 1.04, 2.83). Factors associated with lower alcohol severity included age 50-59 years (PR: 0.46; 0.22, 2.00) compared with age 20-39 years, and having some college/college degree (PR: 0.61; 0.38, 0.97) compared with ≤high school. Factors associated with greater importance to reduce drinking (scores >5) included: moderate/severe depression (PR: 1.43; 1.03, 2.00) and other substance use (PR: 1.49; 1.11, 2.01). Lower importance was associated with incomes above $50,000 (PR: 0.65; 0.46, 0.91) and marijuana use (PR: 0.65; 0.49, 0.87). HIV-specific factors (e.g., CD4 and HIV RNA levels) were not associated with alcohol outcomes. CONCLUSIONS: This study identified modifiable participant characteristics associated with alcohol outcomes in PWH, including anxiety and depression severity, tobacco use, and other substance use.

Montelukast treatment protects nigral dopaminergic neurons against microglial activation in the 6-hydroxydopamine mouse model of Parkinson's disease.

Although the main cause of degeneration of the nigrostriatal dopaminergic (DA) projection in Parkinson's disease (PD) is still controversial, many reports suggest that excessive inflammatory responses mediated by activated microglia can induce neurotoxicity in the nigrostriatal DA system in vivo. Montelukast, which plays an anti-inflammatory role, is used to treat patients with asthma. In addition, recent studies have reported that its administration could reduce neuroinflammatory activities, showing beneficial effects against various neuropathological conditions. These results suggest that montelukast may be a useful drug to alleviate inflammatory responses in PD, even though there are no reports showing its beneficial effects against neurotoxicity in the nigrostriatal DA system. In the present study, our results showed that treatment with montelukast could protect DA neurons against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity and its administration significantly attenuated the production of neurotoxic cytokines such as tumor necrosis factor-α (TNFα) and interleukin-1ß (IL-1ß) from activated microglia in the substantia nigra (SN) and striatum following 6-OHDA treatment. Therefore, we suggest that montelukast can be used as a potential inhibitor of microglial activation to protect DA neurons in the adult brain against PD.

The bacterial quorum-sensing molecule, N-3-oxo-dodecanoyl-L-homoserine lactone, inhibits mediator release and chemotaxis of murine mast cells.

OBJECTIVE: Bacterial colonization relies on communication between bacteria via so-called "quorum-sensing molecules", which include the acyl-homoserine lactone group. Certain acyl-homoserine lactones can modulate mammalian cell function and are thought to contribute to bacterial pathogenicity. Given the role of mast cells in host defense, we investigated the ability of acyl-homoserine lactones to modulate mast cell function. METHODS: We utilized murine primary mast cell cultures to assess the effect of acyl-homoserine lactones on degranulation and cytokine release in response to different stimuli. We also assessed cell migration in response to chemoattractants. The effect of acyl-homoserine lactones in vivo was tested using a passive cutaneous anaphylaxis model. RESULTS: Two of the tested quorum-sensing molecules, N-3-oxo-dodecanoyl-L-homoserine lactone and N-Dodecanoyl-L-homoserine lactone, inhibited IgE dependent and independent degranulation and mediator release from primary mast cells. Further testing of N-3-oxo-dodecanoyl-L-homoserine lactone, the most potent inhibitor and a product of Pseudomonas aeruginosa, revealed that it also attenuated chemotaxis and LPS induced cytokine production. In vivo, N-3-oxo-dodecanoyl-L-homoserine lactone inhibited the passive cutaneous anaphylaxis response in mice. CONCLUSION: The ability of N-3-oxo-dodecanoyl-L-homoserine lactone to stabilize mast cells may contribute to the pathogenicity of P. aeruginosa but could potentially be exploited therapeutically in allergic disease.

Naringin attenuates granule cell dispersion in the dentate gyrus in a mouse model of temporal lobe epilepsy.

Morphological abnormalities of the dentate gyrus (DG) are an important phenotype in the hippocampus of patients with temporal lobe epilepsy. We recently reported that naringin, a bioflavonoid in grapefruit and citrus fruits, exerts beneficial effects in the kainic acid (KA) mouse model of epilepsy. We found that naringin treatment reduced seizure activities and decreased autophagic stress and neuroinflammation in the hippocampus following in vivo lesion with KA. However, it remains unclear whether naringin may also attenuate seizure-induced morphological changes in the DG, collectively known as granule cell dispersion (GCD). To clarify whether naringin treatment reduces GCD, we evaluated the effects of intraperitoneal injection of naringin on GCD and activation of mammalian target of rapamycin complex 1 (mTORC1), an important regulator of GCD, following intrahippocampal injection of KA. Our results showed that naringin treatment significantly reduced KA-induced GCD and mTORC1 activation, which was confirmed by assessing the phosphorylated form of the mTORC1 substrate, 4E-BP1, in the hippocampus. These results suggest that naringin treatment may help prevent epilepsy-induced hippocampal injury by inhibiting mTORC1 activation and thereby reducing GCD in the hippocampus in vivo.

Aging and living with HIV/AIDS.

With individuals either living longer with the disease or contracting it at a later stage in life, HIV/AIDS can no longer be regarded as just a young person's disease. In fact, people older than 50 will represent 50% of HIV/AIDS cases by 2015. The intersection of aging and HIV/AIDS is explored in this article through the use of an individual example highlighting typical age-related issues encountered in living with a chronic HIV infection and two of the more common comorbid conditions. Nursing implications for managing these conditions-depression and dyslipidemia-as well as other considerations for providing care to older adults with HIV/AIDS are addressed.

Design, synthesis and insight into the structure-activity relationship of 1,3-disubstituted indazoles as novel HIF-1 inhibitors.

Design, synthesis and insight into the structure-activity relationship (SAR) of 1,3-disubstituted indazoles as novel HIF-1 inhibitors are described. In particular, the substituted furan moiety on indazole skeleton as well as its substitution pattern turns out crucial for the high HIF-1 inhibition.

Synthesis and structural optimization of multiple H-bonding region of diarylalkyl (thio)amides as novel TRPV1 antagonists.

Structural optimization of multiple H-bonding region and structure-activity relationship of diarylalkyl amides/thioamides as novel TRPV1 antagonists are described. In particular, we identified amide 34o and thioamides 35o and 35r, of which antagonistic activities were highly enhanced by an incorporation of cyano or vinyl-substituent to the multiple H-bonding region. They exhibited potent (45)Ca(2+) uptake inhibitions in rat DRG neuron with IC(50)s of 25, 32 and 28 nM, respectively.