Interventions to improve adherence to pharmacological therapy for chronic obstructive pulmonary disease (COPD).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic lung condition characterised by persistent respiratory symptoms and limited lung airflow, dyspnoea and recurrent exacerbations. Suboptimal therapy or non-adherence may result in limited effectiveness of pharmacological treatments and subsequently poor health outcomes. OBJECTIVES: To determine the efficacy and safety of interventions intended to improve adherence to single or combined pharmacological treatments compared with usual care or interventions that are not intended to improve adherence in people with COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register, CENTRAL, MEDLINE and Embase (search date 1 May 2020). We also searched web-based clinical trial registers. SELECTION CRITERIA: RCTs included adults with COPD diagnosed by established criteria (e.g. Global Initiative for Obstructive Lung Disease). Interventions included change to pharmacological treatment regimens, adherence aids, education, behavioural or psychological interventions (e.g. cognitive behavioural therapy), communication or follow-up by a health professional (e.g. telephone, text message or face-to-face), multi-component interventions, and interventions to improve inhaler technique. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Working in pairs, four review authors independently selected trials for inclusion, extracted data and assessed risk of bias. We assessed confidence in the evidence for each primary outcome using GRADE. Primary outcomes were adherence, quality of life and hospital service utilisation. Adherence measures included the Adherence among Patients with Chronic Disease questionnaire (APCD). Quality of life measures included the St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ). MAIN RESULTS: We included 14 trials (2191 participants) in the analysis with follow-up ranging from six to 52 weeks. Age ranged from 54 to 75 years, and COPD severity ranged from mild to very severe. Trials were conducted in the USA, Spain, Germany, Japan, Jordan, Northern Ireland, Iran, South Korea, China and Belgium. Risk of bias was high due to lack of blinding. Evidence certainty was downgraded due to imprecision and small participant numbers. Single component interventions Six studies (55 to 212 participants) reported single component interventions including changes to pharmacological treatment (different roflumilast doses or different inhaler types), adherence aids (Bluetooth inhaler reminder device), educational (comprehensive verbal instruction), behavioural or psychological (motivational interview). Change in dose of roflumilast may result in little to no difference in adherence (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.22 to 1.99; studies = 1, participants = 55; low certainty). A Bluetooth inhaler reminder device did not improve adherence, but comprehensive verbal instruction from a health professional did improve mean adherence (prescription refills) (mean difference (MD) 1.00, 95% CI 0.46 to 1.54). Motivational interview improved mean adherence scores on the APCD scale (MD 22.22, 95% CI 8.42 to 36.02). Use of a single inhaler compared to two separate inhalers may have little to no impact on quality of life (SGRQ; MD 0.80, 95% CI -3.12 to 4.72; very low certainty). A Bluetooth inhaler monitoring device may provide a small improvement in quality of life on the CCQ (MD 0.40, 95% CI 0.07 to 0.73; very low certainty). Single inhaler use may have little to no impact on the number of people admitted to hospital compared to two separate inhalers (OR 1.47, 95% CI 0.75 to 2.90; very low certainty). Single component interventions may have little to no impact on the number of people expereincing adverse events (very low certainty evidence from studies of a change in pharmacotherapy or use of adherence aids). A change in pharmacotherapy may have little to no impact on exacerbations or deaths (very low certainty). Multi-component interventions Eight studies (30 to 734 participants) reported multi-component interventions including tailored care package that included adherence support as a key component or included inhaler technique as a component. A multi-component intervention may result in more people adhering to pharmacotherapy compared to control at 40.5 weeks (risk ratio (RR) 1.37, 95% CI 1.18 to 1.59; studies = 4, participants = 446; I2 = 0%; low certainty). There may be little to no impact on quality of life (SGRQ, Chronic Respiratory Disease Questionnaire, CAT) (studies = 3; low to very low certainty). Multi-component interventions may help to reduce the number of people admitted to hospital for any cause (OR 0.37, 95% CI 0.22 to 0.63; studies = 2, participants = 877; low certainty), or COPD-related hospitalisations (OR 0.15, 95% CI 0.07 to 0.34; studies = 2, participants = 220; moderate certainty). There may be a small benefit on people experiencing severe exacerbations. There may be little to no effect on adverse events, serious adverse events or deaths, but events were infrequently reported and were rare (low to very certainty). AUTHORS' CONCLUSIONS: Single component interventions (e.g. education or motivational interviewing provided by a health professional) can help to improve adherence to pharmacotherapy (low to very low certainty). There were slight improvements in quality of life with a Bluetooth inhaler device, but evidence is from one study and very low certainty. Change to pharmacotherapy (e.g. single inhaler instead of two, or different doses of roflumilast) has little impact on hospitalisations or exacerbations (very low certainty). There is no difference in people experiencing adverse events (all-cause or COPD-related), or deaths (very low certainty). Multi-component interventions may improve adherence with education, motivational or behavioural components delivered by health professionals (low certainty). There is little to no impact on quality of life (low to very low certainty). They may help reduce the number of people admitted to hospital overall (specifically pharmacist-led approaches) (low certainty), and fewer people may have COPD-related hospital admissions (moderately certainty). There may be a small reduction in people experiencing severe exacerbations, but evidence is from one study (low certainty). Limited evidence found no difference in people experiencing adverse events, serious adverse events or deaths (low to very low certainty). The evidence presented should be interpreted with caution. Larger studies with more intervention types, especially single interventions, are needed. It is unclear which specific COPD subgroups would benefit, therefore discussions between health professionals and patients may help to determine whether they will help to improve health outcomes.

Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo.

The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.

Lay-led and peer support interventions for adolescents with asthma.

BACKGROUND: Adolescents with asthma are at high risk of poor adherence with treatment. This may be compounded by activities that worsen asthma, in particular smoking. Additional support above and beyond routine care has the potential to encourage good self-management. We wanted to find out whether sessions led by their peers or by lay leaders help to reduce these risks and improve asthma outcomes among adolescents. OBJECTIVES: To assess the safety and efficacy of lay-led and peer support interventions for adolescents with asthma. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains reports of randomised trials obtained from multiple electronic and handsearched sources, and we searched trial registries and reference lists of primary studies. We conducted the most recent searches on 25 November 2016. SELECTION CRITERIA: Eligible studies randomised adolescents with asthma to an intervention led by lay people or peers or to a control. We included parallel randomised controlled trials with individual or cluster designs. We included studies reported as full text, those published as abstract only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors screened the searches, extracted numerical data and study characteristics and assessed each included study for risk of bias. Primary outcomes were asthma-related quality of life and exacerbations requiring at least a course of oral steroids. We graded the analyses and presented evidence in a 'Summary of findings' table.We analysed dichotomous data as odds ratios, and continuous data as mean differences (MD) or standardised mean differences, all with a random-effects model. We assessed clinical, methodological and statistical heterogeneity when performing meta-analyses, and we described skewed data narratively. MAIN RESULTS: Five studies including a total of 1146 participants met the inclusion criteria for this review. As ever with systematic reviews of complex interventions, studies varied by design (cluster and individually randomised), duration (2.5 to 9 months), setting (school, day camp, primary care) and intervention content. Most risk of bias concerns were related to blinding and incomplete reporting, which limited the meta-analyses that could be performed. Studies generally controlled well for selection and attrition biases.All participants were between 11 and 17 years of age. Asthma diagnosis and severity varied, as did smoking prevalence. Three studies used the Triple A programme; one of these studies tested the addition of a smoke-free pledge; another delivered peer support group sessions and mp3 messaging to encourage adherence; and the third compared a peer-led asthma day camp with an equivalent camp led by healthcare practitioners.We had low confidence in all findings owing to risk of bias, inconsistency and imprecision. Results from an analysis of asthma-related quality of life based on the prespecified random-effects model were imprecise and showed no differences (MD 0.40, 95% confidence interval (CI) -0.02 to 0.81); a sensitivity analysis based on a fixed-effect model and a responder analysis suggested small benefit may be derived for this outcome. Most other results were summarised narratively and did not show an important benefit of the intervention; studies provided no analysable data on asthma exacerbations or unscheduled visits (data were skewed), and one study measuring adherence reported a drop in both groups. Effects on asthma control favoured the intervention but findings were not statistically significant. Results from two studies with high levels of baseline smoking showed some promise for self-efficacy to stop smoking, but overall nicotine dependence and smoking-related knowledge were not significantly better in the intervention group. Investigators did not report adverse events. AUTHORS' CONCLUSIONS: Although weak evidence suggests that lay-led and peer support interventions could lead to a small improvement in asthma-related quality of life for adolescents, benefits for asthma control, exacerbations and medication adherence remain unproven. Current evidence is insufficient to reveal whether routine use of lay-led or peer support programmes is beneficial for adolescents receiving asthma care.Ongoing and future research may help to identify target populations for lay-led and peer support interventions, along with attributes that constitute a successful programme.

Asthma education for school staff.

BACKGROUND: Teachers and school staff should be competent in managing asthma in schools. Demonstrated low levels of asthma knowledge mean that staff may not know how best to protect a child with asthma in their care, or may fail to take appropriate action in the event of a serious attack. Education about asthma could help to improve this knowledge and lead to better asthma outcomes for children. OBJECTIVES: To assess the effectiveness and safety of asthma education programmes for school staff, and to identify content and attributes underpinning them. SEARCH METHODS: We conducted the most recent searches on 29 November 2016. SELECTION CRITERIA: We included randomised controlled trials comparing an intervention to educate school staff about asthma versus a control group. We included studies reported as full text, those published as abstract only and unpublished data. DATA COLLECTION AND ANALYSIS: At least two review authors screened the searches, extracted outcome data and intervention characteristics from included studies and assessed risk of bias. Primary outcomes for the quantitative synthesis were emergency department (ED) or hospital visits, mortality and asthma control; we graded the main results and presented evidence in a 'Summary of findings' table. We planned a qualitative synthesis of intervention characteristics, but study authors were unable to provide the necessary information.We analysed dichotomous data as odds ratios, and continuous data as mean differences or standardised mean differences, all with a random-effects model. We assessed clinical, methodological and statistical heterogeneity when performing meta-analyses, and we narratively described skewed data. MAIN RESULTS: Five cluster-RCTs of 111 schools met the review eligibility criteria. Investigators measured outcomes in participating staff and often in children or parents, most often at between 1 and 12 months.All interventions were educational programmes but duration, content and delivery varied; some involved elements of training for pupils or primary care providers. We noted risk of selection, performance, detection and attrition biases, although to a differing extent across studies and outcomes.Quanitative and qualitative analyses were limited. Only one study reported visits to the ED or hospital and provided data that were too skewed for analysis. No studies reported any deaths or adverse events. Studies did not report asthma control consistently, but results showed no difference between groups on the paediatric asthma quality of life questionnaire (mean difference (MD) 0.14, 95% confidence interval (CI) -0.03 to 0.31; 1005 participants; we downgraded the quality of evidence to low for risk of bias and indirectness). Data for symptom days, night-time awakenings, restricted activities of daily living and school absences were skewed or could not be analysed; some mean scores were better in the trained group, but most differences between groups were small and did not persist to 24 months.Schools that received asthma education were more adherent to asthma policies, and staff were better prepared; more schools that had received staff asthma training had written asthma policies compared with control schools, more intervention schools showed improvement in measures taken to prevent or manage exercise-induced asthma attacks and more staff at intervention schools reported that they felt able to administer salbutamol via a spacer. However, the quality of the evidence was low; results show imbalances at baseline, and confidence in the evidence was limited by risk of bias and imprecision. Staff knowledge was higher in groups that had received asthma education, although results were inconsistent and difficult to interpret owing to differences between scales (low quality).Available information about the interventions was insufficient for review authors to conduct a meaningful qualitative synthesis of the content that led to a successful intervention, or of the resources required to replicate results accurately. AUTHORS' CONCLUSIONS: Asthma education for school staff increases asthma knowledge and preparedness, but studies vary and all available evidence is of low quality. Studies have not yet captured whether this improvement in knowledge has led to appreciable benefits over the short term or the longer term for the safety and health of children with asthma in school. Randomised evidence does not contribute to our knowledge of content or attributes of interventions that lead to the best outcomes, or of resources required for successful implementation.Complete reporting of the content and resources of educational interventions is essential for assessment of their effectiveness and feasibility for implementation. This applies to both randomised and non-randomised studies, although the latter may be better placed to observe important clinical outcomes such as exacerbations and mortality in the longer term.

Pulse oximeters to self monitor oxygen saturation levels as part of a personalised asthma action plan for people with asthma.

BACKGROUND: We became aware through talking with people with asthma that some are using pulse oximeters to monitor their own blood oxygen levels during an asthma attack. Pulse oximeters are marketed by some suppliers as essential equipment for the home medicine cabinet. We wanted to find out if reliable evidence is available on use of pulse oximeters to self monitor asthma exacerbations at home. We decided to include only trials that used pulse oximeters as part of a personalised asthma action plan because it is important that decisions are made on the basis of symptoms as well as oxygen saturation, and that patients have a clear protocol to follow when their asthma worsens. OBJECTIVES: To determine whether pulse oximeters used as part of a personalised asthma action plan for people with asthma are safer and more effective than a personalised asthma action plan alone. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), which includes reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED) and PsycINFO, and by handsearching. We also searched ClinicalTrials.gov and the World Health Organization (WHO) trials portal. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs). Participants would have included adults, children or both with a diagnosis of asthma. We planned to include trials in which investigators compared participants who used pulse oximeters to monitor oxygen levels at home during an asthma exacerbation as part of a personalised asthma action plan (PAAP) versus those who used a PAAP without a pulse oximeter. We planned to include studies involving people receiving any treatment regimen provided that no medicine was included as part of the randomisation schedule. DATA COLLECTION AND ANALYSIS: We planned to use standard methods as recommended by The Cochrane Collaboration. MAIN RESULTS: We found no studies and no evidence to support or refute the use of home pulse oximetry in self management of asthma; therefore, we can make no recommendations about use of a pulse oximeter as part of a PAAP. AUTHORS' CONCLUSIONS: We found no reliable data to support or refute patient use of pulse oximeters to monitor oxygen saturation levels when experiencing an asthma attack. People should not use a pulse oximeter without seeking advice from a qualified healthcare professional.We identified no compelling rationale for home monitoring of oxygen levels in isolation for most people with asthma. Some people have a reduced perception of the severity of their own breathlessness when exposed to hypoxia. If trials on self monitoring of oxygen levels in the blood by pulse oximeter at home by people with asthma are conducted, the pulse oximeter must be given as part of a personalised asthma action plan.

Impact of an educational intervention on the quality of spirometry performance in a general practice: an audit.

AIMS: To assess the technical performance of spirometry in one general practice, and then to deliver in-house education to effect change. METHODS: Retrospective audit of 45 spirometry reports assessed against possible alternative quality criteria. Three subsequent educational interventions for those clinicians performing and interpreting spirometry. Re-audit of 45 spirometry report sheets four months later against the same criteria. RESULTS: 38% of the initial post-bronchodilator spirometries were technically flawed. Post-education, 2% of spirometries were technically flawed and respiratory referrals fell by 50%. CONCLUSION: The technical quality of practice spirometry can be audited. In-house education significantly reduced spirometry errors and was associated with a 50% reduction in respiratory referrals.

Identification of inhibitors of protein kinase B using fragment-based lead discovery.

Using fragment-based screening techniques, 5-methyl-4-phenyl-1H-pyrazole (IC50 80 microM) was identified as a novel, low molecular weight inhibitor of protein kinase B (PKB). Herein we describe the rapid elaboration of highly potent and ligand efficient analogues using a fragment growing approach. Iterative structure-based design was supported by protein-ligand structure determinations using a PKA-PKB "chimera" and a final protein-ligand structure of a lead compound in PKBbeta itself.

Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase.

Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds 4 (IC50 = 25 microM) and 6c (IC50 = 24 microM) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).

Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.

Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.

Fragment-based lead discovery: leads by design.

Fragment-based lead discovery (also referred to as needles, shapes, binding elements, seed templates or scaffolds) is a new lead discovery approach in which much lower molecular weight (120-250 Da) compounds are screened relative to HTS campaigns. Fragment-based hits are typically weak inhibitors (10 microM-mM), and therefore need to be screened at higher concentration using very sensitive biophysical detection techniques such as protein crystallography and NMR as the primary screening techniques, rather than bioassays. Compared with HTS hits, these fragments are simpler, less functionalized compounds with correspondingly lower affinity. However, fragment hits typically possess high 'ligand efficiency' (binding affinity per heavy atom) and so are highly suitable for optimization into clinical candidates with good drug-like properties.

Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.

Structure-based screening of low-affinity compounds.

Conventional bioassay-based screening remains a mainstream approach for lead discovery. However, its limitations have meant that other, more biophysical methods, such as X-ray crystallography and NMR, are now being developed as lead discovery tools. These methods are particularly effective at detecting the binding of low affinity, low molecular weight compounds and transforming them into novel potent leads using structure-guided chemistry. Here, we describe some of the technologies and approaches that are being developed in structure-based screening using X-ray crystallography, which promise to have a major impact on lead discovery.

Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO.

The protein Keap1 is central to the regulation of the Nrf2-mediated cytoprotective response, and is increasingly recognized as an important target for therapeutic intervention in a range of diseases involving excessive oxidative stress and inflammation. The BTB domain of Keap1 plays key roles in sensing environmental electrophiles and in mediating interactions with the Cul3/Rbx1 E3 ubiquitin ligase system, and is believed to be the target for several small molecule covalent activators of the Nrf2 pathway. However, despite structural information being available for several BTB domains from related proteins, there have been no reported crystal structures of Keap1 BTB, and this has precluded a detailed understanding of its mechanism of action and interaction with antagonists. We report here the first structure of the BTB domain of Keap1, which is thought to contain the key cysteine residue responsible for interaction with electrophiles, as well as structures of the covalent complex with the antagonist CDDO/bardoxolone, and of the constitutively inactive C151W BTB mutant. In addition to providing the first structural confirmation of antagonist binding to Keap1 BTB, we also present biochemical evidence that adduction of Cys 151 by CDDO is capable of inhibiting the binding of Cul3 to Keap1, and discuss how this class of compound might exert Nrf2 activation through disruption of the BTB-Cul3 interface.

Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B.

Protein tyrosine phosphatases regulate signal transduction pathways involving tyrosine phosphorylation and have been implicated in the development of cancer, diabetes, rheumatoid arthritis and hypertension. Increasing evidence suggests that the cellular redox state is involved in regulating tyrosine phosphatase activity through the reversible oxidization of the catalytic cysteine to sulphenic acid (Cys-SOH). But how further oxidation to the irreversible sulphinic (Cys-SO2H) and sulphonic (Cys-SO3H) forms is prevented remains unclear. Here we report the crystal structures of the regulatory sulphenic and irreversible sulphinic and sulphonic acids of protein tyrosine phosphatase 1B (PTP1B), an important enzyme in the negative regulation of the insulin receptor and a therapeutic target in type II diabetes and obesity. We also identify a sulphenyl-amide species that is formed through oxidation of its catalytic cysteine. Formation of the sulphenyl-amide causes large changes in the PTP1B active site, which are reversible by reduction with the cellular reducing agent glutathione. The sulphenyl-amide is a protective intermediate in the oxidative inhibition of PTP1B. In addition, it may facilitate reactivation of PTP1B by biological thiols and signal a unique state of the protein.