Effects of switching from a metered dose inhaler to a dry powder inhaler on climate emissions and asthma control: post-hoc analysis.

OBJECTIVE: To compare the effects of switching from a pressurised metered dose inhaler (pMDI)-based to a dry powder inhaler (DPI)-based maintenance therapy versus continued usual care on greenhouse gas emissions (carbon dioxide equivalents, CO2e) and asthma control. METHODS: This post-hoc analysis was based on a subset of 2236 (53%) patients from the Salford Lung Study in Asthma who at baseline were using a pMDI-based controller therapy. During the study patients were randomised to fluticasone furoate/vilanterol (FF/VI) via the ELLIPTA DPI (switched from pMDI to DPI) (n=1081) or continued their usual care treatment (n=1155), and were managed in conditions close to everyday clinical practice. Annual CO2e (kg) was calculated for the total number of maintenance and rescue inhalers prescribed. Asthma control was assessed by the proportion of ACT responders (composite of ACT total score ≥20 and/or increase from baseline ≥3). RESULTS: The groups were well matched for demographic characteristics and baseline Asthma Control Test (ACT) total score (mean age: 49 years; mean ACT score: usual care, 16.6; FF/VI, 16.5). Annual CO2e kg per patient (maintenance plus rescue therapy) was significantly lower with FF/VI DPI treatment ('switch' group) than usual care (least squares geometric mean 108 kg (95% CI 102 to 114) vs 240 kg (95% CI 229 to 252), p<0.001). Asthma control was consistently superior over the 12 months in the FF/VI DPI group compared with usual care. CONCLUSIONS: Patients switching from a pMDI-based to a DPI-based maintenance therapy more than halved their inhaler carbon footprint without loss of asthma control. The remaining inhaler carbon footprint could be reduced through switches from pMDI to DPI rescue medications or alternative lower-carbon footprint rescue inhalers if available. Asthma control improved in both groups, with greater control demonstrated in those initiated on FF/VI DPI. TRIAL REGISTRATION NUMBER: NCT01706198.

Enantioselective Construction of Tertiary Fluoride Stereocenters by Organocatalytic Fluorocyclization.

1,1-Disubstituted styrenes with internal oxygen and nitrogen nucleophiles undergo oxidative fluorocyclization reactions with in situ generated chiral iodine(III)-catalysts. The resulting fluorinated tetrahydrofurans and pyrrolidines contain a tertiary carbon-fluorine stereocenter. Application of a new 1-naphthyllactic acid-based iodine(III)-catalyst allows the control of tertiary carbon-fluorine stereocenters with up to 96% ee. Density functional theory calculations are performed to investigate the details of the mechanism and the factors governing the stereoselectivity of the reaction.

Carbon footprint impact of the choice of inhalers for asthma and COPD.

In the 1990s, metered dose inhalers (MDIs) containing chlorofluorocarbons were replaced with dry-powder inhalers (DPIs) and MDIs containing hydrofluorocarbons (HFCs). While HFCs are not ozone depleting, they are potent greenhouse gases. Annual carbon footprint (CO2e), per patient were 17 kg for Relvar-Ellipta/Ventolin-Accuhaler; and 439 kg for Seretide-Evohaler/Ventolin-Evohaler. In 2017, 70% of all inhalers sold in England were MDI, versus 13% in Sweden. Applying the Swedish DPI and MDI distribution to England would result in an annual reduction of 550 kt CO2e. The lower carbon footprint of DPIs should be considered alongside other factors when choosing inhalation devices.

Weight loss improves disease activity in patients with psoriatic arthritis and obesity: an interventional study.

BACKGROUND: Obesity is over-represented in patients with psoriatic arthritis (PsA) and associated with higher disease activity, poorer effect of treatment and increased cardiovascular morbidity. Studies on the effects of weight loss are however needed. This study aimed to prospectively study the effects of weight loss treatment with very low energy diet (VLED) on disease activity in patients with PsA (CASPAR criteria) and obesity (body mass index BMI ≥ 33 kg/m2). METHODS: VLED (640 kcal/day) was taken during 12-16 weeks, depending on pre-treatment BMI. Afterwards, an energy-restricted diet was gradually reintroduced. Weight loss treatment was given within a structured framework for support and medical follow-up. Treatment with conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs was held constant from 3 months before, until 6 months after baseline. Patients were assessed with BMI, 66/68 joints count, Leeds enthesitis index, psoriasis body surface area (BSA), questionnaires and CRP at baseline, 3 and 6 months. Primary outcome was the percentage of patients reaching minimal disease activity (MDA) and secondary outcomes were reaching Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) response criteria. RESULTS: Totally 41/46 patients completed the study, 63% women, median age 54 years (IQR 48-62). At baseline increased BMI was associated with higher disease activity and poorer function. The median weight loss was 18.7 kg (IQR 14.6-26.5) or 18.6% (IQR 14.7-26.3) of the baseline weight. A majority of the disease activity parameters improved significantly after weight loss, including 68/66 tender/swollen joints count, CRP, BSA, Leeds enthesitis index, HAQ and patient VAS for global health, pain and fatigue. A larger weight loss resulted in more improvement in a dose-response manner. The percentage of patients with MDA increased from 29 to 54%, (p = 0.002). PsARC was reached by 46.3%. The ACR 20, 50 and 70 responses were 51.2%, 34.1% and 7.3% respectively. CONCLUSIONS: Short-term weight loss treatment with VLED was associated with significant positive effects on disease activity in joints, entheses and skin in patients with PsA and obesity. The study supports the hypothesis of obesity as a promotor of disease activity in PsA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02917434 , registered on September 21, 2016-retrospectively registered.

A five-year prospective study of spinal radiographic progression and its predictors in men and women with ankylosing spondylitis.

BACKGROUND: Knowledge about predictors of new spinal bone formation in patients with ankylosing spondylitis (AS) is limited. AS-related spinal alterations are more common in men; however, knowledge of whether predictors differ between sexes is lacking. Our objectives were to study spinal radiographic progression in patients with AS and investigate predictors of progression overall and by sex. METHODS: Swedish patients with AS, age (mean ± SD) 50 ± 13 years, were included in a longitudinal study. At baseline and at 5-year follow up, spinal radiographs were graded according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Predictors were assessed by questionnaires, spinal mobility tests and blood samples. RESULTS: Of 204 patients included, 166 (81%) were re-examined and 54% were men. Men had significantly higher mean mSASSS at baseline and higher mean increase in mSASSS than women (1.9 ± 2.8 vs. 1.2 ± 3.3; p = 0.005) More men than women developed new syndesmophytes (30% vs. 12%; p = 0.007). Multivariate logistic regression analyses with progression ≥ 2 mSASSS units over 5 years or development of new syndesmophytes as the dependent variable showed that presence of baseline AS-related spinal radiographic alterations and obesity (OR 3.78, 95% CI 1.3 to 11.2) were independent predictors of spinal radiographic progression in both sexes. High C-reactive protein (CRP) was a significant predictor in men, with only a trend seen in women. Smoking predicted progression in men whereas high Bath Ankylosing Spondylitis Metrology Index (BASMI) and exposure to bisphosphonates during follow up (OR 4.78, 95% CI 1.1 to 20.1) predicted progression in women. CONCLUSION: This first report on sex-specific predictors of spinal radiographic progression shows that predictors may partly differ between the sexes. New predictors identified were obesity in both sexes and exposure to bisphosphonates in women. Among previously known predictors, baseline AS-related spinal radiographic alterations predicted radiographic progression in both sexes, high CRP was a predictor in men (with a trend in women) and smoking was a predictor only in men. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00858819 . Registered on 9 March 2009. Last updated 28 May 2015.

Which measuring site in ankylosing spondylitis is best to detect bone loss and what predicts the decline: results from a 5-year prospective study.

BACKGROUND: Studies have shown increased prevalence of osteoporosis and increased risk for vertebral fractures in patients with ankylosing spondylitis (AS). Measurements of bone mineral density (BMD) in the lumbar spine anterior-posterior (AP) projection may be difficult to interpret due to the ligamentous calcifications, and the lateral projection might be a better measuring site. Our objectives were to investigate BMD changes after 5 years at different measuring sites in patients with AS and to evaluate disease-related variables and medications as predictors for BMD changes. METHODS: In a longitudinal study, BMD in Swedish AS patients, 50 ± 13 years old, was measured with dual-energy x-ray absorptiometry (DXA) at the hip, the lumbar spine AP and lateral projections, and the total radius at baseline and after 5 years. Patients were assessed with questionnaires, blood samples, and spinal radiographs for grading of AS-related alterations in the spine with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and assessment of vertebral fractures by the Genant score. Multiple linear regression analyses were used to investigate predictors for BMD changes. RESULTS: Of 204 patients included at baseline, 168 (82%) were re-examined after 5 years (92 men and 76 women). BMD decreased significantly at the femoral neck and radius and increased significantly at the lumbar spine, both for AP and lateral projections. Mean C-reactive protein during follow-up predicted a decrease in the femoral neck BMD (change in %, ß = -0.15, p = 0.046). Use of bisphosphonates predicted an increase in BMD at all measuring sites (p < 0.001 to 0.013), except for the total radius. Use of tumor necrosis factor inhibitors (TNFi) predicted an increase in AP spinal BMD (ß = 3.15, p = 0.012). CONCLUSION: The current study (which has a long follow-up, many measuring sites, and is the first to longitudinally assess the lateral projection of the spine in AS patients) surprisingly showed that lateral projection spinal BMD increased. This study suggests that the best site to assess bone loss in AS patients is the femoral neck and that inflammation has an adverse effect, and the use of bisphosphonates and TNFi has a positive effect, on BMD in AS patients.

Fluorinative ring-opening of cyclopropanes by hypervalent iodine reagents. An efficient method for 1,3-oxyfluorination and 1,3-difluorination.

A new method is presented for 1,3-difluorination and 1,3-oxyfluorination reactions. The process is based on iodonium mediated opening of 1,1-disubstituted cyclopropanes. The reaction proceeds with high chemo- and regioselectivity under mild reaction conditions typically at room temperature in a couple of hours. The reaction probably occurs via electrophilic ring-opening of cyclopropanes.

Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton.

OBJECTIVE: To study the prevalence and risk factors for vertebral fractures (VF) in ankylosing spondylitis (AS) and the relation between VF, measures of disease activity, and bone mineral density (BMD) in different measurement sites. METHODS: Patients with AS (modified New York criteria) underwent examination, answered questionnaires, and gave blood samples. Lateral spine radiographs were scored for VF (Genant score) and syndesmophyte formation through modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). BMD was measured with dual-energy x-ray absorptiometry in the hip, radius, and lumbar spine in anteroposterior and lateral projections with estimation of volumetric BMD (vBMD). RESULTS: Two hundred four patients (57% men) with a mean age of 50 ± 13 years and disease duration 15 ± 11 years were included. VF were diagnosed in 24 patients (12%), but were previously noted clinically in only 3 of the 24. Patients with VF were significantly older (p = 0.004), had longer disease duration (p = 0.011), higher Bath Ankylosing Spondylitis Metrology Index (p = 0.011), mSASSS (p = 0.035), and Bath Ankylosing Spondylitis patient global score-2 (BASG-2) (p = 0.032) and were more often smokers (p = 0.032). All women with a VF were postmenopausal. BMD was significantly lower at all measuring sites in the patients with VF. In logistic regression, high BASG-2, low BMD in femoral neck, and low lumbar vBMD were independently associated with presence of VF. CONCLUSION: VF in AS are common but are often not diagnosed. VF are associated with advanced age, longstanding disease, impaired back mobility, syndesmophyte formation, and lower BMD in both the central and peripheral skeleton. BMD in the femoral neck, total hip, and estimated vBMD showed the strongest association with VF.

Osteoporosis in ankylosing spondylitis - prevalence, risk factors and methods of assessment.

INTRODUCTION: Osteoporosis can be a complication of ankylosing spondylitis (AS), but diagnosing spinal osteoporosis can be difficult since pathologic new bone formation interferes with the assessment of the bone mineral density (BMD). The aims of the current study were to investigate prevalence and risk factors for reduced BMD in a Swedish cohort of AS patients, and to examine how progressive ankylosis influences BMD with the use of dual-energy x-ray absorptiometry (DXA) of the lumbar spine in different projections. METHODS: Methods of assessment were questionnaires, back mobility tests, blood samples, lateral spine radiographs for syndesmophyte grading (mSASSS), DXA of the hip, radius and lumbar spine in anteroposterior (AP) and lateral projections with estimation of volumetric BMD (vBMD). RESULTS: AS patients (modified New York criteria), 87 women and 117 men, mean age 50 ± 13 years and disease duration 15 ± 11 years were included. According to World Health Organization (WHO) criteria 21% osteoporosis and 44% osteopenia was diagnosed in patients > = 50 years. Under age 50 BMD below expected range for age was found in 5%. Interestingly lateral lumbar DXA showed significantly lower BMD and revealed significantly more cases with osteoporosis as compared with AP DXA. Lumbar vBMD was not different between sexes, but women had significantly more lumbar osteoporosis measured with AP DXA (P < 0.001). Men had significantly higher mSASSS (P < 0.001). Low BMD was associated with high age, disease duration, mSASSS, Bath Ankylosing Spondylitis Metrology Index (BASMI), inflammatory parameters and low body mass index (BMI). Increasing mSASSS correlated significantly with decreasing lateral and volumetric lumbar BMD, while AP lumbar BMD showed tendency to increase. CONCLUSIONS: Osteoporosis and osteopenia is common in AS and associated with high disease burden. Lateral and volumetric lumbar DXA are more sensitive than AP DXA in detecting osteoporosis and are less affected by syndesmophyte formation.

Calprotectin in ankylosing spondylitis--frequently elevated in feces, but normal in serum.

OBJECTIVES: To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS) patients by assessing the levels of fecal calprotectin, to study levels of serum calprotectin in AS, and to correlate the concentrations of calprotectin in feces and serum with reported gastrointestinal symptoms, medication, and measures of disease activity. METHODS: All patients fulfilling the Modified New York criteria of AS at the study centers were invited to participate. The patients answered questionnaires concerning medication, symptoms, and disease activity. Physical examination was performed, including back mobility tests. Samples of stools and blood were collected and analyzed for fecal and serum calprotectin. RESULTS: Elevated levels of fecal calprotectin (>50 mg/kg) was found in 140 of 205 AS patients (68%). Levels of fecal calprotectin were associated with increasing age, disease duration, ESR, CRP, and serum calprotectin, but not with gastrointestinal symptoms. Fecal calprotectin was higher in patients using NSAIDs, salicylates, and proton pump inhibitors, but lower in patients using methotrexate and infliximab. Serum calprotectin levels were normal or low in 98% of AS patients and not different from the levels in healthy blood donors. Serum calprotectin levels were positively associated with ESR, CRP, WBC, and PLT. CONCLUSIONS: Two-thirds of AS patients had elevated levels of fecal calprotectin, without associated gastrointestinal symptoms. Serum calprotectin was mostly normal in AS, in contrast to various other inflammatory rheumatic diseases. We suggest that fecal calprotectin may be a marker for subclinical intestinal inflammation in AS and should be measured after stopping NSAIDs, but further endoscopic studies are needed.

Construction of a chiral central nervous system (CNS)-active aminotetralin drug compound based on a synthesis strategy using multitasking properties of (S)-1-phenylethylamine.

This Account describes the design and development of a scalable synthesis for the drug molecule AR-A2 (1) starting from the discovery route originating in medicinal chemistry. Special emphasis is placed on the introduction of the correct (R) stereochemistry on C2, which was ultimately achieved in a diastereoselective imine-reducing step applying NaBH4. After optimization, this transformation was operated on a large pilot-plant scale (2000 L), offering the desired product (11) in 55% yield and 96% diastereomeric excess at a 100 kg batch size. From a synthesis strategy point of view, the choice of (S)-1-phenylethylamine (9) was crucial not only for its role as a provider of the NH2 functionality and the stereo-directing abilities but also as an excellent protecting group in the subsequent N-arylation reaction, according to the Buchwald-Hartwig protocol. As one of the very first examples in its kind, the latter step was scaled up to pilot manufacturing (125 kg in 2500 L vessel size), delivering an outstanding isolated yield of 95%. This consecutive series of chemical transformations was completed with an environmentally friendly removal of the phenethyl appendage. In addition, an elegant method to synthesize the tetralone substrate 6, as well as a novel and robust procedure to use imidazole as a buffer for the selective formation of the mono-HBr salt of AR-A2, will be briefly described.