Pharmacotherapy of Alzheimer's disease: an overview of systematic reviews.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. In this umbrella systematic review (SR), we summarized the efficacy of different pharmacological interventions in improving cognitive function in patients with AD. METHODS: A systematic search was performed through the PubMed, Scopus, Embase, and Cochrane databases for SRs of studies assessing the efficacy of pharmacological interventions versus placebo in improving cognitive function in AD or mild cognitive impairment due to AD. The risk of bias (RoB) was assessed using the Risk of Bias in SRs (ROBIS) tool. RESULTS: Out of 1748 articles found through the database survey, 33 SR articles were included. These studies assessed effects of immunotherapy, cholinesterase inhibitors (ChEIs), memantine, statins, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), antidiabetic agents, Cerebrolysin, RAS-targeting antihypertensive drugs (ARBs and ACEIs), psychostimulants, glycogen synthase kinase 3 (GSK-3) inhibitors, melatonin, and herbal medications on cognitive function in AD patients. There was no notable overall RoB in 18 studies (54.5%), the RoB in 14 studies (42.4%) was high, and in one study (3.0%) it was unclear. CONCLUSIONS: The use of ChEIs, including rivastigmine, galantamine, and donepezil, as well as memantine has demonstrated a positive impact on improving cognitive outcomes of AD patients, but no considerable effects were found for immunotherapies. Melatonin, statins, antihypertensive drugs, antidiabetic agents, Cerebrolysin, psychostimulants, and some herbal drugs such as Danggui-Shaoyao-San and Ginkgo biloba seem to be effective in improving cognitive function of AD patients, but the evidence in this regard is limited.

Alzheimer's Disease: Efficacy of Mono- and Combination Therapy. A Systematic Review.

IMPORTANCE: Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most prevalent cause of dementia. In spite of the urgent need for more effective AD drug therapy strategies, evidence of the efficacy of combination therapy with existing drugs remains unclear. OBJECTIVE: To assess the efficacy of combined drug therapy on cognition and progress in patients with AD in comparison to single agent drug therapy. METHODS: The electronic databases MEDLINE and EMBASE were systematically searched to identify relevant publications. Only randomized controlled clinical trials were included, but no limits were applied to language or time published. Data were extracted from May 27th until December 29th, 2020. RESULTS: Three trials found that a combination of ChEI with additional memantine provides a slight benefit for patients with moderate to severe AD over ChEI monotherapy and placebo. However, a further 4 trials could not replicate this effect. One trial reported benefits of add-on Gingko biloba in donepezil-treated patients with moderate AD (using a formula containing Gingko and other antioxidants) compared to donepezil with placebo. A further trial found no significant effect of combining EGb 761® and donepezil in patients with probable AD over donepezil with placebo. Approaches with idalopirdine, atorvastatin or vitamin supplementation in combination with ChEI have not proven effective and have not been retried since. Fluoxetine and ST101 have shown partial benefits in combination with ChEI over ChEI monotherapy and placebo. However, these effects must be replicated by further research. CONCLUSION: Additional memantine in combination with ChEI might be of slight benefit in patients with moderate to severe AD, but evidence is ambiguous. Longer trials are needed. No major cognitive benefit is missed, if solely appropriate ChEI monotherapy is initiated.

Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting ß2-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting ß2-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study.

BACKGROUND: Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting ß2-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects. RESEARCH QUESTION: Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD? STUDY DESIGN AND METHODS: We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vs three commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively. RESULTS: Patients with COPD initiating IND/GLY and VI/UMEC showed an 11% (incidence rate ratio [IRR], 0.89; 95% CI, 0.80-0.98) and 20% (IRR, 0.80; 95% CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vs FF/BDP, were associated with a 27% (hazard ratio [HR], 0.73; 95% CI, 0.59-0.90) to 42% (HR, 0.58; 95% CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs. INTERPRETATION: Both LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.

Serotonin syndrome in a Parkinson disease patient after intake of an ethanol-containing homeopathic medication.

Serotonin syndrome is due to excess serotonin in the nervous system. We document a case of an elderly Parkinson disease patient who has been neurologically stable on rasagiline and escitalopram for 1 year but developed serotonin syndrome after intake of an ethanol-containing homeopathic medication. The patient presented with seizures, autonomic dysfunction and neuromuscular hyperexcitability. Maintenance medications were discontinued, hydration, sedation and respiratory support were provided with resolution of the symptoms. The combination of escitalopram and ethanol, both metabolized by the cytochrome P450 enzyme system can lead to serotonin syndrome. Our case highlights the importance of drug interactions in patients taking several medications. Additionally, the intake of medicines, may it be conventional or homeopathic medicine, without the guidance of a trained and competent physician, may lead to serious consequences for the patient.

TV 3326 for Alzheimer's dementia: a novel multimodal ChE and MAO inhibitors to mitigate Alzheimer's-like neuropathology.

OBJECTIVES: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and a well-recognized cause of dementia with ageing. In this review, we have represented the ChE and MAO inhibitory potential of TV 3326 against AD based on current scientific evidence. KEY FINDINGS: The aetiology of AD is quite complex and not completely understood. However, it has been observed that AD involves the deposition of abnormal amyloid beta (Aß), along with hyperphosphorylation of tau, oxidative stress, low acetylcholine (ACh) level and biometal dyshomeostasis. Due to the complex nature of AD aetiology, active research is required in the areas of development of multitarget drugs with 2 or more complementary biological functions, as they might represent significant progress in the AD treatment. Interestingly, it has been found that TV 3326 (i.e. ladostigil) is regarded as a novel therapeutic agent since it has the potential to cause inhibition of monoamine oxidase (MAO) A and B, and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain. Furthermore, it has the capacity to reverse memory impairments, which further suggests the ability of this drug to elevate cholinergic activity in the brain. SUMMARY: TV 3326 can avert oxidative-nitrative stress and gliosis. It has also been confirmed that TV 3326 contains neuroprotective and anti-apoptotic properties. Therefore, this distinctive combined inhibition of ChE and MAO along with its neuroprotective property makes TV 3326 a useful drug in the treatment of AD.

Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial.

BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

Dual use of bronchodilators versus monotherapy, and its impact on pulmonary rehabilitation in COPD patients.

INTRODUCTION: Long-acting bronchodilators are the therapy with the best evidence for treating stable chronic obstructive pulmonary disease (COPD). Long-acting combinations of ß2 agonists and anticholinergics (LABA-LAMA) are recommended in advanced stages when monotherapy has not generated the desired effects. Pulmonary Rehabilitation (PR) is an effective non-pharmacological strategy. The aim of this study was to compare the results obtained in patients with COPD who received monotherapy versus dual bronchodilator therapy in terms of functional aerobic capacity, symptoms and quality of life. MATERIALS AND METHODS: Prospective non randomized intervention study; the patients were divided into two groups: in one group patients were treated with LAMA (Tiotropium Bromide, 5 µg every 24 h) and in the other group patients were treated with LABA + LAMA (Indacaterol/Glycopyrronium, 110/50 µg once a day). After receiving the concept of pulmonology, patients were intervened with 8 weeks of PR. The study was approved by the committee of the Clinica Neumológica del Pacifico in Cali and the Institución Universitaria Escuela Nacional del Deporte, Colombia. To determine the differences, t pair test for intragroup, and t-test was performed for intergroup analysis. For all tests, a p-value <0.05 was considered as statistically significant. RESULTS: 53 patients participated in this study, of which 20 were assigned to the LAMA group and 33 to the LAMA + LABA group. Patients in both groups presented changes in the distance of the 6MWT, in the VO2e, dyspnea and in all the SGRQ domains. Regarding the comparison between groups, there were found no differences in the variables at the beginning of the PR and significant differences (p < 0.05) at the end of the 8 week-period in favor of the LABA + LAMA group, in symptoms with the mMRC scale, functional aerobic capacity with the 6 min walking test and in health related quality of life specifically in the symptoms domain, where the dual therapy group obtained better results. CONCLUSION: The addition of LABA to the treatment with LAMA showed better response results compared with the monotherapy in patients with COPD who attended PR.

Indacaterol/glycopyrronium versus tiotropium or glycopyrronium in long-acting bronchodilator-naïve COPD patients: A pooled analysis.

BACKGROUND AND OBJECTIVE: Indacaterol/glycopyrronium (IND/GLY) 110/50 µg once daily (q.d.) has demonstrated greater improvements in lung function, patient-reported outcomes and lower exacerbation rates versus mono long-acting muscarinic antagonists (LAMA) in chronic obstructive pulmonary disease (COPD) patients. However, data are limited on initial treatment with IND/GLY 110/50 µg q.d. versus mono LAMA in COPD patients, not previously on maintenance treatment with long-acting bronchodilators (LABD). METHODS: A pooled analysis of ARISE, SHINE and SPARK trials was conducted to evaluate the efficacy of IND/GLY 110/50 µg q.d. versus open-label (OL) tiotropium (TIO) 18 µg q.d. and GLY 50 µg q.d. in COPD patients, not on maintenance treatment with LABD at study entry (LABD-naïve). Efficacy was assessed after 24/26 weeks of treatment. RESULTS: In total, 998 LABD-naïve patients were included (IND/GLY: 353; OL TIO: 328; GLY: 317). Patients treated with IND/GLY 110/50 µg q.d. experienced greater improvements in trough forced expiratory volume in 1 s (FEV1 ) versus OL TIO 18 µg q.d. (least squares mean treatment difference (Δ): 0.086 L) and GLY 50 µg q.d. (Δ: 0.080 L) after 24/26 weeks. Improvements in electronic diary (eDiary) symptom scores, transition dyspnoea index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score and rescue medication use were also greater with IND/GLY versus OL TIO and GLY. Greater proportion of patients achieved minimal clinically important difference in trough FEV1 , TDI and SGRQ with IND/GLY versus OL TIO and GLY. CONCLUSION: LABD-naïve patients treated with IND/GLY 110/50 µg q.d. achieved improvements in lung function, daily symptoms, dyspnoea, health-related quality of life and rescue medication use versus those who received single LAMA.

Novel acceptor-donor-acceptor structured small molecule-based nanoparticles for highly efficient photothermal therapy.

Herein, acceptor-donor-acceptor structured small molecule (ITIC) based nanoparticles (NPs) were explored for photothermal therapy application. ITIC NPs show red-shift absorption in the near-infrared region, high photostability, and high photothermal conversion efficiency under laser irradiation, presenting both excellent cancer cell cytotoxicity in vitro and tumor ablation in vivo.

Fixed-Dose Combinations of Long-Acting Bronchodilators for the Management of COPD: Global and Asian Perspectives.

Maintenance bronchodilator therapy with long-acting ß-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is the cornerstone treatment for patients with stable chronic obstructive pulmonary disease (COPD). Fixed-dose combinations (FDCs) of LABA/LAMA are recommended for the majority of symptomatic COPD patients by global guidelines; regional guidelines such as the Japanese and Korean guidelines also provide similar recommendations for the use of LABA/LAMA FDCs. This review comprehensively describes the latest clinical evidence from key studies on the efficacy and safety of four approved LABA/LAMA fixed-dose combinations: indacaterol/glycopyrronium, vilanterol/umeclidinium, formoterol/aclidinium, and olodaterol/tiotropium. Additionally, in this review we describe the rationale behind the use of LABA/LAMA FDC therapy, key findings from the preclinical and clinical trial evaluation of respective LABA and LAMA monocomponents, and the efficacy and safety of LABA/LAMA FDCs. Special emphasis is placed on the clinical evidence for the monocomponents and LABA/LAMA FDCs from the Asian population. This detailed overview of the efficacy and safety of LABA/LAMA FDCs in global and Asian COPD patients is envisaged to provide a better understanding of the benefits of these therapies and to inform healthcare providers and patients on their appropriate use.Funding: Novartis Pharma K.K.

When Two Drugs Are Better than Three: Re-Modulating the Therapeutic Plan of a Chronic Obstructive Pulmonary Disease Patient.

We present the case of a 77-year-old man diagnosed with chronic obstructive pulmonary disease (COPD) stage D with emphysema phenotype and treated with triple therapy (salmeterol, fluticasone propionate, and tiotropium) for 1 year without relevant improvements in exertional dyspnea and disease impact. After switching to combination therapy with a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (indacaterol/glycopyrronium), we observed, in a 3-month period, a substantial reduction of the modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT) scores. Moreover, the patient reported a reduction of dynamic hyperinflation and an improvement of ventilatory response to exercise.

Similar treatment outcomes with Ginkgo biloba extract EGb 761 and donepezil in Alzheimer's dementia in very old age: A retrospective observational study.

OBJECTIVE: To provide pilot data for the safety and efficacy of EGb 761 in the oldest-old patients (aged 80 or older). MATERIALS AND METHODS: In a retrospective analysis, we compared treatment outcomes with EGb 761 or donepezil over 12 months in 189 patients aged 80 years or older suffering from Alzheimer's disease (AD). RESULTS: Over 12 months, there was no significant difference in cognitive decline, measured with the mini-mental state examination (MMSE) score, between donepezil and EGb 761 (p = 0.31). We found more adverse events in the donepezil group. CONCLUSION: Results suggest similar effects on cognitive symptoms from the use of EGb 761 in the treatment of dementia in AD together with favorable safety compared to donepezil.
.

Comparisons between traditional medicines and pharmacotherapies for Alzheimer disease: A systematic review and meta-analysis of cognitive outcomes.

OBJECTIVES: To evaluate the clinical evidence for traditional medicines (TMs) used in East Asia on measures of cognition in Alzheimer disease, determine the effect sizes at different time points for the TMs and pharmacotherapies, and assess the tolerability of the TMs. METHODS: We searched 12 databases in English, Chinese, and Japanese for eligible randomised controlled trials that compared orally administered TMs with pharmacotherapy and reported cognitive outcomes. Meta-analyses were conducted for Alzheimer's Disease Assessment Scale-cognitive subscale and/or Mini-Mental State Examination (MMSE). Mean differences and 95% confidence intervals were calculated to evaluate treatment effects. RESULTS: Thirty randomised controlled trials met inclusion criteria. Twenty-nine compared TMs with donepezil. Single studies provided comparisons with galantamine, rivastigmine, or memantine. There were no significant differences between the TM and donepezil groups at 12 or 24 weeks for Alzheimer's Disease Assessment Scale-cognitive subscale or MMSE. Improvements over baseline were significant for MMSE at 12 and 24 weeks within the TM and donepezil groups and remained significant at 1 year. Effect sizes were reduced in the 3 double-blind studies. At 24 weeks, donepezil 10 mg/d generally produced greater improvements in MMSE than 5 mg/d. Tolerability reporting was incomplete and inconsistent between studies. CONCLUSIONS: The results suggested that the clinical benefits of the TMs were not less than donepezil at comparable time points, with both groups showing improvements. However, lack of blinding in most studies and other design and measurement issues are likely to have resulted in overestimation of effect sizes in both groups. Further well-designed studies are needed.

Indacaterol/glycopyrronium: a dual bronchodilator for COPD.

Indacaterol/glycopyrronium (IND/GLY) 110/50mcg was the first once-daily, long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) approved in Europe for the treatment of chronic obstructive pulmonary disease (COPD). Development of IND/GLY was driven by the need to improve the standard of care for patients with this disease, in terms of symptom control and exacerbation frequency. IGNITE, an adaptive, comprehensive, and innovative Phase 3 development program, demonstrated the efficacy of IND/GLY in optimising bronchodilation, reducing symptoms, and reducing exacerbations in patients with COPD. IGNITE challenged contemporary thinking about the pharmacological treatment and management of patients with this disease.

Dual bronchodilator therapy for chronic obstructive pulmonary disease: evidence for the efficacy and Safety of fixed dose combination treatments in the setting of recent guideline updates.

PURPOSE OF REVIEW: Recent updates to the GOLD guidelines emphasize the use of combination LABA and LAMA bronchodilators for patients with chronic obstructive pulmonary disease with persistent dyspnea despite monotherapy or frequent exacerbations despite LAMA monotherapy. There are several commercially available LABA/LAMA fixed dose combination inhalers, which are likely to become the principle therapy for many patients with COPD. RECENT FINDINGS: In the last 4 years, there have been a number of large clinical trials evaluating the efficacy and safety of combined LAMA and LABA bronchodilators. LAMA/LABA fixed dose combination therapies have consistently demonstrated clinically significant improvements to airway obstruction, dyspnea, and quality of life whenever compared with placebo, and more modest improvements compared with bronchodilator monotherapies and combined bronchodilator/inhaled corticosteroid therapy. SUMMARY: New guidelines emphasize combination bronchodilators as a mainstay of therapy for many patients with symptomatic COPD and there are several new combination bronchodilator therapies available to patients. It is important for physicians and patients to understand the range and degree of expected clinical effects and the safety profiles of these new medications.

Predicting treatable traits for long-acting bronchodilators in patients with stable COPD.

PURPOSE: There is currently no measure to predict a treatability of long-acting ß-2 agonist (LABA) or long-acting muscarinic antagonist (LAMA) in patients with chronic obstructive pulmonary disease (COPD). We aimed to build prediction models for the treatment response to these bronchodilators, in order to determine the most responsive medication for patients with COPD. METHODS: We performed a prospective open-label crossover study, in which each long-acting bronchodilator was given in a random order to 65 patients with stable COPD for 4 weeks, with a 4-week washout period in between. We analyzed 14 baseline clinical traits, expression profiles of 31,426 gene transcripts, and damaged-gene scores of 6,464 genes acquired from leukocytes. The gene expression profiles were measured by RNA microarray and the damaged-gene scores were obtained after DNA exome sequencing. Linear regression analyses were performed to build prediction models after using factor and correlation analyses. RESULTS: Using a prediction model for a LABA, traits found associated with the treatment response were post-bronchodilator forced expiratory volume in 1 second, bronchodilator reversibility (BDR) to salbutamol, expression of three genes (CLN8, PCSK5, and SKP2), and damage scores of four genes (EPG5, FNBP4, SCN10A, and SPTBN5) (R2=0.512, p<0.001). Traits associated with the treatment response to a LAMA were COPD assessment test score, BDR, expression of four genes (C1orf115, KIAA1618, PRKX, and RHOQ) and damage scores of three genes (FBN3, FDFT1, and ZBED6) (R2=0.575, p<0.001). The prediction models consisting only of clinical traits appeared too weak to predict the treatment response, with R2=0.231 for the LABA model and R2=0.121 for the LAMA model. CONCLUSION: Adding the expressions of genes and damaged-gene scores to the clinical traits may improve the predictability of treatment response to long-acting bronchodilators.

[Evaluation of effect of indacaterol (Onbrez) and/or glycopyrronium (Seebri) treatment on Quality of Life of COPD patients in medical practice in Poland - observational study (OSQO)]. / Ocena wplywu leczenia indakaterolem (Onbrez) i/lub glikopironium (Seebri) na jakosc zycia chorych na przewlekla obturacyjna chorobe pluc w praktyce medycznej w Polsce ­ badanie obserwacyjne (OSQO).

Indacaterol, as well glycopyronium has been reimbursed lately in Poland, so patients have a greater access to this treatment in medical practice. Physicians do not realize the potential benefit of once daily ultra-LABA indacaterol and/or modern LAMA with fast-acting glycopyrronium on treatment results. AIM: The aim of the study was to evaluate the impact of routinely administered treatment with either indacaterol (Onbrez) or glycopyrronium (Seebri) or both on patient reported outcomes in form of the health status (CCQ score - clinical COPD questionnaire) and level of dyspnoea (mMRC - modified Medical Research Council) in treatment naive COPD patients after the change of treatment as addon from any other COPD treatment in "real life" settings. MATERIALS AND METHODS: This study was designed as an observational, non-interventional and multicenter project in COPD patients being treated with Onbrez and/or Seebri in 32 medical centers in Poland. The observation period covered 6 months from the first taking of Onbrez and/or Seebri. No diagnostic or monitoring or treatment procedures have been applied to the patients, other than those which are applied in the course of standard, current practice. The total number of enrolled patients was 633. Because of inability of verification the medical records or failure to meet data collection requirements 587 patients enrolled to the registry has been evaluated. Within this number of patients 171 had delayed the time of visits or they had not second visit. Due to therapy change additional 20 patients has been withdrawn. 396 patients were taken for the final analysis. RESULTS: Improvement of mMRC and CCQ scores was observed in all treatment groups e.g. indacaterol solely, glycopyrronium solely and combination therapy of indacaterol and glypyrronium. CONCLUSIONS: The study revealed that the best results can be achieved with combination therapy accordingly with clinical recommendation for COPD treatment (GOLD). The results have been achieved in the real world settings, showing that this treatment may be used in daily routine practice by general practitioners.

Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals.

Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.

GOLD 2017 treatment pathways in 'real life': An analysis of the DACCORD observational study.

INTRODUCTION: The 2017 update to the Global Initiative for Obstructive Lung Disease (GOLD) strategy document includes recommendations for treatment intensification or step-down in chronic obstructive pulmonary disease (COPD), although recognises that limited supporting information is available. DACCORD is an ongoing observational, non-interventional study, recruiting patients following COPD maintenance treatment change or initiation, a subset of whom were receiving a long-acting ß2-agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) on entry. Since there were no requirements in terms of prior medication (and no washout before commencing LABA/LAMA FDC), this provides an opportunity to generate 'real world' data to test the GOLD 2017 recommendations. METHODS: To reduce heterogeneity, the current analyses include patients receiving indacaterol/glycopyrronium at baseline, and who, prior to the study, were receiving no COPD maintenance medication ('none'), LABA or LAMA monotherapy ('mono'), LABA plus inhaled corticosteroid (ICS; 'LABA/ICS'), or triple therapy ('triple'). At the baseline visit, data collected included: demographic and disease characteristics; COPD Assessment Test (CAT); and exacerbations in the 6 months prior to entry. At 3, 6, 9 and 12 months data on exacerbations were collected, with CAT recorded at 3 and 12 months. RESULTS: A total of 2724 patients were included in the baseline analyses: 795, 954, 598 and 377 in the 'none', 'mono', 'LABA/ICS' and 'triple' subgroups, respectively. There were no clinically relevant differences in baseline demographics between the four groups. In terms of disease characteristics, the 'triple' group had the highest proportion of patients with a disease duration of more than 1 year since diagnosis and with severe/very severe airflow limitation, but a similar percentage of non-exacerbators compared to the 'none' group. Over the 1-year follow-up, the majority of patients in all four subgroups did not exacerbate (exacerbation rates 0.16, 0.19, 0.21, and 0.26 in the 'none', 'mono', 'LABA/ICS' and 'triple' groups, respectively). At 12 months, 61.4%, 65.0%, 71.0% and 52.4% of patients had a clinically relevant improvement in CAT score. CONCLUSIONS: Overall, the results support the GOLD recommendations in suggesting that a switch from a mono-bronchodilator or LABA plus ICS to LABA/LAMA FDC is a valid treatment option for patients with COPD. The results also validate the use of a LABA/LAMA FDC as initial maintenance treatment for COPD, and provide first 'real world' evidence to support the newly added 'step down' recommendation (from triple to LABA/LAMA FDC).

Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties.

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 µM) and hMAO-B (IC50 = 4.3 µM), significant antioxidant activity (41.33 µM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aß1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.