Vitamin D as Modulator of Drug Concentrations: A Study on Two Italian Cohorts of People Living with HIV Administered with Efavirenz.

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.

Therapeutic Success of Tiotropium/Olodaterol, Measured Using the Clinical COPD Questionnaire (CCQ), in Routine Clinical Practice: A Multinational Non-Interventional Study.

BACKGROUND: The Clinical COPD Questionnaire (CCQ) is a simple patient-reported tool to measure clinical control of chronic obstructive pulmonary disease (COPD). OBJECTIVE: This open-label, single-arm, non-interventional study (NCT03663569) investigated changes in CCQ score during treatment with tiotropium/olodaterol in clinical practice. METHODS: Data were included from consenting COPD patients, enrolled in Bulgaria, Czech Republic, Hungary, Israel, Lithuania, Poland, Romania, Russia, Slovenia, Switzerland and Ukraine, who were receiving a new prescription for tiotropium/olodaterol according to the treating physician in a real-world environment. The primary endpoint was the occurrence of therapeutic success, defined as a 0.4-point decrease in CCQ score after treatment with tiotropium/olodaterol for approximately 6 weeks. RESULTS: Overall, 4819 patients were treated; baseline and Week 6 CCQ scores were available for 4700 patients, mostly classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) B (51.6%) or D (42.7%). After 6 weeks' treatment, 81.4% (95% confidence interval [95% CI] 80.24-82.49) of patients achieved therapeutic success; mean improvement in overall CCQ score was 1.02 points (95% CI 1.00-1.05). Improved CCQ score was seen in 92.2% of patients (95% CI 91.43-92.98), 2.5% had no change and 5.3% showed a worsening. When stratified by prior treatment, the greatest benefit was seen in treatment-naïve patients, with 85.7% achieving therapeutic success, compared with 79.5% of those pretreated with long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) and 74.2% of those pretreated with LABA or long-acting muscarinic antagonist (LAMA) monotherapy. Overall, rescue medication decreased by 1.25 puffs/day (95% CI 1.19-1.31) versus baseline. In total, 29 patients (0.6%) reported drug-related adverse events and 7 patients reported serious adverse events (0.15%). CONCLUSION: In 4700 COPD patients, 6 weeks' treatment with tiotropium/olodaterol, as initial treatment or follow-up to LAMA or LABA monotherapy or LABA/ICS, improved CCQ and decreased rescue medication use. The adverse event profile was consistent with the known safety profile of tiotropium/olodaterol.

Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial.

BACKGROUND: In patients co-infected with HIV and tuberculosis, antiretroviral therapy options are limited due to drug-drug interactions with rifampicin. A previous phase 2 trial indicated that raltegravir 400 mg twice a day or efavirenz 600 mg once a day might have similar virological efficacy in patients given rifampicin. In this phase 3 trial, we assessed the non-inferiority of raltegravir to efavirenz. METHODS: We did a multicentre, open-label, non-inferiority, randomised, phase 3 trial at six sites in Côte d'Ivoire, Brazil, France, Mozambique, and Vietnam. We included antiretroviral therapy (ART)-naive adults (aged ≥18 years) with confirmed HIV-1 infection and bacteriologically confirmed or clinically diagnosed tuberculosis who had initiated rifampicin-containing tuberculosis treatment within the past 8 weeks. Using computerised random numbers, we randomly assigned participants (1:1; stratified by country) to receive raltegravir 400 mg twice daily or efavirenz 600 mg once daily, both in combination with tenofovir and lamivudine. The primary outcome was the proportion of patients with virological suppression at week 48 (defined as plasma HIV RNA concentration <50 copies per mL). The prespecified non-inferiority margin was 12%. The primary outcome was assessed in the intention-to-treat population, which included all randomly assigned patients (excluding two patients with HIV-2 infection and one patient with HIV-1 RNA concentration of <50 copies per mL at inclusion), and the on-treatment population, which included all patients in the intention-to-treat population who initiated treatment and were continuing allocated treatment at week 48, and patients who had discontinued allocated treatment due to death or virological failure. Safety was assessed in all patients who received at least one dose of the assigned treatment regimen. This study is registered with ClinicalTrials.gov, NCT02273765. FINDINGS: Between Sept 28, 2015, and Jan 5, 2018, 460 participants were randomly assigned to raltegravir (n=230) or efavirenz (n=230), of whom 457 patients (230 patients in the raltegravir group; 227 patients in the efavirenz group) were included in the intention-to-treat analysis and 410 (206 patients in the raltegravir group; 204 patients in the efavirenz group) in the on-treatment analysis. At baseline, the median CD4 count was 103 cells per µL and median plasma HIV RNA concentration was 5·5 log10 copies per mL (IQR 5·0-5·8). 310 (68%) of 457 participants had bacteriologically-confirmed tuberculosis. In the intention-to-treat population, at week 48, 140 (61%) of 230 participants in the raltegravir group and 150 (66%) of 227 patients in the efavirenz had achieved virological suppression (between-group difference -5·2% [95% CI -14·0 to 3·6]), thus raltegravir did not meet the predefined criterion for non-inferiority. The most frequent adverse events were HIV-associated non-AIDS illnesses (eight [3%] of 229 patients in the raltegravir group; 21 [9%] of 230 patients in the efavirenz group) and AIDS-defining illnesses (ten [4%] patients in the raltegravir group; 13 [6%] patients in the efavirenz group). 58 (25%) of 229 patients in raltegravir group and 66 (29%) of 230 patients in the efavirenz group had grade 3 or 4 adverse events. 26 (6%) of 457 patients died during follow-up: 14 in the efavirenz group and 12 in the raltegravir group. INTERPRETATION: In patients with HIV given tuberculosis treatment, non-inferiority of raltegravir compared with efavirenz was not shown. Raltegravir was well tolerated and could be considered as an option, but only in selected patients. FUNDING: National French Agency for AIDS Research, Ministry of Health in Brazil, Merck. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.

The combination of low level laser therapy and efavirenz drastically reduces HIV infection in TZM-bl cells.

BACKGROUND: Human immunodeficiency virus (HIV) infection remains a global health challenge despite the use of antiretroviral therapy, which has led to a significant decline in the mortality rates. Owing to the unavailability of an effective treatment to completely eradicate the virus, researchers continue to explore new methods. Low level laser therapy (LLLT) has been widely used to treat different medical conditions and involves the exposure of cells or tissues to low levels of red and near infrared light. The study aimed to determine the effect of combining two unrelated therapies on HIV infection in TZM-bl cells. METHODS: In the current study, LLLT was combined with efavirenz, an HIV reverse transcriptase inhibitor to establish their impact on HIV infection in TZM-bl cells. Both the HIV infected and uninfected cells were laser irradiated using a wavelength of 640 nm with fluencies of 2-10 J/cm2. RESULTS: The impact of HIV, efavirenz and irradiation were determined 24 h post irradiation using biological assays. Luciferase assay results showed that the combination of LLLT and efavirenz significantly reduced HIV infection in cells, despite the undesirable effects observed in the cells as demonstrated by cell morphology, proliferation and cell integrity assay. Flow cytometry results demonstrated that cell death was mainly through necrosis while fluorescence microscopy showed the production of reactive oxygen species in HIV infected cells. CONCLUSION: Efavirenz and LLLT significantly reduced HIV infection in TZM-bl cells. Furthermore, the death of HIV infected cells was due to necrosis.

Effects of Tiotropium/Olodaterol on Activity-Related Breathlessness, Exercise Endurance and Physical Activity in Patients with COPD: Narrative Review with Meta-/Pooled Analyses.

One of the most debilitating symptoms of chronic obstructive pulmonary disease (COPD) is breathlessness, which leads to avoidance of physical activities in daily living and hastens clinical deterioration. Treatment of patients with COPD with inhaled long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) combination therapy improves airflow limitation, reduces breathlessness compared with LAMA or LABA monotherapies, and improves health status and quality of life. A large clinical trial programme focusing on the effects of tiotropium/olodaterol combination therapy demonstrated that this LAMA/LABA combination improves lung function and reduces hyperinflation (assessed by serial inspiratory capacity measurements) compared with either tiotropium alone or placebo in patients with COPD. Tiotropium/olodaterol also increases exercise endurance capacity and improves patient perception of the intensity of breathlessness compared with placebo. In this narrative review, we focus on the relationship between improving symptoms during activity, the ability to remain active in daily life and how this may impact quality of life. We consider the benefits of therapy optimisation by means of dual bronchodilation with tiotropium/olodaterol, and present new data from meta-analyses/pooled analyses showing that tiotropium/olodaterol improves inspiratory capacity compared with placebo and tiotropium and improves exercise endurance time compared with placebo after 6 weeks of treatment. We also discuss the importance of taking a holistic approach to improving physical activity, including pulmonary rehabilitation and exercise programmes in parallel with bronchodilator therapy and psychological programmes to support behaviour change.

Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD: a Post Hoc Analysis of the TONADO® Trials.

INTRODUCTION: Since chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, a composite endpoint of clinically important deterioration (CID) may provide a more holistic assessment of treatment efficacy. We compared long-acting muscarinic antagonist/long-acting ß2-agonist combination therapy with tiotropium/olodaterol versus tiotropium alone using a composite endpoint for CID. CID was evaluated overall and in patients with low exacerbation history (at most one moderate exacerbation in the past year [not leading to hospitalisation]), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 patients and maintenance-naïve patients with COPD. We assessed whether early treatment optimisation is more effective with tiotropium/olodaterol versus tiotropium in delaying and reducing the risk of CID. METHODS: Data were analysed from 2055 patients treated with either tiotropium/olodaterol 5/5 µg or tiotropium 5 µg (delivered via Respimat®) in two replicate, 52-week, parallel-group, double-blind studies (TONADO® 1/2). CID was defined as a decline of at least 0.1 L from baseline in trough forced expiratory volume in 1 s, increase from baseline of at least 4 units in St. George's Respiratory Questionnaire score, or moderate/severe exacerbation. Time to first occurrence of one of these events was recorded as time to first CID. RESULTS: Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P < 0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P < 0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P < 0.0001) and maintenance-naïve patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030). CONCLUSION: In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naïve patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: TONADO® 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011).

COPD is a complicated disease that deteriorates over time. Worsening of COPD is associated with the lungs working less effectively, a fall in quality of life and a rise in sudden flare-ups of the disease. In this study, we looked at lung function, quality of life and flare-ups together using a measure called "clinically important deterioration" (CID). We looked at 2055 people with COPD to compare the effects of taking two bronchodilators (tiotropium and olodaterol) against taking one bronchodilator (tiotropium alone). Bronchodilators are a type of inhaled medication that relax the muscles in the lungs and widen airways, making it easier to breathe. They have also been shown to reduce sudden flare-ups of COPD. Across a wide range of people with COPD, we found that treatment with tiotropium/olodaterol reduced the risk of a CID compared with tiotropium alone. This includes in those patients at an early stage of disease, who may benefit from finding the best treatment option for them as early as possible.

Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies.

Prostate cancer is a major cause of death among men worldwide. Recent preclinical evidence implicates cannabinoids as powerful regulators of cell growth and differentiation, as well as potential anti-cancer agents. The aim of this review was to evaluate the effect of cannabinoids on in vivo prostate cancer models. The databases searched included PubMed, Embase, Scopus, and Web of Science from inception to August 2020. Articles reporting on the effect of cannabinoids on prostate cancer were deemed eligible. We identified six studies that were all found to be based on in vivo/xenograft animal models. Results: In PC3 and DU145 xenografts, WIN55,212-2 reduced cell proliferation in a dose-dependent manner. Furthermore, in LNCaP xenografts, WIN55,212-2 reduced cell proliferation by 66-69%. PM49, which is a synthetic cannabinoid quinone, was also found to result in a significant inhibition of tumor growth of up to 90% in xenograft models of LNCaP and 40% in xenograft models of PC3 cells, respectively. All studies have reported that the treatment of prostate cancers in in vivo/xenograft models with various cannabinoids decreased the size of the tumor, the outcomes of which depended on the dose and length of treatment. Within the limitation of these identified studies, cannabinoids were shown to reduce the size of prostate cancer tumors in animal models. However, further well-designed and controlled animal studies are warranted to confirm these findings.

Acupuncture reduces pain in rats with osteoarthritis by inhibiting MCP2/CCR2 signaling pathway.

Acupuncture is an emerging alternative therapy that has been beneficial for the pain of osteoarthritis (OA). However, the underlying mechanism of protective effect remains unclear. MCP1/CCR2 axis can be stimulated in various periods of OA, and we hypothesize that acupuncture may treat OA by regulating the MCP1/CCR2 axis. This study aimed to explore the effect of acupuncture at points ST35 and ST36 on the effects of hyperalgesia and cartilage in OA rats including the expression of chemokines, nerve growth factor (NGF), and inflammatory-related proteins. OA was induced in male Sprague-Dawley rats by anterior cruciate ligament transection at the right knee. The first acupuncture intervention was performed on the seventh day after surgery and once a day for seven weeks. The knee-pain-related behaviors, histology, and related protein were examined in this study. We have found that electroacupuncture at ST35 and ST36 can significantly alleviate the hyperalgesia and cartilage degeneration as well as reducing nerve sprouting in OA knee joint. Moreover, acupuncture treatment may inhibit the MCP1/CCR2 axis as well as down-regulate inflaming factor and NGF in cartilage and synovial tissue. The data presented here indicate that acupuncture exerts a protective effect against hyperalgesia and cartilage degeneration, and the mechanism might involve in chemokines and NGF pathway.

COPD Maintenance Therapy with Tiotropium/Olodaterol Compared with Tiotropium: An Analysis in the Absence of Additional ICS Therapy.

The American Thoracic Society guidelines recommend long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilation over LAMA or LABA monotherapy as maintenance therapy for patients with chronic obstructive pulmonary disease suffering from dyspnea or exercise intolerance. Previous studies, which included patients receiving background inhaled corticosteroids (ICS), have shown the benefits of dual bronchodilation over monotherapy. This analysis aimed to confirm the benefits of LAMA/LABA over LAMA alone, without any confounding effects from ICS use. This pooled post hoc analysis compared the efficacy of tiotropium/olodaterol with tiotropium alone in patients from the TONADO® and OTEMTO® clinical trials who were not receiving ICS at study entry or during the studies. We analyzed change from baseline in trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) score and Transition Dyspnea Index (TDI) score in all patients, by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, baseline SGRQ score, and Baseline Dyspnea Index score. In this analysis of 1596 patients, tiotropium/olodaterol improved trough FEV1, SGRQ and TDI compared with tiotropium alone. The observed mean differences were: trough FEV1, 0.054 L (95% confidence interval [CI] 0.036, 0.073; p < 0.001); SGRQ, -1.918 (95% CI -2.994, -0.843; p < 0.001); and TDI, 0.575 (95% CI 0.301, 0.848; p < 0.001). Similar improvements were seen in each of the subgroup analyses. Tiotropium/olodaterol therapy significantly improved lung function, symptoms and health status compared with tiotropium alone. In a population free from ICS treatment, these data confirm the benefits of dual bronchodilation versus monotherapy.

Efficacy of Tiotropium/Olodaterol Compared with Tiotropium as a First-Line Maintenance Treatment in Patients with COPD Who Are Naïve to LAMA, LABA and ICS: Pooled Analysis of Four Clinical Trials.

INTRODUCTION: The efficacy of tiotropium/olodaterol compared with tiotropium in patients with chronic obstructive pulmonary disease (COPD) has been demonstrated in a large clinical programme. Currently, randomised controlled trial (RCT) data on dual bronchodilation as first-line maintenance therapy are limited. In this post hoc analysis of pooled data from four RCTs, we compared the efficacy of tiotropium/olodaterol versus tiotropium as maintenance therapy in patients with COPD who were not receiving maintenance treatment with long-acting muscarinic antagonists (LAMAs), long-acting ß2-agonists (LABAs) or inhaled corticosteroids (ICS) ("maintenance naïve") at study entry. METHODS: TONADO® 1/2 (52 weeks) and OTEMTO® 1/2 (12 weeks) were phase III RCTs in patients with COPD. TONADO 1/2 and OTEMTO 1/2 enrolled patients with post-bronchodilator forced expiratory volume in 1 s (FEV1) < 80% predicted (lower limit FEV1 ≥ 30% in OTEMTO 1/2 only). We examined the effect of tiotropium/olodaterol 5/5 µg versus tiotropium 5 µg on trough FEV1 response, St. George's Respiratory Questionnaire (SGRQ) total score and Transition Dyspnoea Index (TDI) focal score at 12 weeks in four pooled studies. RESULTS: The pooled analysis included 1078 maintenance-naïve patients. There were significant improvements with tiotropium/olodaterol versus tiotropium in trough FEV1 [0.056 L; 95% confidence interval (CI) 0.033, 0.079; P < 0.0001], SGRQ score (- 1.780; 95% CI - 3.126 to - 0.434; P = 0.0096) and TDI score (0.409; 95% CI 0.077, 0.741; P = 0.0158) at week 12. For patients receiving tiotropium/olodaterol, the odds of achieving a minimal clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 L, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) were higher versus tiotropium. CONCLUSIONS: In patients who were maintenance naïve at baseline, treatment initiation with tiotropium/olodaterol resulted in greater improvements in lung function, health status and dyspnoea severity compared with tiotropium alone, without compromising patient safety. These results support the use of dual bronchodilation with tiotropium/olodaterol as first-line maintenance treatment in patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov: TONADO® 1 and 2 (NCT01431274 and NCT01431287, registered 8 September 2011) and OTEMTO® 1 and 2 (NCT01964352 and NCT02006732, registered 14 October 2013).

People with chronic obstructive pulmonary disease (COPD) often have problems breathing, which can make it difficult to carry out daily physical tasks. Bronchodilators are a type of medication that relax the muscles in the lungs and widen airways, making it easier to breathe. Evidence suggests that using a combination of two different bronchodilators is more effective than using one bronchodilator on its own.In this article, we look at four large studies that compared the effects of at least 12 weeks of treatment with two bronchodilators (tiotropium/olodaterol) with tiotropium on its own in people who had not received any previous medication for their COPD. The results suggest that people who were treated with tiotropium and olodaterol together had significantly better improvements in lung function, quality of life and breathlessness after 12 weeks than those taking tiotropium alone, without compromising safety. Overall, people treated with tiotropium/olodaterol were 60% more likely to experience a meaningful improvement in at least one of these areas compared with those on tiotropium alone. These results support the use of tiotropium and olodaterol together as a first medication for COPD.

Development of Pediatric Orodispersible Tablets Based on Efavirenz as a New Therapeutic Alternative.

BACKGROUND: Efavirenz is the most used medication in the treatment of Acquired Immunodeficiency Syndrome (AIDS). The limited number of pediatric antiretroviral formulations approved by regulatory agencies is the most significant obstacle to adequate and efficient pharmacotherapy for this group of patients. The efavirenz has excellent therapeutic potential, but has low aqueous solubility/bioavailability. METHODS: To minimize these limitations, multicomponent systems with ß-cyclodextrin and polyvinylpyrrolidone K-30 were obtained. Due to the limited number of pediatric antiretroviral formulations, the development of a pediatric orodispersible tablet is an alternative that is thought easy to administer, since it disintegrates rapidly in the oral cavity. The multicomponent systems were obtained by the method of kneading and characterized by solubility test, X-ray diffraction, differential scanning calorimetry and infrared absorption spectroscopy by Fourier transform. The orodispersible tablets were prepared by direct compression. The quality control of hardness, friability, disintegration, and dissolution was performed. The influence of the components of the formulation on the characteristics of the tablets was evaluated through a 22 factorial design added with three central points, to compare the effect of the dependent variables on the responses. RESULTS: An increase in drug solubility was observed, with a decrease in crystallinity. Besides that, an excellent dissolution profile presented with more than 83% of the drug's content dissolved in less than 15 minutes. Satisfactory disintegration time and friability were observed. CONCLUSION: It was observed that reduced concentrations of mannitol decreased the hardness and disintegration time of the formulations. The orodispersible tablet composed of efavirenz: ß- cyclodextrin: polyvinylpyrrolidone, favors greater absorption and bioavailability. It has several advantages for pediatric patients, as the dosage form disintegrates quickly in the mouth and does not require water for administration, thereby improving patient compliance with the treatment.

Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO® and OTEMTO® Studies.

INTRODUCTION: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting ß2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. METHODS: TONADO® 1&2 and OTEMTO® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). RESULTS: Overall, 151 patients received tiotropium; 148 received tiotropium/olodaterol. Mean differences from baseline with tiotropium/olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV1, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/olodaterol versus tiotropium for trough FEV1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046). CONCLUSION: In patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/olodaterol in patients receiving tiotropium alone. TRIAL REGISTRATION: TONADO® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).

Global recommendations suggest that people with chronic obstructive pulmonary disease (COPD) can start treatment with one of two types of inhaled medicine: either a long-acting muscarinic antagonist (LAMA) or a long-acting ß₂-agonist (LABA). Doctors can also prescribe these treatments together (LAMA/LABA) if needed. To help doctors decide whether to prescribe single or combined treatment, we looked at people with COPD who were taking LAMA alone at the beginning of two large studies (TONADO^® and OTEMTO^®). In these studies, people with COPD could either stay on LAMA alone (tiotropium) or switch to combined LAMA/LABA treatment (tiotropium/olodaterol). We looked to see if there were any changes in the functioning of the lungs (measured using forced expiratory volume in 1 s), quality of life (measured using the St. George's Respiratory Questionnaire) or breathlessness (measured using the Transition Dyspnoea Index) between the start of the study and after 12 weeks of treatment. We showed that lung function, health-related quality of life and breathlessness were significantly better in people taking tiotropium/olodaterol for 12 weeks compared with those on tiotropium alone. Overall, our results support global recommendations and suggest that many people with COPD who are treated with tiotropium could benefit from stepping up to tiotropium/olodaterol.

A comparison of tiotropium/olodaterol vs tiotropium alone in terms of treatment effect for chronic obstructive pulmonary disease: A meta-analysis.

BACKGROUND: Combinations of long-acting bronchodilators with different mechanisms of action are recommended to improve prognosis and reduce risk of adverse events of chronic obstructive pulmonary disease (COPD). It is unclear whether the new combination therapy with long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) was superior to tiotropium alone. METHODS: We measured the efficacy of the TIO/OLO combination vsTIO alone for COPD patients based on electronic databases up to February 2019. After rigorous quality review, data was extracted from eligible trials. All the main outcomes were pooled analysis using RevMan software. RESULTS: A total of 6 randomized controlled trials (RCTs) were identified. The pooled results of our meta-analysis demonstrated that FEV1 [MD = 0.03, 95% CI (-0.01,0.07), P = .18], FVC [MD = -0.03, 95%CI (-0.06,0.00), P = .09] and FEV1%pred [MD = 0.35, 95%CI (-0.30, 0.99), P = .29] all showed no significant difference between the 2 groups. The overall incidence of adverse effects (AEs) [OR = 1.01,95%CI (0.93,1.09), P = .87] and serious AEs [OR = 1.04,95% CI (0.82, 1.32), P = .72] in the combination group was similar to that of the TIO alone group, without statistical significance. CONCLUSION: These studies reported that the TIO/OLO combination did not show superior effects than tiotropium alone for COPD. Additionally, both therapies were well tolerated.

Behavioral effects of chronic WIN 55,212-2 administration during adolescence and adulthood in mice.

Marijuana, a psychoactive drug that activates cannabinoid-1 (CB1) receptors in the brain, is the most prevalently abused illicit drug among American adolescents and young adults. However, the long-term consequences of adolescent exposure to cannabinoids on the brain and behavior remain poorly understood. In both humans and nonhumans, adolescence is characterized by the maturation of the endocannabinoid neurotransmitter system in the prefrontal cortex and striatum-brain regions that underlie choice and decision making and are densely packed with CB1 receptors. In the current study, the effects of chronic WIN 55,212-2 (a CB1 agonist) exposure during adolescence on reversal learning and delay discounting were compared with those of adult-onset exposure using mice. Mice were administered 3.0 mg/kg/day WIN 55,212-2 or vehicle for 21 days beginning in adolescence (postnatal days 28-49) or adulthood (postnatal days 90-111). For the reversal-learning task, there was no difference in errors or omissions to criterion following a reversal in adolescent-exposed mice but adult-exposed mice showed a delay in beginning the reversal, suggesting that adolescents, but not adults, are resilient to this drug. Adult mice given WIN 55,212-2 in adolescence displayed greater impulsivity in the form of preference for smaller-sooner reinforcers over larger-delayed ones in the delay-discounting procedure, but this was seen to a lesser extent with adult-onset exposure. These data underscore the importance of variables related to the timing and duration of exposure as well as the specific and persistent behavioral endpoints affected by chronic cannabinoid administration. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

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.

Prevalence of Rilpivirine and Etravirine Resistance Mutations in HIV-1 Subtype C-Infected Patients Failing Nevirapine or Efavirenz-Based Combination Antiretroviral Therapy in Botswana.

Rilpivirine (RPV) and Etravirine (ETR) are approved second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment. There is a cross-resistance HIV mutation profile between first- and second-generation NNRTI drugs. We determined the prevalence of HIV-1 drug resistance mutations (DRMs) to RPV and ETR in Botswana. A total of 168 HIV-1 polymerase gene sequences from participants failing nevirapine (NVP)- or efavirenz (EFV)-containing regimens were analyzed for DRMs using the Stanford University HIV drug resistance database. Forty-one sequences were from an adult antiretroviral therapy (ART) study, the Tshepo study, and 127 from a prevention of mother-to-child transmission (PMTCT) study, the Mashi study, all conducted in Botswana. Prevalence of RPV and ETR highest DRM in the adult ART study (n = 41) were K101E (26.2%), E138A (23.8%), and Y181C (26.2%). The PMTCT cohort's (n = 127) high prevalence mutations were Y181C (15.7%), E138A (15%), and K101E (11%). A total of 42.9% and 3.2% of patients in the adult ART study and PMTCT study, respectively, had three or more NNRTI mutations at virologic failure. We identified HIV-1 mutations conferring resistance to RPV and ETR even though they have not been used in Botswana. Of concern was the high proportion of sequences from the adult ART study that displayed multiple DRMs; as the number of NNRTI mutations increases, the level of cross-resistance increases. It is plausible that patients displaying such profiles maybe at increased risk of failing second-generation NNRTI drugs, hence, calls for genotyping in patients with prior NVP or efavirenz exposure before prescription of RPV- or ETR-containing cART.

Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist.

BACKGROUND: Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids. AIM: To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2. METHODS: Male Balb/c mice weighing 20-30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 µg/50 µL intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 µg/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 µg/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus. RESULTS: WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05). CONCLUSIONS: Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.

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.

Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study.

INTRODUCTION: We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD. METHODS: This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of - 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed. RESULTS: In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28-77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34-3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group. CONCLUSION: In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02799784. FUNDING: GlaxoSmithKline.