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Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of Dsg2mut/mut mice, a well characterized mouse model of ACM. We also found that ACM disease features can be reversed in rat ventricular myocytes expressing mutant JUP by the pro-resolving epoxy fatty acid (EpFA) 14,15-eicosatrienoic acid (14-15-EET), whereas 14,15-EE-5(Z)E which antagonizes actions of the putative 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Soluble epoxide hydrolase (sEH), an enzyme that rapidly converts pro-resolving EpFAs into polar, far less active or even pro-inflammatory diols, is highly expressed in cardiac myocytes in Dsg2mut/mut mice. Inhibition of sEH prevented progression of myocardial injury in Dsg2mut/mut mice and led to recovery of contractile function. This was associated with reduced myocardial expression of genes involved in the innate immune response and fewer pro-inflammatory macrophages expressing CCR2, which mediate myocardial injury in Dsg2mut/mut mice. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM and, further, that inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.
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Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation. Here, we demonstrate that systemic treatment with ICI induces sEH expression in multiple murine cancer models. Dietary omega-3 polyunsaturated fatty acid supplementation and pharmacologic sEH inhibition, both alone and in combination, significantly enhance anti-tumor activity of ICI in these models. Notably, pharmacological abrogation of the sEH pathway alone or in combination with ICI counter-regulates an ICI-induced pro-inflammatory and pro-tumorigenic cytokine storm. Thus, modulating endogenous EpFA levels through dietary supplementation or sEH inhibition may represent a unique strategy to enhance the anti-tumor activity of paradigm cancer therapies.
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Epóxido Hidrolases , Neoplasias , Camundongos , Humanos , Animais , Epóxido Hidrolases/metabolismo , Ácidos Graxos/metabolismo , Inflamação/metabolismo , Neoplasias/terapia , Imunoterapia , Microambiente TumoralRESUMO
Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.
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Neoplasias Colorretais , Humanos , Animais , Camundongos , Estudos Retrospectivos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transdução de Sinais , Hipóxia , Queratinas/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular TumoralRESUMO
Colorectal cancer (CRC) is the third most common malignancy across the globe and, despite advances in treatment strategies, survival rates remain low. Rectal cancer (RC) accounts for most of these cases, and traditional management strategies for advanced disease include total neoadjuvant therapy (TNT) with chemoradiotherapy followed by curative surgery. Unfortunately, approximately 10-15% of patients have no response to treatment or have recurrence at a short interval following radiotherapy. The introduction of immunotherapy in the form of immune checkpoint blockade (ICB) in metastatic colorectal cancer has improved clinical outcomes, yet most patients with RC present with microsatellite stable disease, which lacks the immune-rich microenvironment where ICB is most effective. There is evidence that combining radiotherapy with ICB can unlock the mechanisms that drive resistance in patients; however, the sequencing of these therapies is still debated. This review offers a comprehensive overview of clinical trials and preclinical models that use radiotherapy-immunotherapy combinations in RC in an attempt to extrapolate the ideal sequencing of the two treatment modalities. The results highlight the dearth of evidence to answer the question of whether ICB should be given before, during, or after radiotherapy, yet it is suggested that improving the relevance of our preclinical models will provide a platform with higher translational value and will lead to appropriate clinical trial designs.
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The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.
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Neoplasias Colorretais , Animais , Humanos , Camundongos , Adenosil-Homocisteinase/genética , Adenosil-Homocisteinase/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Metabolômica , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
OBJECTIVES: To examine adherence to Australian Health Practitioner Regulation Agency (AHPRA) and Australian Orthopaedic Association (AOA) advertising guidelines by AOA members. DESIGN, SETTING: Cross-sectional survey, Australia. PARTICIPANTS: Two samples of AOA member orthopaedic surgeons: 81 randomly selected from a list of AOA members with publicly available contact details (AOA random sample); and a sample obtained by searching with Google for "orthopaedic surgeon" and the name of the major city in each of the eight Australian states and territories in turn; the top eight results for each search were considered for inclusion (AOA Google sample). MAIN OUTCOME MEASURES: Non-compliance of advertising material, by surgeon sample, with the AHPRA and AOA guidelines; associations between non-compliance and sample, state, location (metropolitan, regional), and subspecialty. RESULTS: Of the 81 surgeons in the AOA random sample, 52 (64%) were non-compliant with at least one aspect of the AHPRA guidelines, and 53 (65%) were non-compliant with at least one aspect of the AOA guidelines. Of the 59 surgeons in the AOA Google sample, 48 were non-compliant with the AHPRA guidelines (81%) and 46 with the AOA guidelines (78%). Incidence of non-compliance with the AHPRA guidelines was influenced by sample source (AOA Google v AOA random: incidence rate ratio [IRR], 1.37; 95% CI, 1.01-1.87), but not non-compliance with the AOA guidelines (IRR, 1.09; 95% CI, 0.77-1.55). CONCLUSION: A large proportion of AOA members who advertise online do not comply with AHPRA and AOA advertising guidelines.
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Cirurgiões Ortopédicos , Ortopedia , Publicidade , Austrália , Estudos Transversais , HumanosRESUMO
OBJECTIVE: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. DESIGN: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. RESULTS: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002). CONCLUSION: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.
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Biomarcadores Tumorais , Neoplasias do Colo , Humanos , Biomarcadores Tumorais/genética , Células Estromais/patologia , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/patologia , Neoplasias do Colo/patologia , PrognósticoRESUMO
Pre-operative chemoradiotherapy reduces local recurrence rates in locally advanced rectal cancer. 10-20% of patients undergo complete response to chemoradiotherapy, however, many patients show no response. The mechanisms underlying this are poorly understood; identifying molecular and immunological factors underpinning heterogeneous responses to chemoradiotherapy, will promote development of treatment strategies to improve responses and overcome resistance mechanisms. This review describes the advances made in pre-clinical modelling of colorectal cancer, including genetically engineered mouse models, transplantation models, patient derived organoids and radiotherapy platforms to study responses to chemoradiotherapy. Relevant literature was identified through the PubMed and MEDLINE databases, using the following keywords: rectal cancer; mouse models; organoids; neo-adjuvant treatment; radiotherapy; chemotherapy. By delineating the advantages and disadvantages of available models, we discuss how modelling techniques can be utilized to address current research priorities in locally advanced rectal cancer. We provide unique insight into the potential application of pre-clinical models in the development of novel neo-adjuvant treatment strategies, which will hopefully guide future clinical trials.
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BACKGROUND: Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study's results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. METHODS: Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6-11 years and weighing 17-45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population. RESULTS: In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data. CONCLUSIONS: Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing < 45 kg.Registration: The phase 1 study of this report is registered at EudraCT with the identifier 2018-000734-35.
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Anticorpos Monoclonais/farmacocinética , Peptídeo Relacionado com Gene de Calcitonina , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Criança , Ensaios Clínicos Fase I como Assunto , Humanos , PediatriaRESUMO
Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing. Safety and tolerability assessments included physical examinations, adverse event reporting, laboratory evaluations, and immunogenicity. Following single-dose administration, the mean concentration-time profiles for the 2 treatment groups (autoinjector, n = 106; and prefilled syringe, n = 110) were similar. The point estimates for the back-transformed ratio (autoinjector/prefilled syringe) of geometric least squares means of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration, and area under the plasma concentration-time curve from time 0 extrapolated to infinity were 1.03, 1.04, and 1.05, respectively, with the 90% confidence intervals entirely contained within bioequivalence margins of 0.8 to 1.25. For both groups, median time to maximum observed concentration was 5 days and mean terminal elimination half-life was approximately 29 days. Treatment-related adverse events were reported by 39 (36%) subjects in the autoinjector group and 26 (24%) in the prefilled syringe group, and the majority were nonserious injection site reactions. The incidence of treatment-emergent antidrug antibody response was low and evenly distributed between the autoinjector (n = 3; 3%) and prefilled syringe (n = 4; 4%) groups. These results indicate that the fremanezumab autoinjector presentation provides an easy-to-use bioequivalent PK profile with a similar safety and tolerability profile to that of the prefilled syringe.
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Anticorpos Monoclonais/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Área Sob a Curva , Desenho de Equipamento , Feminino , Meia-Vida , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Equivalência Terapêutica , Adulto JovemRESUMO
Recent advances in synthetic biology research have been underpinned by an exponential increase in available genomic information and a proliferation of advanced DNA assembly tools. The adoption of plasmid vector assembly standards and parts libraries has greatly enhanced the reproducibility of research and the exchange of parts between different labs and biological systems. However, a standardized modular cloning (MoClo) system is not yet available for cyanobacteria, which lag behind other prokaryotes in synthetic biology despite their huge potential regarding biotechnological applications. By building on the assembly library and syntax of the Plant Golden Gate MoClo kit, we have developed a versatile system called CyanoGate that unites cyanobacteria with plant and algal systems. Here, we describe the generation of a suite of parts and acceptor vectors for making (1) marked/unmarked knock-outs or integrations using an integrative acceptor vector, and (2) transient multigene expression and repression systems using known and previously undescribed replicative vectors. We tested and compared the CyanoGate system in the established model cyanobacterium Synechocystis sp. PCC 6803 and the more recently described fast-growing strain Synechococcus elongatus UTEX 2973. The UTEX 2973 fast-growth phenotype was only evident under specific growth conditions; however, UTEX 2973 accumulated high levels of proteins with strong native or synthetic promoters. The system is publicly available and can be readily expanded to accommodate other standardized MoClo parts to accelerate the development of reliable synthetic biology tools for the cyanobacterial community.
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Cianobactérias/genética , Engenharia Genética/métodos , Biologia Sintética/métodos , Clonagem Molecular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Vetores Genéticos , Regiões Promotoras Genéticas , Synechocystis/genéticaRESUMO
OBJECTIVE: To determine pharmacokinetic (PK) profiles of fluticasone propionate (FP) and salmeterol (SAL) in healthy volunteers following administration as two inhalations from the FS Spiromax 500/50 µg and Seretide Accuhaler 50/500 µg inhalers, without (study 1, n = 79) and with charcoal block (study 2, n = 77). Safety was also assessed. MATERIALS AND METHODS: In two single-center, open-label, randomized two-period crossover studies, PK parameters were calculated from plasma drug concentrations obtained pre-dose through 36 hours post-dose. Bioequivalence was established if the 90% confidence intervals for the geometric mean ratios of the area under the plasma drug concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t) and the maximum observed plasma concentration (Cmax) for the comparison of both FP and SAL were within 0.80 - 1.25. RESULTS: In study 1, in subjects administered FS Spiromax, the mean (standard deviation (SD)) FP AUC0-t and Cmax were 1,622.64 (419.44) pg×h/mL and 151.36 (40.37) pg/mL, respectively, vs. 1,487.52 (341.25) pg×h/mL and 137.57 (33.64) pg/mL with Seretide Accuhaler. Mean (SD) SAL AUC0-t and Cmax with FS Spiromax were 408.42 (155.40) pg×h/mL and 269.48 (105.74) pg/mL, respectively, vs. 401.79 (125.32) pg×h/mL and 265.66 (87.28) pg/mL with Seretide Accuhaler. Comparable data were seen in study 2 with charcoal block. Bioequivalence of FS Spiromax with Seretide Accuhaler was observed both without and with charcoal block for FP and SAL for both AUC0-t and Cmax. Both study treatments were well tolerated, with a similar incidence of adverse events reported with the single use of FS Spiromax (23% study 1, 16% study 2) and Seretide Accuhaler (22%, 15%). CONCLUSION: FS Spiromax 500/50 µg (± charcoal block) was bioequivalent to Seretide Accuhaler 50/500µg.â©.
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Broncodilatadores/administração & dosagem , Fluticasona/administração & dosagem , Nebulizadores e Vaporizadores , Xinafoato de Salmeterol/administração & dosagem , Administração por Inalação , Área Sob a Curva , Broncodilatadores/farmacocinética , Estudos Cross-Over , Fluticasona/farmacocinética , Humanos , Xinafoato de Salmeterol/farmacocinética , Equivalência TerapêuticaRESUMO
Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ2 and Pearson r2 values were calculated for PD (maximum effect [Emax ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [Cmax ], time to Cmax [Tmax ], and abuse quotient [PK AQ; Cmax /Tmax ]) for all treatments. In the oral study, correlations were strongest between Emax of "at the moment" Drug Liking and PK parameters (Cmax [ρ2 = 0.4446], PK AQ [ρ2 = 0.5179], Tmax [ρ2 = 0.5093], and early systemic exposure [ρ2 = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.
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Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Hidrocodona/farmacologia , Hidrocodona/farmacocinética , Transtornos Relacionados ao Uso de Opioides , Administração Intranasal , Administração Oral , Adolescente , Adulto , Analgésicos Opioides/sangue , Estudos Cross-Over , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Método Duplo-Cego , Humanos , Hidrocodona/sangue , Pessoa de Meia-Idade , Comprimidos , Adulto JovemRESUMO
BACKGROUND: Breath-actuated inhalers (BAIs) eliminate the need for hand-breath coordination required of pressurized metered-dose inhalers (MDIs). This pharmacokinetic study compared systemic exposure following beclomethasone dipropionate delivery through BAI versus MDI. METHODS: This open-label, three-period crossover, single-dose study randomized healthy subjects aged 18-45 years (N = 72) to 1 of 6 treatment sequences containing beclomethasone dipropionate BAI 160 mcg (40 mcg/inhalation, 4 inhalations), beclomethasone dipropionate BAI 320 mcg (80 mcg/inhalation, 4 inhalations), and beclomethasone dipropionate MDI 320 mcg (80 mcg/inhalation, 4 inhalations). Blood samples were collected predose through 24 hours postdose for determination of plasma concentrations of beclomethasone-17-monopropionate (17-BMP), the active metabolite of beclomethasone dipropionate. The primary pharmacokinetic parameters were area under the plasma drug concentration-time curve (AUC) from time 0 (predose) until the last measurable drug concentration (AUC0-t) and maximum plasma drug concentration (Cmax) for 17-BMP. Safety was assessed by adverse events, vital signs, clinical laboratory tests, and physical examinations. RESULTS: Plasma concentrations of 17-BMP peaked at a median of 10 minutes after the last inhalation of all study treatments and remained measurable for at least 18 hours in most subjects. Mean elimination half-life was â¼4 hours. The AUC0-t and Cmax for 17-BMP were 11% and 14% higher, respectively, when beclomethasone dipropionate 320 mcg was administered through BAI versus MDI, but the 90% confidence intervals of the geometric least squares mean BAI:MDI ratio for each parameter were fully contained within the bioequivalence boundaries of 0.80-1.25. Plasma concentrations of 17-BMP following beclomethasone dipropionate 160 mcg BAI were approximately half those with 320 mcg through BAI or MDI. All treatments were safe and generally well tolerated. CONCLUSIONS: Systemic availability of 17-BMP following administration of beclomethasone dipropionate was bioequivalent between BAI and MDI at the 320-mcg dose, and approximately dose proportional at the 160- and 320-mcg doses using the BAI.
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Beclometasona/análogos & derivados , Inaladores Dosimetrados , Administração por Inalação , Adolescente , Adulto , Beclometasona/administração & dosagem , Beclometasona/farmacocinética , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Adulto JovemRESUMO
BACKGROUND: Breath-actuated inhalers (BAI) may simplify the delivery of inhaled medications compared with other devices. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI versus matching placebo in adolescent and adult patients with persistent asthma. METHODS: This phase III, 12-week, double-blind study enrolled patients with asthma aged ≥12 years who were previously treated with a stable dose of inhaled corticosteroid or noncorticosteroid therapy. After a run-in period of 14 to 21 days, patients were randomly assigned in a 1:1:1 ratio to beclomethasone dipropionate BAI 80 or 160 micrograms/day (40 or 80 micrograms twice daily) or placebo BAI. The primary end point was the standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks (AUEC[0-12 weeks]). Secondary end points included peak expiratory flow, rescue medication use, asthma symptoms, and the time to withdrawal due to meeting predefined criteria for worsening asthma. Additional end points evaluated quality of life, instructions for use, and safety. RESULTS: The full analysis and the safety sets included 270 and 273 patients, respectively. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had significant improvements in FEV1 AUEC(0-12 weeks) versus placebo (p ≤ 0.001). Improvements in secondary end points were also apparent in patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day compared with placebo. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had greater increases in Asthma Quality of Life Questionnaire scores versus placebo patients at week 12. Of 98 patients who participated in the instructions-for-use substudy, 87 (88.8%) used the inhaler successfully on their first attempt. Treatment was generally safe and well tolerated. CONCLUSION: Beclomethasone dipropionate BAI 80 and 160 micrograms/day were effective and well-accepted treatments in patients with asthma, with safety comparable to beclomethasone dipropionate delivered via a metered-dose inhaler.Clinical trial NCT02040779,
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Asma/tratamento farmacológico , Beclometasona/administração & dosagem , Nebulizadores e Vaporizadores/normas , Adolescente , Adulto , Idoso , Criança , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Inaladores Dosimetrados/normas , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) eliminates the need to coordinate actuation with inhalation. To characterize dose response, efficacy, and safety of fluticasone propionate (Fp) MDPI, a dose-ranging study was conducted with placebo and active comparators. METHODS: This 12-week, double-blind, parallel-group study randomized patients aged ≥12 years with uncontrolled persistent asthma not previously treated with inhaled corticosteroid therapy (N = 622) to twice-daily treatment with Fp MDPI (12.5, 25, 50, or 100 µg), placebo MDPI, or open-label Fp dry powder inhaler (DPI) 100 µg. The primary efficacy endpoint was change from baseline over 12 weeks in trough (morning pre-dose and pre-rescue bronchodilator) forced expiratory volume in 1 second (FEV1). Blood samples were collected from a patient subset to evaluate pharmacokinetics. Adverse events were monitored. RESULTS: Fp MDPI 25, 50, and 100 µg significantly improved change from baseline in trough FEV1 over 12 weeks compared with placebo (p < 0.01). There were no substantial differences in FEV1 change from baseline over 12 weeks between any Fp MDPI dose and Fp DPI 100 µg. Maximum observed concentration (Cmax) of Fp increased with increasing Fp MDPI doses; time of Cmax was similar across doses and treatments. Systemic exposures for Fp MDPI 25 and 50 µg were lower than that for Fp DPI 100 µg. The safety profile of Fp MDPI was consistent with that of Fp DPI. CONCLUSIONS: In this study, Fp MDPI 25 and 50 µg provided comparable efficacy and safety to Fp DPI 100 µg, with lower systemic exposure.
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Asma/tratamento farmacológico , Broncodilatadores/farmacocinética , Broncodilatadores/uso terapêutico , Fluticasona/farmacocinética , Fluticasona/uso terapêutico , Administração por Inalação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Fluticasona/administração & dosagem , Fluticasona/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Adulto JovemRESUMO
OBJECTIVE: Evaluate fluticasone propionate (Fp) using a novel, inhalation-driven, multidose dry powder inhaler (MDPI) in patients with severe persistent asthma, versus placebo MDPI and Fp dry powder inhaler (DPI). METHODS: Patients with persistent asthma despite use of high-dose inhaled corticosteroids were randomized to Fp MDPI 50, 100, 200, or 400 mcg; Fp DPI 250 mcg; or placebo MDPI twice daily for 12 weeks. The primary outcome measure was change from baseline in trough forced expiratory volume in 1 second (FEV1) over the 12-week period, compared with placebo; secondary measures included change from baseline in peak expiratory flow (PEF), rescue inhaler use, and time to withdrawal due to meeting stopping criteria. Safety included adverse events and laboratory evaluations. RESULTS: Six hundred forty patients were randomized; 459 (72%) completed the study. Numerical dose-related improvements in FEV1 were observed in all Fp MDPI groups over 12 weeks but were not significantly greater versus placebo. Increases in morning PEF (baseline to week 12) were substantially greater than placebo in all Fp MDPI groups. The Fp MDPI and Fp DPI groups had substantial reductions in rescue inhaler use from baseline to end point versus placebo (p ≤ 0.05). Efficacy was comparable between Fp MDPI and Fp DPI. No new safety signals were detected; the safety profile of Fp MDPI was similar to that of Fp DPI. CONCLUSIONS: Clinical benefit observed with Fp MDPI in patients with persistent asthma was comparable to Fp DPI. Safety was reassuring with no unexpected findings. These results support further evaluation of Fp MDPI in asthma. (ClinicalTrials.gov identifier NCT01576718; EudraCT number 2010-023601-35).
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Asma/tratamento farmacológico , Broncodilatadores/farmacocinética , Broncodilatadores/uso terapêutico , Fluticasona/farmacocinética , Fluticasona/uso terapêutico , Administração por Inalação , Adolescente , Adulto , Idoso , Área Sob a Curva , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Fluticasona/administração & dosagem , Fluticasona/efeitos adversos , Meia-Vida , Humanos , Estimativa de Kaplan-Meier , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Testes de Função Respiratória , Adulto JovemRESUMO
A systematic review of the literature was completed by the Evidence-Based Practice Group for the Patient population, Intervention/Issue, Comparison Intervention, Outcomes, Timing (PICOT) question: "Does the use of a peripheral nerve block increase the risk for falls and difficulty ambulation in patients after lower extremity surgery through postoperative day 2?" A search of multiple databases using specified key terms resulted in 258 articles for total knee arthroplasty or total hip arthroplasty. These were reduced to 13 with exclusion criteria and became primary evidence. Numbers Needed to Harm and Numbers Needed to Treat (NNT) were calculated. Numbers Needed to Harm supported the PICOT question. Further research of postoperative falls and nursing interventions to reduce or prevent falls is suggested before creation of a Clinical Practice Guideline.
Assuntos
Acidentes por Quedas , Artroplastia de Quadril , Artroplastia do Joelho , Bloqueio Nervoso , Caminhada , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Fluticasone propionate (Fp) is an inhaled corticosteroid with well-established safety and efficacy profiles. This study evaluated the systemic pharmacokinetics of Fp inhaled from a novel, inhalation-driven multidose dry powder inhaler (MDPI) that does not require coordination of actuation with inhalation. METHODS: This was a single-center, open-label, randomized, 3-period crossover, single-dose study in healthy Japanese and Caucasian subjects aged 20-45 years, inclusive. Subjects were randomized to one of six treatment sequences including combinations of four inhalations of Fp MDPI 100 µg (400 µg total dose), Fp MDPI 200 µg (800 µg total dose), and Fp Diskus(®) 100 µg (400 µg total dose). The primary objective was to assess pharmacokinetics (maximum plasma concentration [Cmax] and area under concentration-vs.-time curve [AUC]) for each treatment. Safety and tolerability were also assessed. RESULTS: Thirty subjects (15 Caucasian, 15 Japanese) met entry criteria and were randomized; all 30 subjects completed the study. At the inhaled Fp total doses evaluated (400 and 800 µg), the shapes of plasma concentration-vs.-time curves and systemic exposure (AUC0-t and Cmax) were similar in Japanese and Caucasian subjects. Geometric mean ratios (Japanese/Caucasian) for AUC0-t ranged from 1.11 to 1.15, and for Cmax ranged from 0.90 to 1.05, with no substantial differences between ethnic groups. In both ethnic groups, and in the combined population, systemic exposure (AUC0-t and Cmax) was highest for Fp MDPI 800 µg, followed by Fp MDPI 400 µg, and last by Fp Diskus 400 µg. No clinical laboratory, vital signs, or physical examination findings were considered clinically significant. CONCLUSIONS: Systemic exposure following inhaled single doses of Fp was comparable in healthy adult Japanese and Caucasian subjects for each total dose and inhaler. The new MDPI provided more efficient drug delivery than Diskus, suggesting that Fp MDPI may provide similar clinical efficacy at a lower inhaled dose compared with Diskus. Single-dose inhaled Fp (400-800 µg) was generally well tolerated in healthy adults.
Assuntos
Corticosteroides/administração & dosagem , Corticosteroides/farmacocinética , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Inaladores de Pó Seco , Fluticasona/administração & dosagem , Fluticasona/farmacocinética , Administração por Inalação , Corticosteroides/efeitos adversos , Corticosteroides/sangue , Adulto , Aerossóis , Área Sob a Curva , Povo Asiático , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Estudos Cross-Over , Desenho de Equipamento , Feminino , Fluticasona/efeitos adversos , Fluticasona/sangue , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Projetos Piloto , Pós , População Branca , Adulto JovemRESUMO
BACKGROUND: A novel inhalation-driven multidose dry powder inhaler (MDPI) that eliminates the need for the patient to coordinate device actuation with inhalation has been developed for delivery of inhaled asthma medications. OBJECTIVE: To characterize the pharmacokinetics of single-dose fluticasone propionate (Fp) MDPI compared with single doses of Fp dry powder inhaler (DPI) and a metered-dose inhaler (MDI) in healthy subjects. METHODS: This was a single-center, open-label, randomized, three-period crossover, single-dose pilot study in healthy adults ages 18 to 45 years. Eligible subjects (N = 18) were randomized to one of six treatment sequences that contained three treatment arms: Fp MDPI 400 µg/inhalation × two inhalations (800 µg total dose); Fp DPI 250 µg/inhalation × four (1000 µg total dose); and Fp MDI 220 µg/inhalation × four (880 µg total dose). Pharmacokinetics (area under concentration-versus-time curve [AUC], maximum plasma concentration [Cmax], time to Cmax [tmax], and elimination half-life [t½]), safety, and tolerability were assessed for each treatment. RESULTS: Plasma Fp concentration-versus-time curves were comparable across treatments. Geometric mean AUC0-t and Cmax for Fp MDPI 800 µg were 19% and 18% higher, respectively, compared with Fp DPI 1000 µg, and 47% and 82% higher, respectively, compared with Fp MDI 880 µg. Median tmax (60.0-60.6 minutes) and median t1/2 (9.1-9.8 hours) were comparable across the three treatments. Single-dose Fp was well tolerated, with no new safety issues noted. CONCLUSION: Single-dose administration of Fp MDPI 800 µg produced systemic exposure comparable with those for Fp DPI 1000 µg and Fp MDI 880 µg.