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Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).
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COVID-19 , Humanos , SARS-CoV-2 , Galectina 3 , Inflamação , Resultado do TratamentoRESUMO
Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.
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Leucemia Mieloide Aguda , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Animais , Diferenciação Celular , Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genéticaRESUMO
This Pulmonary Perspective summarizes the content and main conclusions of an international workshop on personalized respiratory medicine coorganized by the Barcelona Respiratory Network ( www.brn.cat ) and the AJRCCM in June 2014. It discusses (1) its definition and historical, social, legal, and ethical aspects; (2) the view from different disciplines, including basic science, epidemiology, bioinformatics, and network/systems medicine; (3) the bottlenecks and opportunities identified by some currently ongoing projects; and (4) the implications for the individual, the healthcare system and the pharmaceutical industry. The authors hope that, although it is not a systematic review on the subject, this document can be a useful reference for researchers, clinicians, healthcare managers, policy-makers, and industry parties interested in personalized respiratory medicine.
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Medicina de Precisão/tendências , Pneumologia/tendências , Biologia Computacional/ética , Biologia Computacional/métodos , Biologia Computacional/tendências , Humanos , Medicina de Precisão/ética , Medicina de Precisão/métodos , Pneumologia/ética , Pneumologia/métodos , EspanhaRESUMO
PURPOSE: Overexpression of galectin-3, a ß-galactoside-binding lectin, is associated with fibrotic diseases and cancer. Selvigaltin is an oral galectin-3 inhibitor, previously administered as a 50 mg capsule. This study aimed to evaluate the relative bioavailability and food effect of selvigaltin as a 100 mg tablet in healthy volunteers. METHODS: In this single-dose, randomized, three-period, crossover study (GALBA-1; NCT05747573), participants received selvigaltin as a 100 mg tablet (under fasted and fed conditions) or as two 50 mg capsules (under fasted conditions). Primary endpoints included plasma and urine pharmacokinetic (PK) parameters. Secondary endpoints were safety and tolerability. RESULTS: Of the 13 enrolled participants, 12 completed the study. Under fasted conditions, geometric mean maximum observed plasma concentration (Cmax) and systemic exposure (AUC0âinf) of selvigaltin were 161.0% and 84.0% higher, respectively, after administration of a tablet vs. capsules. Under fed vs. fasted conditions, geometric mean Cmax of the selvigaltin tablet was 20.0% lower, whereas AUC0âinf was unaffected. Geometric mean percentage of total dose of selvigaltin excreted in urine over 0â96 h was 30.3% and 35.9% for the tablet under fasted and fed conditions, respectively, and 14.5% for the capsules. No treatment-emergent severe or serious adverse events or study discontinuations due to a treatment-emergent adverse event were reported. CONCLUSION: The tablet formulation of selvigaltin displayed higher bioavailability vs. the capsule formulation, with minimal effect of food on PK. Selvigaltin was well-tolerated during all treatments. These findings warrant further clinical development of the tablet formulation of selvigaltin without specific food restrictions. CLINICAL TRIAL REGISTRATION: NCT05747573; February 28, 2023.
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PURPOSE: We aimed to assess the predictive value of galectin-3 (Gal-3) in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint blockades (ICBs) therapy using both enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). METHODS: This retrospective study was conducted at Seoul National University Hospital. Patients with EGFR/ALK-wild-type advanced or metastatic NSCLC who received ICBs between December 2013 and December 2019 were enrolled. Patients with archived blood samples collected prior to ICB treatment were assigned to the ELISA cohort. In addition, those with tissue samples from sites of recurrence or metastasis were assigned to an IHC cohort. Then, we analyzed Gal-3 expression in both cohorts. RESULTS: Fifty-six patients in the ELISA cohort were grouped into low (N = 36) and high (N = 20) groups, using the mean Gal-3 ELISA level (13.24 pg/ml) as a cutoff. The high group demonstrated trends toward reduced progression-free survival (PFS) (0.9 vs. 3.7 months, p = 0.196) and significantly shorter overall survival (OS) (1.6 vs. 12.3 months, p = 0.018) than the low group. We categorized 94 patients in the IHC cohort into negative (N = 31) and positive (N = 63) groups based on Gal-3 IHC positivity. However, the median PFS (4.6 vs. 4.6 months for the negative vs. positive IHC group, respectively, p = 0.345) and OS (16.4 vs. 9.0 months, p = 0.137) were not significantly different. CONCLUSION: High blood Gal-3 levels may predict inferior survival in patients with advanced or metastatic NSCLC treated with ICBs.
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Carcinoma Pulmonar de Células não Pequenas , Galectina 3 , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/patologia , Estudos RetrospectivosRESUMO
Lung cancer, COPD and cardiovascular diseases are highlighted as some of the most common disease that cause mortality, and for that reason are the most active areas for drug development. This perspective paper overviews the urgent need to develop a health care system for a rapidly growing patient population in Japan, including forthcoming demands on clinical care, expecting outcomes, and economics. There is an increasing requirement to build on the strengths of the current health care system, thereby delivering urgent solutions for the future. There is also a declaration from the Ministry of Health, Labour and Welfare (MHLW), to develop new biomarker diagnostics, which is intended for patient stratification, aiding in diagnostic phenotype selection for responders to drug treatment of Japanese patients. This perspective was written by the panel in order to introduce novel technologies and diagnostic capabilities with successful implementation. The next generation of personalized drugs for targeted and stratified patient treatment will soon be available in major disease areas such as, lifestyle-related cancers, especially lung cancers with the highest mortality including a predisposing disorder chronic obstructive pulmonary disease, cardiovascular disease, and other diseases. Mass spectrometric technologies can provide the "phenotypic fingerprint" required for the concept of Personalized Medicine. Mass spectrometry-driven target biomarker diagnoses in combination with high resolution computed tomography can provide a critical pathway initiative facilitated by a fully integrated e-Health infrastructure system. We strongly recommend integrating validated biomarkers based on clinical proteomics, medical imaging with clinical care supported by e-Health model to support personalized treatment paradigms to reduce mortality and healthcare costs of chronic and co-morbid diseases in the elderly population of Japan.
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Atenção à Saúde/tendências , Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Idoso , Biomarcadores , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Descoberta de Drogas , Humanos , Japão/epidemiologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Crescimento Demográfico , Proteômica , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/mortalidadeRESUMO
Although the available inhaled corticosteroid (ICS)/long-acting beta( 2)-agonist (LABA) combinations principally work in a similar fashion, they differ in several important ways, leading to different efficacy. The ICS/LABA combination product budesonide/formoterol can be used as both maintenance and reliever therapy, providing a fixed maintenance dose, which does not change, and replacing short-acting beta(2)-agonists as relievers thereby allowing intervention to address the underlying inflammation at the earliest sign of symptomatic worsening. This approach is not suitable for other combination products such as salmeterol/fluticasone. Here we review the pharmacological differences of budesonide/ formoterol and salmeterol/fluticasone that permit the use of budesonide/formoterol as both maintenance and reliever therapy.
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Agonistas Adrenérgicos beta/farmacologia , Albuterol/análogos & derivados , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Budesonida/farmacologia , Glucocorticoides/farmacologia , Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/farmacologia , Albuterol/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Progressão da Doença , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Xinafoato de Salmeterol , Resultado do TratamentoRESUMO
BACKGROUND: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study is a worldwide, randomized, prospective study to investigate early intervention with inhaled corticosteroids in recent-onset mild persistent asthma. OBJECTIVE: To evaluate the safety and tolerability of long-term treatment with once-daily budesonide therapy in patients with mild persistent asthma. METHODS: Patients aged 5 to 66 years with mild persistent asthma for fewer than 2 years and no previous regular corticosteroid treatment received budesonide or placebo once daily for 3 years, in addition to their usual asthma therapy. The daily budesonide dose was 200 microg for children younger than 11 years and 400 microg for those 11 years or older. RESULTS: Overall, 7,221 patients were included in the safety analysis, and a total of 21,520 adverse events were reported (10,850 in the budesonide group and 10,670 in the placebo group). The most commonly reported events included respiratory infections, rhinitis, pharyngitis, bronchitis, viral infections, and sinusitis. The number of deaths and serious adverse events were similar for children and adults in both treatment groups. Fewer asthma-related serious adverse events were reported with budesonide (162) compared with placebo (276). Oral candidiasis was reported more frequently with budesonide (1.2%) than with placebo (0.5%); the frequencies of other adverse effects previously reported to be associated with inhaled corticosteroids (psychiatric disorders, skin disorders, and allergic reactions) were similar. CONCLUSIONS: Three-year treatment with budesonide once daily (200 or 400 microg) is safe and well tolerated in children and adults with newly detected mild persistent asthma.
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Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Budesonida/administração & dosagem , Budesonida/efeitos adversos , Administração por Inalação , Adolescente , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. OBJECTIVE: To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. METHODS: In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients). RESULTS: Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. CONCLUSIONS: Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy.
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Aborto Espontâneo , Asma/tratamento farmacológico , Broncodilatadores/efeitos adversos , Budesonida/efeitos adversos , Anormalidades Congênitas , Aborto Espontâneo/epidemiologia , Adolescente , Adulto , Broncodilatadores/administração & dosagem , Broncodilatadores/uso terapêutico , Budesonida/administração & dosagem , Budesonida/uso terapêutico , Criança , Pré-Escolar , Anormalidades Congênitas/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Resultado da GravidezRESUMO
PURPOSE: To examine final height in relation to target height in asthmatic patients with and without glucocorticoid treatment while growing up compared with healthy individuals. METHODS: In 1990 and 1993, questionnaires were distributed to all individuals born in 1974 and 1977 in the counties of Jämtland and Gästrikland in Sweden. All individuals reporting use of anti-asthmatic drugs or symptoms indicating possible obstructive airway disease, and a sample of healthy volunteers were invited to a clinical examination. RESULTS: Overall, 356 asthmatic patients and 384 healthy individuals were identified. In 1998-1999, all subjects were invited to a follow-up study and final height was analysed in relation to target height in 152 asthmatic patients and 131 healthy individuals. It was found that both men and women achieved a higher mean final height than the calculated mean target height. There were no significant differences between controls and asthma patients treated either with or without glucocorticoids. Most of the patients treated with glucocorticoids started their therapy during adolescence and 92% had used inhaled budesonide. There was no trend towards a decrease in final height in relation to target height when inhaled budesonide treatment was initiated prior to adolescence or with lifelong cumulative dose of inhaled budesonide. CONCLUSIONS: Asthmatic adolescents treated with inhaled budesonide achieve normal final height in relation to their target height.