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Background Advances in antiretroviral therapy (ART) enable people with HIV to live longer, healthier lives. However, older people with HIV (OPWH) are more susceptible to long-term toxicity and drug interactions associated with ART. Racial and ethnic minorities have specific social determinants of health, which increase their risks of negative outcomes. Objective To determine if there were differences in the safety and effectiveness of ART in White, Black, and Hispanic OPWH. Methods A retrospective observational study was conducted on patients receiving care between January 1, 2017, and December 31, 2022, at two affiliated HIV clinics in South Florida. The primary effectiveness endpoint was the percentage of OPWH with undetectable viral load (< 50 copies/mL) throughout the study. Secondary safety endpoints were changes in median metabolic, hepatic, and renal parameters. A two-way analysis of variance or the Chi-square test was used to determine differences between groups. Results A total of 116 White, 42 Black, and 40 Hispanic OPWH were included. Upon enrollment, most patients (90.7%) were receiving ART. Of these, the percentage with undetectable viral load was lower among Black (61.8%) compared with White (85.8%; P < 0.01) or Hispanic (83.3%; P < 0.05) patients. Similarly, throughout the study after the first visit, the percentage with undetectable viral load was lower among Black (61.6%) compared with White (84.7%; P < 0.05) or Hispanic (83.3%; P = 0.12) patients. However, there were no significant differences in the percentage of virally suppressed (< 200 copies/mL) participants throughout the study after the first visit between Black (88.5%), White (94.9%), and Hispanic (96.7%) patients. Additionally, no significant changes in safety endpoints were observed among the groups throughout the study. Conclusion Fewer Black OPWH had undetectable viral load upon enrollment and throughout the study compared with White or Hispanic OPWH, suggesting the need to provide more targeted interventions for Black patients.
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Antirretrovirais , Infecções por HIV , Idoso , Humanos , Hispânico ou Latino , HIV , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Grupos Raciais , Estudos Retrospectivos , Brancos , Negro ou Afro-Americano , Antirretrovirais/uso terapêuticoRESUMO
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled ß2-adrenergic receptor (ß2AR) agonists (ß2-agonists) promote - with limited efficacy - bronchodilation in asthma. All ß2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a ß2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on ß2AR-mediated bronchoprotection. Consistent with our findings using human ß2ARs, Cmpd-6 allosterically potentiated ß2-agonist binding to guinea pig ß2ARs and downstream signaling of ß2ARs. In contrast, Cmpd-6 had no such effect on murine ß2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced ß2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated ß2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced ß2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of ß2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.
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Asma , Humanos , Camundongos , Animais , Cobaias , Cloreto de Metacolina/farmacologia , Cloreto de Metacolina/uso terapêutico , Ligantes , Asma/tratamento farmacológico , Asma/genética , Asma/complicações , Pulmão/metabolismo , Sítios de Ligação , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismoRESUMO
Background: The efficiency of the patient care process of short-term medical service trips is often not assessed. The Gregory School of Pharmacy has organized annual medical camps in rural Uganda, however, the paper health records used for documentation and communication between stations have shown several limitations that hinder an optimal patient care process. Therefore, our objective was to implement an electronic health record system in these medical camps to improve the workflow and optimize the patient care process. Methods: An electronic health record system that functioned over a battery-operated local area network was developed and implemented. Patient health information was entered and reviewed at the different stations using mobile devices. The impact of electronic health records (used in 2019) on the patient care process was assessed using the number of patients served per physician per hour and the number of prescriptions filled per hour and comparing these to paper records (used in 2017). Results: Electronic health records were successfully implemented and communication across stations was fluid, thus improving transitions. Importantly, 45% more patients were served per physician per hour and 38% more prescriptions were dispensed per hour when using electronic (2019) compared to paper records (2017), despite having a smaller team in 2019. Conclusion: Implementation of electronic health records in rural Uganda improved the patient care process and the efficiency of the medical camp.
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INTRODUCTION: Pharmacy programs employ a variety of remediation methods intended to bring underperforming students to a level of competency. Our objective was to evaluate pharmacy students' perceptions of eligibility criteria and academic outcomes of remediation and potential predictors for lack of success in the original and remediated course. METHODS: Palm Beach Atlantic University School of Pharmacy revised its remediation policy in fall 2017, shifting from a course-centric to student-centric policy. Pharmacy students (N = 265) were surveyed in spring 2019 regarding eligibility criteria and academic outcomes of remediation. Enrolled students who remediated under the revised policy were surveyed on the lack of success in the original course and the remediation process. RESULTS: Students viewed remediation as an opportunity to prevent delayed graduation. They agreed with the revised, student-centric eligibility criteria and with the new approach allowing all courses to be remediated. First-year students provided lower scores, whereas students who never failed a course gave higher scores. Students agreed that remediation produces proficient students who are as competent as those who passed the original course. The main reason for failing the original course was lack of study time. Students who failed remediation tended to spend more time on external activities and used less remediation resources. CONCLUSIONS: A student-centric approach to remediation with active involvement from students and faculty support was successful in producing students who are viewed just as proficient and competent as students who passed the original course. Predictors for success were study time and the use of remediation resources.
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Educação em Farmácia , Estudantes de Farmácia , Logro , Avaliação Educacional , Humanos , PercepçãoRESUMO
Expression of bronchodilatory ß2-adrenoceptors and bronchoconstrictive muscarinic M3-receptors alter with airway size. In COPD, (a combination of) ß2-agonists and muscarinic M3-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to ß2-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (ß2-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 µM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 µM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD.
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Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Glicopirrolato/farmacologia , Indanos/farmacologia , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/farmacologia , Animais , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Cobaias , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptor Muscarínico M3/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Receptores Adrenérgicos beta 2/metabolismoRESUMO
Nitric oxide (NO) is produced by a family of isoenzymes, nitric oxide synthases (NOSs), which all utilize L-arginine as substrate. The production of NO in the lung and airways can play a number of roles during lung development, regulates airway and vascular smooth muscle tone, and is involved in inflammatory processes and host defense. Altered L-arginine/NO homeostasis, due to the accumulation of endogenous NOS inhibitors and competition for substrate with the arginase enzymes, has been found to play a role in various conditions affecting the lung and in pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, and bronchopulmonary dysplasia. Different therapeutic strategies to increase L-arginine levels or bioavailability are currently being explored in pre-clinical and clinical studies. These include supplementation of L-arginine or L-citrulline and inhibition of arginase.
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With the ability to switch between proliferative and contractile phenotype, airway smooth muscle (ASM) cells can contribute to the progression of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), in which airway obstruction is associated with ASM hypertrophy and hypercontractility. A-kinase anchoring proteins (AKAPs) have emerged as important regulatory molecules in various tissues, including ASM cells. AKAPs can anchor the regulatory subunits of protein kinase A (PKA), and guide cellular localization via various targeting domains. Here we investigated whether disruption of the AKAP-PKA interaction, by the cell permeable peptide stearated (st)-Ht31, alters human ASM proliferation and contractility. Treatment of human ASM with st-Ht31 enhanced the expression of protein markers associated with cell proliferation in both cultured cells and intact tissue, although this was not accompanied by an increase in cell viability or cell-cycle progression, suggesting that disruption of AKAP-PKA interaction on its own is not sufficient to drive ASM cell proliferation. Strikingly, st-Ht31 enhanced contractile force generation in human ASM tissue with concomitant upregulation of the contractile protein α-sm-actin. This upregulation of α-sm-actin was independent of mRNA stability, transcription or translation, but was dependent on proteasome function, as the proteasome inhibitor MG-132 prevented the st-Ht31 effect. Collectively, the AKAP-PKA interaction appears to regulate markers of the multi-functional capabilities of ASM, and this alter the physiological function, such as contractility, suggesting potential to contribute to the pathophysiology of airway diseases.
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BACKGROUND AND PURPOSE: Pharmacy schools must have a framework to ensure students have the necessary knowledge, skills, attitudes, and behaviors to be successful during advanced pharmacy practice experiences (APPEs). EDUCATIONAL ACTIVITY AND SETTING: Ten summative assessments, called APPE-readiness assessments (ARAs), were developed based on eight competencies encompassing skills, behaviors, and attitudes that must be demonstrated prior to APPEs. All eight competencies were assessed in the course Case Studies in Pharmacotherapy IV, which is offered in the final semester of the didactic curriculum immediately prior to APPEs. A 15-question pre- and post-survey was conducted to assess student confidence in performing each APPE-readiness competency. Cohort data was evaluated by the curriculum and assessment committee to assess curriculum effectiveness and areas for improvement. FINDINGS: Upon completion of the course, the average first-attempt pass rate across all ARAs was 92.4%. All students who failed on the first attempt passed on the second attempt, thereby demonstrating APPE-readiness. Out of 62 students, 45 and 44 completed the pre- and post-survey, respectively. Prior to the ARAs, the overall average of students who felt (strongly) confident about their ability to perform each competency was 82.2 ± 2.1%. This increased to 92.6 ± 1.6% after the ARAs. SUMMARY: The development of an APPE-readiness assessment plan focusing on skills, attitudes, and behaviors provides insight into student and cohort performance and allows for continuous quality assurance of the pre-APPE curriculum.
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Educação em Farmácia/métodos , Conhecimentos, Atitudes e Prática em Saúde , Preceptoria/métodos , Estudantes de Farmácia/psicologia , Currículo/tendências , Educação em Farmácia/tendências , Avaliação Educacional/métodos , Humanos , Preceptoria/tendências , Estudantes de Farmácia/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
Epithelial-to-mesenchymal transition (EMT) plays a role in chronic obstructive pulmonary diseases (COPD). Cyclic adenosine monophosphate (cAMP) can inhibit transforming growth factor-ß1 (TGF-ß1) mediated EMT. Although compartmentalization via A-kinase anchoring proteins (AKAPs) is central to cAMP signaling, functional studies regarding their therapeutic value in the lung EMT process are lacking. The human bronchial epithelial cell line (BEAS-2B) and primary human airway epithelial (pHAE) cells were exposed to TGF-ß1. Epithelial (E-cadherin, ZO-1) and mesenchymal markers (collagen Ó, α-SMA, fibronectin) were analyzed (mRNA, protein). ELISA measured TGF-ß1 release. TGF-ß1-sensitive AKAPs Ezrin, AKAP95 and Yotiao were silenced while using siRNA. Cell migration was analyzed by wound healing assay, xCELLigence, Incucyte. Prior to TGF-ß1, dibutyryl-cAMP (dbcAMP), fenoterol, rolipram, cilostamide, and forskolin were used to elevate intracellular cAMP. TGF-ß1 induced morphological changes, decreased E-cadherin, but increased collagen Ó and cell migration, a process that was reversed by the inhibitor of δ/epsilon casein kinase I, PF-670462. TGF-ß1 altered (mRNA, protein) expression of Ezrin, AKAP95, and Yotiao. St-Ht31, the AKAP antagonist, decreased E-cadherin (mRNA, protein), but counteracted TGF-ß1-induced collagen Ó upregulation. Cigarette smoke (CS) increased TGF-ß1 release, activated TGF signaling, augmented cell migration, and reduced E-cadherin expression, a process that was blocked by TGF-ß1 neutralizing antibody. The silencing of Ezrin, AKAP95, and Yotiao diminished TGF-ß1-induced collagen Ó expression, as well as TGF-ß1-induced cell migration. Fenoterol, rolipram, and cilostamide, in AKAP silenced cells, pointed to distinct cAMP compartments. We conclude that Ezrin, AKAP95, and Yotiao promote TGF-ß1-mediated EMT, linked to a TGF-ß1 release by CS. AKAP members might define the ability of fenoterol, rolipram, and cilostamide to modulate the EMT process, and they might represent potential relevant targets in the treatment of COPD.
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Proteínas de Ancoragem à Quinase A/metabolismo , Transição Epitelial-Mesenquimal , Fumar/efeitos adversos , Fator de Crescimento Transformador beta1/farmacologia , Proteínas de Ancoragem à Quinase A/genética , Biomarcadores/metabolismo , Caderinas/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
PURPOSE: Sepsis and septic shock are significant health issues in the United States. Novel treatment options focusing on mitigating the dysregulated host response while reducing the need for vasopressor support are needed. This review discusses ascorbic acid, thiamine, and steroids as monotherapy and in combination for the treatment of sepsis and septic shock. SUMMARY: The results of clinical studies using ascorbic acid, thiamine, and steroids as monotherapy or in combination are reviewed. High doses of IV ascorbic acid improved organ failure evidenced by changes in SOFA scores, declining CRP and PCT levels, and reduced vasopressor use. Thiamine initiation improved lactate levels in thiamine deficient patients in one study and demonstrated quicker lactate clearance and lower 28-day mortality in another study. Steroid studies demonstrated greatest benefit when initiating hydrocortisone and fludrocortisone early in septic shock. Combination therapy with ascorbic acid, thiamine and steroids reduced hospital mortality and vasopressor use in sepsis and septic shock in a small single-center study. CONCLUSION: Initial studies in patients with sepsis and septic shock demonstrated beneficial effects of ascorbic acid, thiamine, and steroids as monotherapy or in combination without safety concerns. However, the efficacy and safety of these therapies warrant further validation in larger clinical studies.
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Sepse , Choque Séptico , Ácido Ascórbico , Humanos , Sepse/diagnóstico , Sepse/tratamento farmacológico , Choque Séptico/tratamento farmacológico , Tiamina , VitaminasAssuntos
Alergia e Imunologia , Arginase/antagonistas & inibidores , Asma/tratamento farmacológico , Invenções , Terapia de Alvo Molecular/métodos , Rinite Alérgica/tratamento farmacológico , Animais , Arginase/metabolismo , Asma/metabolismo , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Cobaias , Humanos , Óxido Nítrico/metabolismo , Rinite Alérgica/metabolismoRESUMO
The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk. Peripheral PCLS were obtained from patients with mild to moderate COPD and non-COPD controls. AHR to methacholine was measured in large and small airways using video-assisted microscopy. Airway smooth muscle mass and alveolar airspace size were determined in the same slices. A mathematical model was used to identify potential changes in biomechanical properties underlying AHR. In guinea pigs, lipopolysaccharide increased the sensitivity of large (>150 µm) airways toward methacholine by 4.4-fold and the maximal constriction of small airways (<150 µm) by 1.5-fold. Similarly increased small airway responsiveness was found in COPD patients. In both lipopolysaccharide-challenged guinea pigs and patients, airway smooth muscle mass was unaltered, whereas increased alveolar airspace correlated with small airway hyperresponsiveness in guinea pigs. Fitting the parameters of the model indicated that COPD weakens matrix mechanical properties and enhances stiffness differences between the airway and the parenchyma, in both species. In conclusion, this study demonstrates small airway hyperresponsiveness in PCLS from COPD patients. These changes may be related to reduced parenchymal retraction forces and biomechanical changes in the airway wall. PCLS from lipopolysaccharide-exposed guinea pigs may be useful to study mechanisms of small airway hyperresponsiveness in COPD.
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Remodelação das Vias Aéreas/fisiologia , Músculo Liso/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Adulto , Idoso , Animais , Asma/patologia , Asma/fisiopatologia , Modelos Animais de Doenças , Feminino , Cobaias , Humanos , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Liso/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/fisiopatologiaRESUMO
Budesonide is a hydrophobic glucocorticoid with high anti-inflammatory activity for the treatment of asthma, inflammatory bowel disease and rheumatoid arthritis. A micellar drug-delivery system based on lipid-DNA may provide a strategy to maximize its drug efficacy and reduce adverse effects. In this work, we report the use of lipid-DNAA (UU11mer), featuring two hydrophobic alkyl chains and forming micelles at a comparatively low critical micelle concentration, to render budesonide water-soluble with a high loading capacity (LC). The inhibition of interleukin-8 (IL-8) release shows that the new delivery system retains the inhibitory activity in cell-based assays. In conclusion, this research provides a novel approach to formulate and administer budesonide in a non-invasive manner, which dramatically improves its water-solubility while retaining its bioavailability.
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Budesonida/administração & dosagem , DNA/química , Sistemas de Liberação de Medicamentos , Glucocorticoides/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Budesonida/química , Budesonida/farmacologia , Linhagem Celular , Química Farmacêutica/métodos , Portadores de Fármacos/química , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Interleucina-8/antagonistas & inibidores , Lipídeos/química , Micelas , SolubilidadeRESUMO
Bone morphogenetic protein (BMP) signaling regulates vascular smooth muscle maturation, endothelial cell proliferation, and tube formation. The endogenous BMP antagonist Follistatin-like 1 (Fstl1) is highly expressed in pulmonary vascular endothelium of the developing mouse lung, suggesting a role in pulmonary vascular formation and vascular homeostasis. The aim of this study was to investigate the role of Fstl1 in the pulmonary vascular endothelium. To this aim, Fstl1 was conditionally deleted from endothelial and endothelial-derived cells using Tie2-cre driven Fstl1-KO mice (Fstl1-eKO mice). Endothelial-specific Fstl1 deletion was postnatally lethal, as â¼70% of Fstl1-eKO mice died at three weeks after birth. Deletion of Fstl1 from endothelium resulted in a reduction of right ventricular output at three weeks after birth compared with controls. This was associated with pulmonary vascular remodeling, as the percentage of actin-positive small pulmonary vessels was increased at three weeks in Fstl1-eKO mice compared with controls. Endothelial deletion of Fstl1 resulted in activation of Smad1/5/8 signaling and increased BMP/Smad-regulated gene expression of Jagged1, Endoglin, and Gata2 at one week after birth compared with controls. In addition, potent vasoconstrictor Endothelin-1, the expression of which is driven by Gata2, was increased in expression, both on the mRNA and protein levels, at one week after birth compared with controls. At three weeks, Jagged1 was reduced in the Fstl1-eKO mice whereas Endoglin and Endothelin-1 were unchanged. In conclusion, loss of endothelial Fstl1 in the lung is associated with elevated BMP-regulated genes, impaired small pulmonary vascular remodeling, and decreased right ventricular output.
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COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, ß2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress.
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Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Cromanos/farmacologia , Hipersensibilidade/prevenção & controle , Piperazinas/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Linhagem Celular Transformada , Cromanos/química , Misturas Complexas/antagonistas & inibidores , Misturas Complexas/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Cobaias , Humanos , Sulfeto de Hidrogênio/agonistas , Sulfeto de Hidrogênio/sangue , Hipersensibilidade/etiologia , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Inflamação , Interleucina-8/antagonistas & inibidores , Interleucina-8/genética , Interleucina-8/imunologia , Lipopolissacarídeos/administração & dosagem , Pulmão , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Estresse Oxidativo , Piperazinas/química , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Alcatrões/química , Alcatrões/toxicidade , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologiaRESUMO
BACKGROUND: The long-acting anticholinergic tiotropium has recently been registered for the treatment of asthma, and its use is associated with a reduction in exacerbation frequency. Anti-inflammatory and anti-remodeling effects of tiotropium have been demonstrated in in vitro and in vivo models. Because tiotropium treatment is used in combination with inhaled corticosteroids, potential additive effects between the two would be clinically relevant. Therefore, the aim of this study was to investigate additive effects between tiotropium and ciclesonide on airway inflammation and remodeling in guinea pig models of asthma. METHODS: Guinea pigs (n = 3-8/group) were sensitized and challenged with ovalbumin in an acute (single challenge) and a chronic model (12 weekly challenges) of allergic asthma. Animals were treated with vehicle, nebulized tiotropium (0.01-0.3 mM) and/or intranasally instilled ciclesonide (0.001-1 mg/kg) before each challenge. Bronchoalveolar lavage fluid and lungs were collected for analysis of airway inflammation and remodeling. RESULTS: Tiotropium and ciclesonide treatment, alone or in combination, did not inhibit airway inflammation in the acute asthma model. In a dose-finding study, low doses of tiotropium and ciclesonide inhibited airway eosinophilia and airway smooth muscle thickening in the chronic asthma model. Threshold doses of 0.01 mM tiotropium (nebulizer concentration) and 0.01 mg/kg ciclesonide were selected to investigate potential additive effects between both drugs. At these doses, tiotropium and ciclesonide did not inhibit airway eosinophilia or airway smooth muscle thickening when administered alone, but significantly inhibited these allergen-induced responses when administered in combination. CONCLUSIONS: Combined treatment with low doses of tiotropium and ciclesonide inhibits airway inflammation and remodeling in a guinea pig model of chronic asthma, suggesting that combined treatment with anticholinergics and corticosteroids may have anti-inflammatory and anti-remodeling activity in allergic airway diseases. Since tiotropium is registered as a therapy for asthma added on to corticosteroid treatment, these beneficial effects of the combination therapy may be clinically relevant.
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Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/imunologia , Asma/prevenção & controle , Modelos Animais de Doenças , Pregnenodionas/administração & dosagem , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Animais , Antialérgicos/administração & dosagem , Asma/induzido quimicamente , Broncodilatadores/administração & dosagem , Doença Crônica , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Cobaias , Masculino , Ovalbumina , Resultado do TratamentoRESUMO
Previous studies suggest that the large-conductance Ca(2+)-activated K(+) (BKCa) channel and Rho-kinase play major roles in the control of urinary bladder tone. Here, we investigated their involvement in ß-adrenoceptor (AR)-mediated relaxation of rat and human bladder. Concentration-response curves of isoprenaline and mirabegron-induced bladder relaxation were generated against passive tension and KCl- and carbachol-induced tone, in the absence or presence of the BKCa channel inhibitor iberiotoxin (100 nM) or the Rho-kinase inhibitor Y27,632 (1 µM). Myosin light chain (MLC) phosphorylation was studied by Western blot. In rat, iberiotoxin only slightly altered isoprenaline- and mirabegron-induced relaxation against KCl-induced tone but attenuated relaxation by both agonists against carbachol-induced tone. Y27,632 enhanced isoprenaline- or mirabegron-induced relaxation only against carbachol-induced tone. In humans, iberiotoxin slightly enhanced relaxation by both agonists against carbachol-induced pre-contraction. Y27,632 did not change isoprenaline-induced relaxation but enhanced that by mirabegron. Under passive tension, MLC phosphorylation was markedly reduced by both ß-AR agonists, an effect insensitive to Y27,632. In the presence of carbachol, both ß-AR agonists increased MLC phosphorylation, an effect reduced by Y27,632 only in the presence of 1 µM carbachol. These results indicate that the extent of BKCa channel and Rho-kinase involvement in relaxation induced by ß-AR agonists depends on pre contractile stimulus and species.
Assuntos
Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Relaxamento Muscular/fisiologia , Receptores Adrenérgicos beta 3/metabolismo , Bexiga Urinária/fisiologia , Quinases Associadas a rho/metabolismo , Acetanilidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Adulto , Idoso , Amidas/farmacologia , Animais , Feminino , Humanos , Técnicas In Vitro , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , Peptídeos/farmacologia , Fosforilação , Piridinas/farmacologia , Ratos Wistar , Especificidade da Espécie , Tiazóis/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
ß2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the ß2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with ß2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy.