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1.
BMC Pulm Med ; 24(1): 307, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38956524

RESUMO

Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.


Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Doença de Gilbert , Hiperbilirrubinemia , Indóis , Pirazóis , Piridinas , Quinolonas , Humanos , Doença de Gilbert/genética , Doença de Gilbert/tratamento farmacológico , Masculino , Aminofenóis/efeitos adversos , Aminofenóis/uso terapêutico , Feminino , Adulto , Fibrose Cística/tratamento farmacológico , Fibrose Cística/complicações , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Indóis/efeitos adversos , Benzodioxóis/efeitos adversos , Benzodioxóis/uso terapêutico , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Hiperbilirrubinemia/induzido quimicamente , Adulto Jovem , Pirróis/efeitos adversos , Adolescente , Glucuronosiltransferase/genética , Pirrolidinas , Quinolinas
2.
J Law Med ; 31(2): 217-224, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38963243

RESUMO

Until the discovery of the gene for cystic fibrosis (CF) in 1989, diagnostic developments were limited, and treatment focused on symptom alleviation. However, following the genetic breakthrough, some 2,000 mutations of the gene have been identified. More recently CF transmembrane conductance regulator modulator triple therapy (CFTRm) has been introduced in the form of triple therapy with ivacaftor, lumacaftor and tezacaftor (ETI), in the United States from 2019, Europe from 2020 and then Australia from 2021. The new treatment option has revolutionised both the quality of life and life expectancy of many persons diagnosed with CF. This editorial reviews major developments in the clinical care that can now be provided to patients, and reflects on the legal and ethical ramifications of the improved situation for many patients in the contexts of medical negligence, damages assessment, family law and criminal law. It also considers the difficult issues of access and equity caused by the limited availability of the triple therapy in low- and middle-income countries.


Assuntos
Aminofenóis , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Quinolonas , Humanos , Quinolonas/uso terapêutico , Aminofenóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Indóis/uso terapêutico , Austrália , Imperícia/legislação & jurisprudência , Estados Unidos
3.
Medicine (Baltimore) ; 103(27): e38801, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968495

RESUMO

DA-9601 extracted from Artemisia asiatica contains a bioactive compound - eupatilin - that can protect against gastric mucosal damage through anti-inflammatory and anti-oxidative properties and is approved for treating acute and chronic gastritis in Korea, but their ability to protect gastrointestinal (GI) bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is unclear. We aimed to compare the protective effects of DA-9601 to those of proton pump inhibitors (PPI) and rebamipide against upper and lower GI bleeding in patients with rheumatoid arthritis (RA) undergoing long-term NSAIDs therapy using the Korean Health Insurance Review and Assessment database. In this nationwide retrospective cohort study, we evaluated patients with RA who concurrently received NSAIDs for >3 months with DA-9601, PPI, or rebamipide between January 2015 and December 2017. The index date was the date of NSAIDs initiation, and all patients were followed up until December 2020 to detect upper and lower GI bleeding. In total, 24,258 patients with RA were eligible, and 5468 (22.5%), 4417 (18.2%), and 14,373 (59.3%) received DA-9601, PPI, or rebamipide, respectively, on the index date. During follow-up, upper and lower GI bleeding occurred in 508 (2.1%) and 402 (1.6%) patients with RA, respectively. The incidence rate of upper and lower GI bleeding was 615/100,000 and 485/100,000 person-years, respectively. Among patients with RA receiving DA-9601, PPI, or rebamipide, the frequencies of NSAIDs-induced upper GI bleeding were 0.5%, 0.4%, and 1.2%, respectively. The frequencies of NSAIDs-induced lower GI bleeding were 0.4%, 0.4%, and 0.9%, respectively. The incidence of NSAIDs-induced upper GI bleeding in patients with RA receiving DA-9601, PPI, and rebamipide was 601/100,000, 705/100,000, and 596/100,000 person-years, respectively, while the incidence of NSAIDs-induced lower GI bleeding in the same groups was 449/100,000, 608/100,000, and 465/100,000 person-years, respectively. In the multivariate Cox regression analysis, no significant difference was observed in lower and upper GI bleeding hazards between patients with RA using DA-9601, PPI, and rebamipide. Our results suggest that DA-9601 may exhibit protection against NSAIDs-induced GI bleeding that is comparable to those of PPI and rebamipide in patients with RA.


Assuntos
Alanina , Anti-Inflamatórios não Esteroides , Artrite Reumatoide , Hemorragia Gastrointestinal , Inibidores da Bomba de Prótons , Quinolonas , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/complicações , Feminino , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Alanina/análogos & derivados , Alanina/uso terapêutico , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/prevenção & controle , Inibidores da Bomba de Prótons/uso terapêutico , Estudos Retrospectivos , Anti-Inflamatórios não Esteroides/efeitos adversos , Quinolonas/uso terapêutico , Quinolonas/efeitos adversos , Idoso , Adulto
4.
BMC Pharmacol Toxicol ; 25(1): 39, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987799

RESUMO

BACKGROUND: Statins are widely used in cardiovascular disease (CVD) as a common lipid-lowering drug, while quinolones are widely used for the treatment of infectious diseases. It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination. Data suggest combinations of statin and quinolone may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis. This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction. METHODS: The purpose of this systematic review was to collect and evaluate the evidence surrounding statin-quinolone drug interactions and to discuss related risk mitigation strategies. The following databases were searched: PubMed (Medline), Embase, Scopus, and Cochrane Library. The systematic electronic literature search was conducted with the following search terms. In this study, three types of search terms were used: statins-related terms, quinolones-related terms, and drug interactions-related terms. RESULTS: There were 16 case reports that met the criteria for qualitative analysis. Patients were involved in the following adverse reactions: rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1), or myopathy (n = 1). In the included literature, patients vary in the dose and type of statins they take, including simvastatin (n = 10) at a dose range of 20-80 mg/d and atorvastatin (n = 4) at a dose of 80 mg/d. There were 2 patients with unspecified statin doses, separately using simvastatin and atorvastatin. The quinolones in combination were ciprofloxacin (n = 9) at a dose range of 800-1500 mg/d, levofloxacin (n = 6) at a dose range of 250-1000 mg/d, and norfloxacin (n = 1) in an unspecified dose range. 81% of the case patients were over 60 years of age, and about 1/3 had kidney-related diseases such as diabetic nephropathy, post-transplantation, and severe glomerulonephritis. Nearly two-third of the patients were on concomitant cytochrome P450 3A4 (CYP3A4) inhibitors, P-glycoprotein (P-gp) inhibitors, or organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors. CONCLUSION: Patients treated with statin-quinolone combination should be monitored more closely for changes in aspartate aminotransferase or creatine kinase (CK) levels, and muscle symptoms, especially in patients with ciprofloxacin or levofloxacin, with simvastatin and high-dose atorvastatin, over 60 years of age, with kidney-related diseases, and on concomitant CYP3A4 inhibitors.


Assuntos
Interações Medicamentosas , Inibidores de Hidroximetilglutaril-CoA Redutases , Quinolonas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Quinolonas/uso terapêutico , Quinolonas/efeitos adversos , Rabdomiólise/induzido quimicamente , Antibacterianos/efeitos adversos
5.
Respir Res ; 25(1): 269, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38982492

RESUMO

BACKGROUND: Cystic Fibrosis causing mutations in the gene CFTR, reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. METHODS: Small molecule potentiators, previously identified in CFTR binding studies, were tested for activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. RESULTS: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. CONCLUSION: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.


Assuntos
Aminofenóis , Brônquios , Regulador de Condutância Transmembrana em Fibrose Cística , Células Epiteliais , Quinolonas , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Quinolonas/farmacologia , Aminofenóis/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Fumaça/efeitos adversos , Células Cultivadas , Células HEK293 , Agonistas dos Canais de Cloreto/farmacologia , Agonistas dos Canais de Cloreto/uso terapêutico , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo
6.
BMC Microbiol ; 24(1): 248, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38971718

RESUMO

BACKGROUND: The usage of fluoroquinolones in Norwegian livestock production is very low, including in broiler production. Historically, quinolone-resistant Escherichia coli (QREC) isolated from Norwegian production animals rarely occur. However, with the introduction of a selective screening method for QREC in the Norwegian monitoring programme for antimicrobial resistance in the veterinary sector in 2014; 89.5% of broiler caecal samples and 70.7% of broiler meat samples were positive. This triggered the concern if there could be possible links between broiler and human reservoirs of QREC. We are addressing this by characterizing genomes of QREC from humans (healthy carriers and patients) and broiler isolates (meat and caecum). RESULTS: The most frequent mechanism for quinolone resistance in both broiler and human E. coli isolates were mutations in the chromosomally located gyrA and parC genes, although plasmid mediated quinolone resistance (PMQR) was also identified. There was some relatedness of the isolates within human and broiler groups, but little between these two groups. Further, some overlap was seen for isolates with the same sequence type isolated from broiler and humans, but overall, the SNP distance was high. CONCLUSION: Based on data from this study, QREC from broiler makes a limited contribution to the incidence of QREC in humans in Norway.


Assuntos
Antibacterianos , Galinhas , Farmacorresistência Bacteriana , Infecções por Escherichia coli , Escherichia coli , Quinolonas , Animais , Galinhas/microbiologia , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Humanos , Noruega , Infecções por Escherichia coli/veterinária , Infecções por Escherichia coli/microbiologia , Farmacorresistência Bacteriana/genética , Quinolonas/farmacologia , Antibacterianos/farmacologia , Genômica , Plasmídeos/genética , Doenças das Aves Domésticas/microbiologia , Testes de Sensibilidade Microbiana , Genoma Bacteriano/genética , DNA Girase/genética , DNA Topoisomerase IV/genética , Carne/microbiologia , Mutação , Proteínas de Escherichia coli/genética , Ceco/microbiologia
9.
J Med Chem ; 67(13): 11254-11272, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38889244

RESUMO

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).


Assuntos
Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos , Leucemia Mieloide Aguda , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/farmacocinética , Descoberta de Drogas , Ratos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Quinolonas/farmacocinética , Quinolonas/síntese química , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular
10.
J Appl Microbiol ; 135(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38908908

RESUMO

AIMS: This research focused on assessing the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants and antimicrobial susceptibility in Salmonella strains isolated from Thai canal water. METHODS AND RESULTS: From 2016 to 2020, 333 water samples were collected from six canals across Bangkok, Thailand. Salmonella spp. was isolated, PMQR genes were detected through polymerase chain reactions, and the antimicrobial susceptibility was examined using the disk diffusion method. The results indicated a 92.2% prevalence of Salmonella spp. in canal water, being serogroups B and C the most frequently detected. Overall, 35.3% of isolates harbored PMQR genes, being qnrS the most prevalent gene (97.2%, n = 137/141). Other PMQR genes, including qnrB, qnrD, oqxAB, and aac(6')-Ib-cr, were detected. Notably, six isolates harbored multiple PMQR genes. Furthermore, 9.3% and 3.8% of the overall isolates were resistant to nalidixic acid (NAL) and ciprofloxacin (CIP), respectively. PMQR-positive isolates showed higher rates of non-susceptibility to both NAL (48.2%, n = 68/141) and CIP (92.2%, n = 130/141) compared to PMQR-negative isolates (NAL: 8.9%, n = 23/258; CIP: 11.2%, n = 30/258). CONCLUSIONS: The high prevalence of Salmonella spp., significant PMQR-positive, and reduced susceptibility isolates in canal water is of public health concern in Bangkok.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Plasmídeos , Quinolonas , Salmonella , Microbiologia da Água , Tailândia , Salmonella/genética , Salmonella/efeitos dos fármacos , Salmonella/isolamento & purificação , Quinolonas/farmacologia , Plasmídeos/genética , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Proteínas de Bactérias/genética , Ciprofloxacina/farmacologia , Genes Bacterianos/genética
11.
Sci Rep ; 14(1): 13306, 2024 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858411

RESUMO

This study aimed to compare the clinical efficacy and investigate patients' preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty patients with DED were randomly treated with either 3% diquafosol or 2% rebamipide ophthalmic solution for 4 weeks, followed by an additional 4-week treatment using the other eye drop after a 2-week washout period. Objective and subjective assessments, including the corneal and conjunctival staining score, tear breakup time (TBUT), Schirmer 1 test, tear osmolarity, tear matrix metalloproteinase-9 (MMP-9), lipid layer thickness (LLT) and ocular surface disease index (OSDI), were performed at baseline, 4 weeks, 6 weeks, and 10 weeks. Patient preferences were assessed based on four categories (comfort, efficacy, convenience, willingness to continue) using a questionnaire and the overall subjective satisfaction score for each drug was obtained at the end of the trial. In total, 28 eyes from 28 patients were included in the analysis. Both diquafosol and rebamipide significantly improved the OSDI (p = 0.033 and 0.034, respectively), TBUT (p < 0.001 and 0.026, respectively), and corneal (p < 0.001 and 0.001, respectively) and conjunctival (p = 0.017 and 0.042, respectively) staining after 4 weeks of treatment. An increase in Schirmer test scores was observed only after rebamipide treatment (p = 0.007). No significant changes were detected in tear osmolarity, MMP-9, and LLT following both treatments. The patients' preference was slightly greater for diquafosol (46.4%) than rebamipide (36.7%), presumably due to rebamipide's bitter taste. The self-efficacy of both drugs and overall satisfaction scores were comparable. These findings indicate that two mucin secretagogues showed comparable effects in ameliorating symptoms and improving signs (TBUT, corneal and conjunctival staining) in patients with DED.


Assuntos
Alanina , Síndromes do Olho Seco , Mucinas , Quinolonas , Nucleotídeos de Uracila , Humanos , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Quinolonas/uso terapêutico , Estudos Prospectivos , Mucinas/metabolismo , Nucleotídeos de Uracila/uso terapêutico , Nucleotídeos de Uracila/administração & dosagem , Alanina/análogos & derivados , Alanina/uso terapêutico , Idoso , Lágrimas/metabolismo , Estudos Cross-Over , Soluções Oftálmicas , Polifosfatos/uso terapêutico , Resultado do Tratamento , Adulto , Metaloproteinase 9 da Matriz/metabolismo
12.
Eur J Med Chem ; 275: 116626, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38944934

RESUMO

The global microbial resistance is a serious threat to human health, and multitargeting compounds are considered to be promising to combat microbial resistance. In this work, a series of new thiazolylquinolones with multitargeting antimicrobial potential were developed through multi-step reactions using triethoxymethane and substituted anilines as start materials. Their structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Antimicrobial evaluation revealed that some of the target compounds could effectively inhibit microbial growth. Especially, carbothioamido hydrazonyl aminothiazolyl quinolone 8a showed strong inhibitory activity toward drug-resistant Staphylococcus aureus with MIC value of 0.0047 mM, which was 5-fold more active than that of norfloxacin. The highly active compound 8a exhibited negligible hemolysis, no significant toxicity in vitro and in vivo, low drug resistance, as well as rapidly bactericidal effects, which suggested its favorable druggability. Furthermore, compound 8a was able to effectively disrupt the integrity of the bacterial membrane, intercalate into DNA and inhibit the activity of topoisomerase IV, suggesting multitargeting mechanism of action. Compound 8a could form hydrogen bonds and hydrophobic interactions with DNA-topoisomerase IV complex, indicating the insertion of aminothiazolyl moiety was beneficial to improve antibacterial efficiency. These findings indicated that the active carbothioamido hydrazonyl aminothiazolyl quinolone 8a as a chemical therapeutic candidate demonstrated immense potential to tackle drug-resistant bacterial infections.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Quinolonas , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Quinolonas/farmacologia , Quinolonas/química , Quinolonas/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química , Humanos , Relação Dose-Resposta a Droga , Staphylococcus aureus/efeitos dos fármacos , Animais
13.
Int J Mol Sci ; 25(12)2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38928197

RESUMO

Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.


Assuntos
Antineoplásicos , Neoplasias da Mama , Naftoquinonas , Humanos , Naftoquinonas/farmacologia , Naftoquinonas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Células MCF-7 , Quinolonas/farmacologia , Quinolonas/química , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células em Três Dimensões/métodos , Doxorrubicina/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos
14.
J Med Econ ; 27(1): 897-906, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38939921

RESUMO

AIMS: We aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems. MATERIAL AND METHODS: This retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation. RESULTS: People with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV1 [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9). CONCLUSION: CF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.


Cystic fibrosis (CF) is a disease caused by a single faulty gene called CFTR, which affects the lungs, pancreas, and other organs. Medications known as CFTR modulators help improve the function of this faulty gene and have shown benefits for people with CF. In Sweden, two such medicines, lumacaftor and ivacaftor (LUM/IVA), have been available since July 2018 for treating CF. This study looks at the impact of CF on patients, caregivers, and the healthcare system, as well as the benefits of CFTR modulators. Using data from Swedish national healthcare and social insurance registries, the study compared 743 people with CF in 2019 to about 7400 people without CF, matched by sex, birth year, and location. The findings show that people with CF had 24 times higher direct healthcare costs, including outpatient visits, hospitalizations, and CF-related medications, totaling 23,233 Euros. Indirect costs, such as work absences for those over 18 with CF anssd caregivers' absences to care for sick children, were 9,629 Euros, which is five times higher than the general population. Those over 6 years old treated with LUM/IVA showed improved lung health, reduced hospitalizations (though not significantly), and needed fewer antibiotics. Caregivers' work absences decreased, but there was no change in work absences for adults with CF. Overall, treatment with LUM/IVA improved clinical outcomes and reduced the burden on caregivers and society.


Assuntos
Aminofenóis , Aminopiridinas , Benzodioxóis , Efeitos Psicossociais da Doença , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Combinação de Medicamentos , Quinolonas , Sistema de Registros , Humanos , Fibrose Cística/tratamento farmacológico , Masculino , Feminino , Suécia , Aminofenóis/uso terapêutico , Aminofenóis/economia , Quinolonas/uso terapêutico , Quinolonas/economia , Estudos Retrospectivos , Benzodioxóis/uso terapêutico , Benzodioxóis/economia , Aminopiridinas/uso terapêutico , Aminopiridinas/economia , Criança , Adolescente , Adulto , Adulto Jovem , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Cuidadores , Pessoa de Meia-Idade , Absenteísmo , Gastos em Saúde/estatística & dados numéricos , Serviços de Saúde/estatística & dados numéricos , Serviços de Saúde/economia
15.
BMC Oral Health ; 24(1): 645, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824583

RESUMO

OBJECTIVES: This study aimed to evaluate the preventive and therapeutic effects of rebamipide gargle in comparison with benzydamine in head and neck cancer patients undergoing radiotherapy with or without chemotherapy. MATERIALS AND METHODS: Phase III randomized clinical trial was conducted from January 2021 till August 2022 on one hundred patients with head and neck cancer receiving high doses of radiotherapy. These patients were equally allocated into either rebamipide group or benzydamine group, The measured outcomes were the incidence of oral mucositis ≥ grade1, according to the WHO mucositis scale, in addition to the duration, and the onset of oral mucositis. RESULTS: There was no statistically significant difference between the two groups, regarding the incidence of a severe grade of oral mucositis (WHO grades 3), as well as the onset and duration of oral mucositis. Both gargles succeeded to prevent the development of WHO grade 4 oral mucositis. Side effects reported were mainly burning sensation in benzydamine group and nausea in rebamipide group. CONCLUSION: Rebamipide mouthwash was as beneficial as benzydamine mouthwash in minimizing the incidence of severe oral mucositis induced by treatment of head and neck cancer. However, rebamipide gargle proved to be superior to benzydamine in terms of reduction in the severity of the radiation-induced oral mucositis. TRIAL REGISTRATION: The trial was registered in the protocol Registration and Result system of Clinical Trials (Registration ID: NCT04685395)0.28-12-2020.


Assuntos
Alanina , Benzidamina , Neoplasias de Cabeça e Pescoço , Antissépticos Bucais , Quinolonas , Estomatite , Humanos , Estomatite/prevenção & controle , Estomatite/etiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Benzidamina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Feminino , Quinolonas/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Antissépticos Bucais/uso terapêutico , Quimiorradioterapia/efeitos adversos , Lesões por Radiação/prevenção & controle , Idoso , Adulto
16.
Chem Commun (Camb) ; 60(55): 7093-7096, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38899811

RESUMO

In this communication, we explored the synthesis of novel alkoxy-functionalised dihydropyrimido[4,5-b]quinolinones using a microwave-assisted multicomponent reaction. All the synthesized molecules were screened for anti-proliferative and anti-invasive activity against glioblastoma cells. 5c shows the most potent anti-proliferative activity with a half maximal effective concentration of less than 3 µM against primary patient-derived glioblastoma cells. 5c effectively inhibited invasion and tumor growth of 3D primary glioma cultures in a basement membrane matrix. This suggests that the novel compounds could inhibit both the proliferation and invasive spread of glioma and they were selected for further study.


Assuntos
Antineoplásicos , Proliferação de Células , Quinolonas , Humanos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Estrutura Molecular , Relação Estrutura-Atividade
17.
Circ Res ; 135(2): 280-297, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38847080

RESUMO

BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles, including small extracellular vesicles or exosomes, and their molecular cargo are known to modulate cell-to-cell communication during multiple cardiac diseases. However, the role of systemic extracellular vesicle biogenesis inhibition in HF models is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of tipifarnib, a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a [Ras associated binding protein 27a], nSMase2 [neutral sphingomyelinase 2], and Alix [ALG-2-interacting protein X]) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery were randomly assigned to groups with and without tipifarnib treatment (10 mg/kg 3 times/wk) and monitored for 8 weeks, and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced left ventricular dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of tipifarnib in TAC mice reduced circulating exosomes to baseline and remarkably improved left ventricular functions, hypertrophy, and fibrosis. Tipifarnib treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR 331-5p, which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR 331-5p is crucial for inhibiting the fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR 331-5p that acts as a potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib-mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling in HF.


Assuntos
Vesículas Extracelulares , Insuficiência Cardíaca , Quinolonas , Animais , Masculino , Camundongos , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Modelos Animais de Doenças , Vesículas Extracelulares/efeitos dos fármacos , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/prevenção & controle , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Distribuição Aleatória , Regulação para Cima/efeitos dos fármacos , MicroRNAs , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo
18.
ACS Infect Dis ; 10(7): 2419-2442, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38862127

RESUMO

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331, exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596, a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598, a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.


Assuntos
Antimaláricos , Plasmodium falciparum , Quinolonas , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/farmacocinética , Animais , Plasmodium falciparum/efeitos dos fármacos , Camundongos , Quinolonas/farmacologia , Quinolonas/química , Quinolonas/farmacocinética , Malária/tratamento farmacológico , Malária/prevenção & controle , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Feminino , Relação Estrutura-Atividade
19.
Nat Commun ; 15(1): 5345, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38937474

RESUMO

Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Farnesiltranstransferase , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/metabolismo , Farnesiltranstransferase/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Animais , Camundongos , Vício Oncogênico/genética , Terapia de Alvo Molecular , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Oncogenes/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Quinolonas
20.
Int J Immunopathol Pharmacol ; 38: 3946320241260262, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38876119

RESUMO

INTRODUCTION: TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin. METHODS: Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7th day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry. RESULTS: Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin. CONCLUSION: The combination of deucravacitinib and shikonin is a promising clinical application.


Assuntos
Quimioterapia Combinada , Imiquimode , Naftoquinonas , Psoríase , Pele , Animais , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Camundongos , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Modelos Animais de Doenças , Citocinas/metabolismo , Camundongos Endogâmicos BALB C , Masculino , Feminino , Benzimidazóis , Quinolonas
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