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1.
Methods Mol Biol ; 2558: 35-43, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36169854

RESUMO

MAO activity measurement can be monitored by direct peroxidase-free assays following different spectroscopy methods. Typically, these are assays that follow the conversion of different MAO substrates into its corresponding products monitored in either absorbance or fluorescence. Herein, we describe the assays for enzyme activity assessment with MAO B and particularly the MAO A substrate kynuramine, as well as the MAO B substrate benzylamine. Moreover, we also describe MAO activity determination using the tertiary amine substrate allyl amine 1-methyl-4-(1-methyl-1 H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP). These are very useful methods for the investigation of MAO inhibitory activity by molecules known to be HRP-interfering. In the present chapter we demonstrate the application of these methods in MAO activity and Michaelis-Menten curve determinations as well as inhibitory activity experiments.


Assuntos
Cinuramina , Monoaminoxidase , Aminas , Benzilaminas , Cinética , Monoaminoxidase/metabolismo , Pirrolidinas
2.
Expert Opin Pharmacother ; 23(13): 1479-1484, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36124780

RESUMO

INTRODUCTION: Overactive bladder (OAB) is associated with physical, emotional, and financial burden. After failed conservative measures, second-line therapy includes medications, such as antimuscarinics and beta-3 adrenergic receptor (ß3AR) agonists. Antimuscarinics are most commonly prescribed but have systemic side effects that lead to poor compliance. ß3AR agonists include mirabegron and vibegron. Mirabegron is a first-generation ß3AR agonist that is effective for frequency, urgency urinary incontinence (UUI) and urgency, but has interactions with cytochrome P450 enzymes (CYPs) and cardiovascular sequelae. Vibegron is a second-generation ß3AR agonist that is highly selective and does not interact with CYPs. It is effective for reducing UUI episodes and daily micturition number and has a favorable side effect profile. AREAS COVERED: Clinical background, pharmacology, and clinical studies for vibegron. EXPERT OPINION: Vibegron is a welcomed addition to the OAB therapeutic landscape. This single dose, once daily option is effective, especially for patients with wet OAB, with a favorable side effect profile. Sub-analyses of patients ≥ 65 years have shown continued efficacy and safety. The few drug interactions are of benefit, especially for older patients with polypharmacy. As long-term data accrues, vibegron has the potential to drive the OAB therapeutic market.


Assuntos
Bexiga Urinária Hiperativa , Incontinência Urinária , Acetanilidas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Humanos , Antagonistas Muscarínicos/efeitos adversos , Pirimidinonas , Pirrolidinas , Receptores Adrenérgicos beta 3/uso terapêutico , Tiazóis , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico
3.
Cells ; 11(18)2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36139502

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease in which neuronal apoptosis and associated inflammation are involved in its pathogenesis. However, there is still no specific treatment that can stop PD progression. Isoalantolactone (IAL) plays a role in many inflammation-related diseases. However, its effect and mechanism in PD remain unclear. In this study, results showed that IAL administration ameliorated 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD-related pathological impairment and decreased motor activity in mice. Results from in vitro mechanistic studies showed that IAL regulated apoptosis-related proteins by activating the AKT/Nrf2 pathway, thereby suppressing the apoptosis of SN4741 cells induced by N-methyl-4-phenylpyridinium Iodide (MPP+). On the other hand, IAL inhibited LPS-induced release of pro-inflammatory mediators in BV2 cells by activating the AKT/Nrf2/HO-1 pathway and inhibiting the NF-κB pathway. In addition, IAL protected SN4741 from microglial activation-mediated neurotoxicity. Taken together, these results highlight the beneficial role of IAL as a novel therapy and potential PD drug due to its pharmacological profile.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , 1-Metil-4-fenilpiridínio , Animais , Apoptose , Fator de Transcrição de Proteínas de Ligação GA , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Iodetos/efeitos adversos , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , NF-kappa B/metabolismo , Doença de Parkinson/metabolismo , Proteínas Proto-Oncogênicas c-akt , Pirrolidinas , Sesquiterpenos
4.
Tuberculosis (Edinb) ; 136: 102252, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36063660

RESUMO

Due to several obstacles in treating tuberculosis (TB), the search for new therapeutic alternatives remains a global priority. The nitrogenous heterocyclic compounds are promising in searching for new anti-Mycobacterium tuberculosis molecules, and our previous results highlight the potential of tetrahydropyridines. After exploring the antimycobacterial potential and putative mechanism of action of a tetrahydropyridine derivative (NUNL02), we seek to measure the oxidative stress caused by NUNL02 inside the extracellular replicating M. tuberculosis since it could be the reason for the NUNL02 bactericidal effect against replicating and starved M. tuberculosis; and to evaluate the anti-M. tuberculosis activity of NUNL02 against the intracellular bacillus (even combined with an anti-TB drug) to explore the potential of this tetrahydropyridine as a promising adjuvant for TB therapy. Briefly, we assessed the activity of NUNL02 against the H37Rv strain and evaluated the combination of NUNL02 and rifampicin (RIF), at previously defined subinhibitory concentrations, against intramacrophage M. tuberculosis. NUNL02, in addition to promote the oxidative stress inside the extracellular replicating M. tuberculosis as a possible indirect mechanism of action, also presented bactericidal potential as promising as RIF against intracellular bacilli. Thus, our findings reinforce NUNL02 as a promising scaffold for the development of new options for TB.


Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Pirrolidinas/farmacologia , Rifampina/farmacologia
5.
Chem Commun (Camb) ; 58(77): 10841-10844, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36073180

RESUMO

An efficient approach to access α-arylacetylene-substituted pyrrolidine and piperidine derivatives has been developed through a samarium diiodide-mediated addition-elimination process of pyrrolidine and piperidine N-α-radicals with arylacetylene sulfones.


Assuntos
Samário , Sulfonas , Iodetos , Piperidinas , Pirrolidinas
6.
J Org Chem ; 87(18): 12087-12095, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36049485

RESUMO

A study involving the use of Mg-MeOH for the double reductive cleavage of both N-S and C-S bonds in a series of 11 benzo-fused cyclic sulfonamides is reported. Examples where the sulfonamide nitrogen atom is part of a pyrrolidine ring effectively undergo reduction, as long as a methoxy substituent is not para-positioned in the aromatic ring, relative to the sulfonyl group. In contrast, if the nitrogen atom is contained within an aromatic ring (pyrrole or indole), the presence of a para-methoxy substituent does not prohibit reduction. If deuterated methanol is used, aromatic ortho-deuterium incorporation was observed. To better understand how structure affects reactivity, density functional theory calculations were performed using three functionals. Results using CAM-B3LYP were found to best correlate with experimental observations, and these demonstrate the impact that the different aromatic substitution patterns and types of N-atom have on the lowest unoccupied molecular orbital (LUMO) energies and adiabatic electron affinities.


Assuntos
Metanol , Sulfonamidas , Deutério , Indóis , Nitrogênio , Pirróis , Pirrolidinas , Sulfanilamida
7.
Molecules ; 27(18)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36144776

RESUMO

Insomnia affects 4.4-4.8% of the world's population, but because the effect of hypnotic drugs is limited and may cause harmful side-effects, scientists are turning their attention to developing drugs that act on the orexin system. Daridorexant, a selective dual-orexin receptor antagonist (DORA), has exhibited promising results in both animal and human studies. Its activity was evaluated based on the physiology-based pharmacodynamic and pharmacokinetic model. The use of daridorexant is considered safe, with no clinically significant side-effects including deprivation of next-morning residual effects. In this manuscript we conducted a comprehensive review of daridorexant including pharmacodynamics, animal and human research, pharmacokinetics and safety.


Assuntos
Antagonistas dos Receptores de Orexina , Distúrbios do Início e da Manutenção do Sono , Animais , Humanos , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Imidazóis , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/uso terapêutico , Orexinas , Pirrolidinas , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
8.
Molecules ; 27(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36144811

RESUMO

Herein, we report the design and synthesis of a series of chiral pyrrolidine-substituted ferrocene-derived ligands. The proficiency of this novel structural motif was demonstrated in the Rh-catalyzed asymmetric hydrogenation of dehydroamino acid esters and α-aryl enamides. The products were obtained with full conversions and excellent levels of enantioselectivities of up to >99.9% ee and 97.7% ee, respectively, using a BINOL-substituted phosphine-phosphoaramidite ligand which possesses planar, central, and axial chirality elements.


Assuntos
Ródio , Alcenos , Catálise , Compostos Ferrosos , Hidrogenação , Ligantes , Metalocenos , Pirrolidinas , Ródio/química , Estereoisomerismo
9.
Nutrients ; 14(18)2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36145248

RESUMO

Ganoderma lucidum, one of the most valued medicinal mushrooms, has been used for health supplements and medicine in China. Our previous studies have proved that Ganoderma lucidum extract (GLE) could inhibit activation of microglia and protect dopaminergic neurons in vitro. In the present study, we investigated the anti-neuroinflammatory potential of GLE in vivo on Parkinsonian-like pathological dysfunction. Male C57BL/6J mice were subjected to acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion, and a treatment group was administered intragastrically with GLE at a dose of 400 mg/kg. Immunohistochemistry staining showed that GLE efficiently repressed MPTP-induced microglia activation in nigrostriatal region. Accordingly, Bio-plex multiple cytokine assay indicated that GLE treatment modulates abnormal cytokine expression levels. In microglia BV-2 cells incubated with LPS, increased expression of iNOS and NLRP3 were effectively inhibited by 800 µg/mL GLE. Furthermore, GLE treatment decreased the expression of LC3II/I, and further enhanced the expression of P62. These results indicated that the neuroprotection of GLE in an experimental model of PD was partially related to inhibition of microglia activation in vivo and vitro, possibly through downregulating the iNOS/NLRP3 pathway, inhibiting abnormal microglial autophagy and lysosomal degradation, which provides new evidence for Ganoderma lucidum in PD treatment.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Reishi , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia
10.
Molecules ; 27(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36080188

RESUMO

Recently, the strategy of multivalency has been widely employed to design glycosidase inhibitors, as glycomimetic clusters often induce marked enzyme inhibition relative to monovalent analogs. Polyhydroxylated pyrrolidines, one of the most studied classes of iminosugars, are an attractive moiety due to their potent and specific inhibition of glycosidases and glycosyltransferases, which are associated with many crucial biological processes. The development of multivalent pyrrolidine derivatives as glycosidase inhibitors has resulted in several promising compounds that stand out. Herein, we comprehensively summarized the different synthetic approaches to the preparation of multivalent pyrrolidine clusters, from total synthesis of divalent iminosugars to complex architectures bearing twelve pyrrolidine motifs. Enzyme inhibitory properties and multivalent effects of these synthesized iminosugars were further discussed, especially for some less studied therapeutically relevant enzymes. We envision that this comprehensive review will help extend the applications of multivalent pyrrolidine iminosugars in future studies.


Assuntos
Imino Açúcares , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases , Imino Açúcares/farmacologia , Pirrolidinas/farmacologia
11.
Asian Pac J Cancer Prev ; 23(9): 2965-2971, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36172658

RESUMO

BACKGROUND: Occult hepatitis C virus (HCV) infection (OCI) is diagnosed based on the detection of HCV-RNA in non-serum reservoirs, such as peripheral blood mononuclear cells (PBMCs) and/or hepatocytes with undetectable HCV-RNA in the serum. The current study was designed to shed more light on the presence of occult HCV in a population of cases who achieved an SVR after receiving treatments for HCV-infection and its significance. METHODS: This cross-sectional study evaluated 111 chronic HCV patients treated at Theodor Bilharz Research Institute, Egypt and achieved a sustained virological response (SVR) 12 -24 weeks after treatment with Direct acting antiviral drugs (DAAs). The treatment lasted 12 or 24 weeks using generic medications including Sofosbuvir (SOF) 400 mg/day and Daclatasvir (DCV) 60 mg/day ± weight-based Ribavirin (RBV) 600-1000 mg/day. After achieving the SVR 12 -24 weeks, all patients were subjected to clinical examination and full laboratory investigations. All the candidates were assessed for fibrosis pre/post-treatment by transient elastography (Fibroscan©). Eighty-seven patients (78.4%) received dual therapy (SOF/DCV) and 24 patients (21.6%) received triple therapy (SOF/DCV/RBV). One hundred and seven patients received the regimen for 12 weeks (96.4%) and only four patients received the regimen for 24 weeks (3.6%). All patients were examined in terms of HCV RNA in plasma and PBMCs. RESULTS: Nine patients (8.1%) were positive for PBMCs HCV RNA. The presence of Occult HCV infection (OCI) was significantly correlated with age, level of AFP, and the degree of liver stiffness. CONCLUSION: The OCI was present in 8.1% of the patients who achieved an SVR 12 - 24 weeks. These patients were mostly aged and with elevated AFP and advanced fibrosis. Monitoring and follow-up of those patients may help to assess the outcomes.


Assuntos
Hepatite C Crônica , Hepatite C , Idoso , Antivirais/uso terapêutico , Carbamatos , Estudos Transversais , Quimioterapia Combinada , Egito/epidemiologia , Fibrose , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Imidazóis , Leucócitos Mononucleares , Pirrolidinas , RNA , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Valina/análogos & derivados , alfa-Fetoproteínas
12.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S324, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36163982

RESUMO

CONTEXT: Ruxolitinib (JAK inhibitor) is effective in myelofibrosis, but suboptimal responses occur potentially from PI3K/AKT activation. In INCB50465-201 (NCT02718300), add-on parsaclisib (PI3Kδ inhibitor) showed preliminary efficacy in myelofibrosis patients. JAK inhibitors are associated with thrombocytopenia and patients with low platelet count (PC) are generally difficult to treat. OBJECTIVE: Evaluate efficacy and safety of add-on parsaclisib in a subgroup analysis of study INCB50465-201 by baseline PC. DESIGN: Open-label, phase 2. SETTING: Clinical study. PATIENTS: Primary/secondary myelofibrosis patients with a suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM]; or palpable spleen 5-10 cm below LSM and active symptoms) after ≥6 months of receiving ruxolitinib (5-25 mg BID; stable dose ≥8 weeks). INTERVENTIONS: Patients on stable ruxolitinib dose randomized to either add-on parsaclisib 10 or 20 mg QD for 8 weeks then same dose QW or parsaclisib 5 or 20 mg QD for 8 weeks then 5 mg QD. MAIN OUTCOME MEASURES: Spleen volume (SV), Myelofibrosis-Symptoms Assessment Form Total Symptom Score (MFSAF-TSS v3.0), and safety based on baseline PC (low PC, 50-<100×109/L; higher PC, ≥100×109/L). RESULTS: At data cutoff (08/27/2020), 67 patients (low PC, n=21; higher PC, n=46) were enrolled. For low versus higher PC, the median prior duration of ruxolitinib treatment was 34.7 versus 14.9 months and baseline median (range) MFSAF-TSS was 21.4 (0.6-47) versus 10.0 (0-43), respectively. For low versus higher PC patients: 9/18 (50%) versus 15/38 (39.4%) had spleen volume reduction (SVR) ≥10% at week 12, 6/17 (35.2%) versus 13/35 (37.1%) at week 24; 0 versus 1 had SVR ≥35% at week 12, 2 versus 1 at week 24; median change in MFSAF-TSS was -20.5% versus -22.2% at week 12, -26.1% versus -23.1% at week 24, respectively. Nonhematologic treatment-emergent adverse events were mostly grade 1 or 2; most common (≥25%) were dyspnea (7/21, 33%), falls (7/21, 33%), and peripheral edema (6/21, 29%) for low PC; diarrhea (13/46, 28%) for higher PC. Thrombocytopenia led to parsaclisib interruption in 9/21 low-PC versus 3/46 higher-PC patients and ruxolitinib interruption in 1/21 low-PC patients. CONCLUSIONS: Add-on parsaclisib showed promising efficacy and combination therapy was generally well-tolerated in myelofibrosis patients with low or higher baseline PC.


Assuntos
Anemia , Inibidores de Janus Quinases , Mielofibrose Primária , Trombocitopenia , Humanos , Inibidores de Janus Quinases/uso terapêutico , Nitrilas , Fosfatidilinositol 3-Quinases , Contagem de Plaquetas , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt , Pirazóis , Pirimidinas , Pirrolidinas , Resultado do Tratamento
13.
J Am Chem Soc ; 144(37): 16698-16702, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36043852

RESUMO

We report a joint experimental-theoretical study of the never reported before structure and infrared spectra of gas phase monohydrated nicotine (NIC) and nornicotine (NOR) and use them to assign their protonation sites. NIC's biological activity is strongly affected by its protonation site, namely, the pyrrolidine (Pyrro-NICH+, anticipated active form) and pyridine (Pyri-NICH+) forms; however, these have yet to be directly experimentally determined in either the nicotinic acetylcholine receptor (nAChR, no water present) or the acetylcholine-binding protein (AChBP, a single water molecule is present) but can only be inferred to be Pyrro-NICH+ from the intermolecular distance to the neighboring residues (i.e., tryptophan). Our temperature-controlled double ion trap infrared spectroscopic experiments assisted by the collisional stripping method and high-level theoretical calculations yield the protonation ratio of Pyri:Pyrro = 8:2 at 240 K for the gas phase NICH+···(H2O) complex, which resembles the molecular cluster present in the AChBP. Therefore, a single water molecule in the gas phase enhances this ratio in NICH+ relative to the 3:2 for the nonhydrated gas phase NICH+ in a trend that contrasts with the almost exclusive presence of Pyrro-NICH+ in aqueous solution. In contrast, the Pyri-NORH+ protomer is exclusively observed, a fact that may correlate with its weaker biological activity.


Assuntos
Nicotina , Receptores Nicotínicos , Acetilcolina , Sítios de Ligação , Proteínas de Transporte/química , Modelos Moleculares , Subunidades Proteicas/metabolismo , Piridinas , Pirrolidinas , Receptores Nicotínicos/química , Triptofano
14.
Cancer Chemother Pharmacol ; 90(4): 325-334, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36001108

RESUMO

PURPOSE: Fedratinib is an orally administered Janus kinase (JAK) 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib. This study evaluated the effect of multiple doses of the dual CYP3A4 and CYP2C19 inhibitor, fluconazole, on the pharmacokinetics of a single dose of fedratinib. METHODS: In this non-randomized, fixed-sequence, open-label study, healthy adult participants first received a single oral dose of fedratinib 100 mg on day 1. Participants then received fluconazole 400 mg on day 10 and fluconazole 200 mg once daily on days 11-23, with a single oral dose of fedratinib 100 mg on day 18. Pharmacokinetic parameters were calculated for fedratinib administered with and without fluconazole. RESULTS: A total of 16 participants completed the study and were included in the pharmacokinetic population. Coadministration of fedratinib with fluconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t) of fedratinib by 21% and 56%, respectively, compared with fedratinib alone. Single oral doses of fedratinib 100 mg administered with or without fluconazole were well tolerated. CONCLUSIONS: Systemic exposure after a single oral dose of fedratinib was increased by up to 56% when fedratinib was coadministered with fluconazole compared with fedratinib alone. TRIAL REGISTRY: CLINICALTRIALS.GOV: NCT04702464.


Assuntos
Fluconazol , Pirrolidinas , Adulto , Área Sob a Curva , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Fluconazol/farmacocinética , Voluntários Saudáveis , Humanos , Pirrolidinas/farmacocinética , Sulfonamidas/farmacocinética
15.
Sci Rep ; 12(1): 14612, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028552

RESUMO

We evaluated the efficacy and safety of trifluridine/tipiracil (TAS-102) plus bevacizumab in treating refractory metastatic colorectal cancer (mCRC) in a retrospective, observational study. Patients refractory or intolerant to standard therapies received TAS-102 (30-35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days) plus bevacizumab 5 mg/kg on days 1 and 15. Clinical and pathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) data were collected and analysed. Thirty-five patients were treated from July 2019 to October 2021 (median age 64 years). The majority of patients (68.6%) were receiving TAS-102 plus bevacizumab as third-line treatment. Patients received a median of 4 (range 2-15) cycles of treatment. Among 31 patients evaluable for response (88.6%), ORR and DCR were 3.2% and 51.6%, respectively. After a median 11.6 months' follow-up, median PFS was 4.3 (95% confidence interval [CI] 3.4-5.1) months and median OS was 9.3 (95% CI 6.6-12.1) months. The most common grade 3-4 toxicities were neutropenia, asthenia and nausea/vomiting, and there were no treatment-related deaths. This real-world study confirms the efficacy and safety of TAS-102 plus bevacizumab in patients with refractory mCRC.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Combinação de Medicamentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Pirrolidinas , Estudos Retrospectivos , Timina , Trifluridina , Uracila
16.
J Med Econ ; 25(1): 1092-1100, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35993729

RESUMO

AIMS: To evaluate the cost-effectiveness of vibegron compared with other oral pharmacologic therapies as treatment for overactive bladder (OAB). METHODS: A semi-Markov model with monthly cycles was developed to support a lifetime horizon of vibegron 75 mg from a US commercial payor or Medicare perspective. The model incorporated efficacy (reductions in daily micturitions and urinary incontinence episodes), adverse events, OAB-related comorbidities, drug-drug interactions, anticholinergic burden, and treatment persistence. Direct costs and quality-adjusted life years (QALY) were accumulated over time. The primary outcome was the cost per QALY incremental cost-effectiveness ratio (ICER). One-way (OWSA) and probabilistic sensitivity analyses (PSA) were performed. RESULTS: For commercial payors, vibegron was cost-effective at a willingness-to-pay (WTP) threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $9,311) and at a WTP threshold of $150,000/QALY versus mirabegron 25 mg (ICER, $141,957) and versus an anticholinergic basket based on market share (ICER, $118,121). For Medicare, vibegron was cost-effective at a WTP threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $12,154) and at a WTP threshold of $100,000/QALY versus mirabegron 25 mg (ICER, $99,150) and versus an anticholinergic market basket (ICER, $60,756). For commercial payors and Medicare, OWSAs for vibegron versus mirabegron indicated cost-effectiveness was most sensitive to vibegron persistence at 1 and 12 months. PSAs indicated that vibegron was cost-effective versus mirabegron 50 mg 98.6% and 100% of the time at $50,000/QALY for commercial payors and Medicare payors, respectively. LIMITATIONS: Due to lack of real-world data available on persistence, vibegron was assumed to have the same persistence as mirabegron 50 mg. Long-term efficacy was assumed to be sustained beyond 52 weeks in the absence of clinical trials longer than 52 weeks. CONCLUSIONS: Vibegron is cost-effective from a commercial payor (WTP threshold $150,000/QALY) and Medicare (WTP threshold $100,000/QALY) perspective when compared with other oral pharmacologic treatments for OAB.


Overactive bladder (OAB) affects more than 30 million adults in the United States. OAB is a condition associated with frequent and sudden urges to urinate. Drugs for treating OAB may improve symptoms for patients. Anticholinergic drugs are one type of drug available for treating OAB. Anticholinergic drugs may cause side effects such as dry mouth and constipation. Newer types of drugs called ß3-adrenergic receptor agonists are available for treating OAB symptoms. Vibegron is a member of the ß3-adrenergic receptor agonist class of drugs. Vibegron does not cause the same side effects related to anticholinergic drugs such as dry mouth and constipation. ß3-adrenergic receptor agonists work well for OAB symptoms but may be more expensive than anticholinergic drugs. It is important to choose drugs that work well and that are a reasonable price. This study assessed if vibegron is cost-effective for people enrolled in US private insurance and Medicare plans. Compared with other common drugs such as anticholinergic drugs for OAB, vibegron is cost-effective for people enrolled in private insurance and Medicare plans. This was in part because vibegron works better for longer and causes fewer adverse effects than other drugs. Vibegron may be considered "good value for money" for patients with OAB.


Assuntos
Bexiga Urinária Hiperativa , Acetanilidas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Idoso , Antagonistas Colinérgicos/uso terapêutico , Análise Custo-Benefício , Humanos , Medicare , Antagonistas Muscarínicos , Pirimidinonas , Pirrolidinas , Resultado do Tratamento , Estados Unidos , Bexiga Urinária Hiperativa/tratamento farmacológico
17.
Int J Pharm ; 625: 122106, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-36029993

RESUMO

Nanofibers (NFs) provide several delivery advantages like their great flexibility and similarity with extracellular matrix (ECM) which qualify them to be the unique model of a wound dressing. NFs could create mats of polymeric matrix loaded with an active agent enhancing its solubility and stability. In our study, Gentiopicroside (GPS) and Thymoquinone (TQ) loaded in NFs polymeric mats composed of coblended polyvinyl pyrrolidine (PVP) and methyl ether Polyethylene glycol (m-PEG) were fabricated via electrospinning technique. A morphological study using Scanning Electron Microscopy (SEM) was performed for all formulae as well as in vitro release study using High-performance Liquid chromatography (HPLC) for sample analysis. The optimized formula (F3) was chosen for further assays using Fourier-Transform Infrared Spectroscopy (FTIR), and Differential Scanning Calorimetry (DSC). Study of the antibacterial effect, and in vivo healing action for diabetic infected wounds to quantify Tumor necrosis factor-alpha and Cyclooxygenase-2 were also investigated. F3 achieved the highest % cumulative release (99.79 ± 6.47 for GPS and 96.89 ± 6.87 for TQ) at 60 min, and a smaller diameter (200 nm) showing significant anti-bacterial effects with well-organized skin architecture demonstrating great healing signs. Our results revealed that m-PEG/PVP NFs mats loaded with GPS and TQ could be considered an optimal wound care dressing.


Assuntos
Diabetes Mellitus Experimental , Éteres Metílicos , Nanofibras , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Bandagens , Benzoquinonas , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos Iridoides , Nanofibras/química , Polietilenoglicóis , Polímeros/química , Polivinil , Pirrolidinas , Ratos
18.
PLoS One ; 17(8): e0272567, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35980912

RESUMO

Real-world data on the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV infection and compensated cirrhosis is limited, especially for the 8-week regimen and in an Asian population. This retrospective study enrolled 159 consecutive patients with HCV and compensated cirrhosis who were treated with GLE/PIB at a single center in Taiwan. Sustained virological response (SVR) and adverse events (AEs) were evaluated. Among the 159 patients, 91 and 68 were treated with GLE/PIB for 8 and 12 weeks, respectively. In the per protocol analysis, both the 8- and 12-week groups achieved 100% SVR (87/87 vs. 64/64); and in the evaluable population analysis, 95.6% (87/91) of the 8-week group and 94.1% (64/68) of the 12-week group achieved SVR. The most commonly reported AEs, which included pruritus (15.4% vs. 26.5%), abdominal discomfort (9.9% vs. 5.9%), and skin rash (5.5% vs. 5.9%), were mild for the 8- and 12-week groups. Two patients in the 8-week group exhibited total bilirubin elevation over three times the upper normal limit. One of these two patients discontinued GLE/PIB treatment after 2 weeks but still achieved SVR. Both 8- and 12-week GLE/PIB treatments are safe and effective for patients of Taiwanese ethnicity with HCV and compensated cirrhosis.


Assuntos
Hepatite C Crônica , Hepatite C , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis , Ciclopropanos , Hepacivirus , Hepatite C/induzido quimicamente , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Prolina/análogos & derivados , Prolina/uso terapêutico , Pirrolidinas/uso terapêutico , Quinoxalinas/efeitos adversos , Estudos Retrospectivos , Sulfonamidas
19.
Bioorg Med Chem ; 71: 116942, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35930851

RESUMO

An elevated plasma level of soluble ST2 (sST2) is a risk biomarker for graft-versus-host disease (GVHD) and death in patients receiving hematopoietic cell transplantation (HCT). sST2 functions as a trap for IL-33 and amplifies the pro-inflammatory type 1 and 17 response while suppressing the tolerogenic type 2 and regulatory T cells activation during GVHD development. We previously identified small-molecule ST2 inhibitors particularly iST2-1 that reduces plasma sST2 levels and improved survival in two animal models. Here, we reported the structure-activity relationship of the furanylmethylpyrrolidine-based ST2 inhibitors based on iST2-1. Based on the biochemical AlphaLISA assay, we improved the activity of iST2-1 by 6-fold (∼6 µM in IC50 values) in the inhibition of ST2/IL-33 and confirmed the activities of the compounds in a cellular reporter assay. To determine the inhibition of the alloreactivity in vitro, we used the mixed lymphocyte reaction assay to demonstrate that our ST2 inhibitors decreased CD4+ and CD8+ T cells proliferation and increased Treg population. The data presented in this work are critical to the development of ST2 inhibitors in future.


Assuntos
Doença Enxerto-Hospedeiro , Animais , Linfócitos T CD8-Positivos/metabolismo , Furanos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Pirrolidinas/farmacologia , Relação Estrutura-Atividade
20.
J Org Chem ; 87(18): 12196-12213, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36007261

RESUMO

A novel carbenoid-mediated approach to thioisomünchnones was developed by intermolecular copper-catalyzed reactions of diazoacetamides with aromatic and heteroaromatic thioamides bearing a pyrrolidine moiety. The direction of the reaction can be switched toward 2-amino-2-heteroarylacrylamides by replacing the pyrrolidine with an aniline group or by the use of 2-cyano-2-diazoacetamides. The proposed mechanism and DFT calculations allowed us to rationalize the effect of substituents on the reaction direction. Effective methods were found for the synthesis of previously unknown both 2-heteroarylthioisomünchones and 2-heteroarylacrylamides, based on a wide scope of available reagents with a similar structure. Some of the synthesized thioisomünchnones exhibited multicolor fluorescence in the solid state and solutions.


Assuntos
Cobre , Tioamidas , Acrilamidas , Compostos de Anilina , Catálise , Cobre/química , Estrutura Molecular , Pirrolidinas , Tioamidas/química
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