Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42.264
Filtrar
1.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502086

RESUMO

In recent years, enzymes have risen as promising therapeutic tools for different pathologies, from metabolic deficiencies, such as fibrosis conditions, ocular pathologies or joint problems, to cancer or cardiovascular diseases. Treatments based on the catalytic activity of enzymes are able to convert a wide range of target molecules to restore the correct physiological metabolism. These treatments present several advantages compared to established therapeutic approaches thanks to their affinity and specificity properties. However, enzymes present some challenges, such as short in vivo half-life, lack of targeted action and, in particular, patient immune system reaction against the enzyme. For this reason, it is important to monitor serum immune response during treatment. This can be achieved by conventional techniques (ELISA) but also by new promising tools such as microarrays. These assays have gained popularity due to their high-throughput analysis capacity, their simplicity, and their potential to monitor the immune response of patients during enzyme therapies. In this growing field, research is still ongoing to solve current health problems such as COVID-19. Currently, promising therapeutic alternatives using the angiotensin-converting enzyme 2 (ACE2) are being studied to treat COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/uso terapêutico , COVID-19/tratamento farmacológico , Terapia Enzimática/métodos , Proteínas Recombinantes/uso terapêutico , Enzima de Conversão de Angiotensina 2/farmacologia , Ensaios Clínicos Fase II como Assunto , Composição de Medicamentos/métodos , Estabilidade Enzimática , Terapia Enzimática/história , Terapia Enzimática/tendências , Meia-Vida , História do Século XX , História do Século XXI , Humanos , Proteínas Recombinantes/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
2.
Molecules ; 26(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34443355

RESUMO

Amitraz, a member of the formamidine pesticide family, commonly used for ectoparasite control, is applied as a dip or low-pressure hand spray to cattle and swine, and the neck collar on dogs. Data on amitraz were generated mainly on laboratory animals, hens, dogs, and baboons. The data on the toxicity and disposition of amitraz in animals and its residues in the milk are inadequate. Therefore, the present study was intended to analyze the disposition kinetics of amitraz and its pattern of elimination in the milk of lactating does after a single dermal application at a concentration of 0.25%. Blood at predetermined time intervals and milk twice daily were collected for eight days post application. The drug concentration was assayed by high-performance liquid chromatography (HPLC). Amitraz was detected in whole blood as early as 0.5 h, which attained a peak concentration at 12 ± 5 h, followed by a steady decline; however, detection persisted until 168 h. Amitraz was present in the blood at its 50% Cmax even after 48 h, and was still detectable after 7 days. The disposition after a single dermal application was best described non-compartmentally. The mean terminal half-life (t1/2), mean residence time (MRT), and area under the curve (AUC0-t) were 111 ± 31 h, 168 ± 39 h, and 539 ± 211 µg/mL/h, respectively. The apparent volume of distribution (Vdarea) was 92 ± 36 mL/g with an observed clearance (Cl) of 0.57 ± 0.33 mL/kg/h. Thus, the drug was well absorbed, widely distributed and slowly eliminated from the animal body. Amitraz achieved milk concentration approximating 0.2 per cent of the total dose after a single exposure and the steady-state elimination of amitraz in milk above the recommended maximum residue limit (MRL) of 0.01 mg/kg can act as a source of public health concern when applied on lactating animals.


Assuntos
Cervos , Lactação , Resíduos de Praguicidas/metabolismo , Toluidinas/metabolismo , Animais , Ácidos Cólicos , Feminino , Meia-Vida , Cinética
3.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204256

RESUMO

The marine carotenoids fucoxanthin and siphonaxanthin are powerful antioxidants that are attracting focused attention to identify a variety of health benefits and industry applications. In this study, the binding energy of these carotenoids with the SARS-CoV-2 Spike-glycoprotein was predicted by molecular docking simulation, and their inhibitory activity was confirmed with SARS-CoV-2 pseudovirus on HEK293 cells overexpressing angiotensin-converting enzyme 2 (ACE2). Siphonaxanthin from Codium fragile showed significant antiviral activity with an IC50 of 87.4 µM against SARS-CoV-2 pseudovirus entry, while fucoxanthin from Undaria pinnatifida sporophyll did not. The acute toxicities were predicted to be relatively low, and pharmacokinetic predictions indicate GI absorption. Although further studies are needed to elucidate the inhibition of viral infection by siphonaxanthin, these results provide useful information in the application of these marine carotenoids for the treatment and prevention of COVID-19.


Assuntos
Antivirais/farmacologia , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacos , Xantofilas/química , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/química , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Clorófitas/química , Clorófitas/metabolismo , Células HEK293 , Meia-Vida , Humanos , Simulação de Acoplamento Molecular , Feófitas/química , Feófitas/metabolismo , Ratos , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologia , Xantofilas/uso terapêutico
4.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199388

RESUMO

The chemical fungicide fludioxonil is widely used to control post-harvest fungal disease in cherries. This study was implemented to investigate the dissipation behaviours and residues of fludioxonil on cherries. A reliable and efficient analytical method was established. Cherry samples from four product areas were analyzed by QuEChERS and HPLC-MS/MS methods with acceptable linearity (R2 > 0.99), accuracy (recoveries of 81-94%), and precision (relative standard deviation of 2.5-11.9%). The limits of quantification (LOQs) and limits of detection (LODs) of cherries were 0.01 mg/kg and 0.005 mg/kg. The dissipation of fludioxonil on cherries followed first order kinetics with half-lives of 33.7-44.7 days. The terminal residues of fludioxonil were all lower than 5.00 mg/kg, which is the MRL recommended by the European Commission. According to Chinese dietary patterns and terminal residue distributions, the risk quotient (RQs) of fludioxonil was 0.61%, revealing that the evaluated cherries exhibited an acceptably low dietary risk to consumers.


Assuntos
Exposição Dietética/análise , Dioxóis/análise , Fungicidas Industriais/análise , Prunus/química , Pirróis/análise , Cromatografia Líquida de Alta Pressão , Meia-Vida , Cinética , Limite de Detecção , Estrutura Molecular , Prunus/microbiologia , Espectrometria de Massas em Tandem
5.
Eur J Pharm Sci ; 165: 105941, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256102

RESUMO

Single-domain antibodies, VHHs or nanobodies, represent a promising set of alternatives to conventional therapeutic antibodies, gaining substantial attention in the field of cancer immunotherapy. However, inherent drawbacks of nanobodies such as fast clearance from blood circulation and lack of immune effector functions often led to unsatisfactory therapeutic efficacy. We previously reported that dinitrophenyl modification of an anti-EGFR VHH conferred Fc-dependent immune effector functions and elongated serum half-life on it through recruiting of hapten antibodies, resulting in improved immunotherapy efficacy in vivo. In the present work, we further tested the versatility of this approach in the case of an anti-PD-L1 blockade VHH (KN035). Site-specific dinitrophenyl conjugation did not impair the binding capacity of KN035 portion to PD-L1, but indirectly restored its immune effector functions, manifested by the observed antibody dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against PD-L1 positive tumor cells. Significant delay of blood clearance of dinitrophenylated KN035 was evidenced by the prolonged half-life of ca. 22 h. This approach, using small hapten molecule conjugation, loaded additional antibody-mediated tumor killing mechanisms to PD-L1 blockade VHH and therefore improved efficacy is anticipated in the future in vivo therapeutic studies. Thus, our results underscore the power of this versatile approach for achieving desirable properties of VHH-based or similar therapeutics.


Assuntos
Antígeno B7-H1 , Neoplasias , Dinitrofenóis , Meia-Vida , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico
6.
Eur J Pharm Sci ; 165: 105928, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265405

RESUMO

Conjugation with polyethylene glycol (PEG), PEGylation, has been considered a useful tool to improve drug-like properties of novel small molecules and biologics in drug discovery. PEG40 or 40 kDa PEG is a double-branched PEG, routinely employed to improve the pharmacokinetics (PK) of therapeutics, including successful marketed products such as Pegasys® and Omontys®. However, less is known about the extent of contribution of PEG40 to the overall PK of the PEGylated product. Considering the half-life of PEG40 conjugated PEGylated products ranges from 1 to 14 days in human, this information is immensely valuable. After successfully developing a high sensitivity NMR based analytical method to quantitate PEG40 in mice serum after intravenous (IV) administration (Khandelwal et al., 2019), here, we extend its application to measure PEG40 in serum after IV administration and subcutaneous (SC) absorption in routinely employed non-clinical species in drug discovery, namely, mice, rats and cynomolgus monkeys. We utilized non-compartmental analysis and compartmental modeling to characterize the PK of PEG40 in these non-clinical species. Finally, we employed allometric scaling and Wajima (MRT-Css) method to predict the PK of PEG40 in human after IV administration and SC absorption. In general, our data shows that intrinsic PK parameters of PEG40 in mice, rats and cynomolgus monkeys are in the range of published literature values for PEG40-conjugated products, unless saturable clearance mechanisms are involved. We observed a bioavailability (F) of ~68% in CD-1 mice after SC administration of PEG40. In rats, the clearance (CL) and volume of distribution at steady state (Vss) after IV infusion of PEG40 were 0.079 mL/min/kg and 0.19 L/kg, respectively; and SC bioavailability was ~20%. In cynomolgus monkeys, after IV infusion, CL and Vss of PEG40 were 0.037 mL/min/kg and 0.20 L/kg, respectively; and SC bioavailability was ~69%. In addition, our findings indicate flip-flop kinetics of PEG40 in rodents, but not in cynomolgus monkeys. Finally, in human, intrinsic CL and Vss of PEG40 were projected to be 0.02 mL/min/kg (0.084 L/h) and 0.22 L/kg, respectively. This comprehensive report of PK of PEG40 in non-clinical species and its subsequent prediction in humans is expected to be useful to drug discovery and development scientists for efficient decision-making and optimal resource utilization.


Assuntos
Polietilenoglicóis , Administração Intravenosa , Animais , Disponibilidade Biológica , Meia-Vida , Humanos , Macaca fascicularis , Camundongos , Ratos
7.
Chem Pharm Bull (Tokyo) ; 69(7): 646-651, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193713

RESUMO

With the aim of studying the pharmacokinetics of letermovir, which is a newly developed antiviral agent for human cytomegalovirus, a rapid and simple ultra-performance liquid chromatography coupled with mass spectrometry (UPLC/MS) method was developed and validated for the quantification of letermovir in human plasma. Separation was performed in reverse phase mode using an ACQUITY UPLC BEH C18 column (130 Å, 1.7 µm, 2.1 × 50 mm) at a flow rate of 0.3 mL/min, 10 mM ammonium acetate-0.1% formic acid solution as mobile phase A, and acetonitrile as mobile phase B with a gradient elution. The method was validated over a linear range of 10-1000 ng/mL with a coefficient of determination (R2) >0.99 using weighted linear regression analysis. The intra- and inter-assay accuracy (nominal%) and precision (relative standard deviation%) were within ±15 and ≤15%, respectively. The specificity, recovery, matrix effect, stability, and dilution integrity of this method were also within acceptable limits. This method could be useful in studying the pharmacokinetics and pharmacodynamics, as well as performing the therapeutic drug monitoring of letermovir.


Assuntos
Acetatos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Quinazolinas/sangue , Espectrometria de Massas em Tandem/métodos , Acetatos/farmacocinética , Antivirais/sangue , Antivirais/farmacocinética , Meia-Vida , Humanos , Limite de Detecção , Quinazolinas/farmacocinética , Reprodutibilidade dos Testes
8.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200910

RESUMO

To increase the half-life of growth hormones, we proposed its long-lasting regulation through the ubiquitin-proteasome system (UPS). We identified lysine residues (K67, K141, and K166) that are involved in the ubiquitination of human growth hormone (hGH) using ubiquitination site prediction programs to validate the ubiquitination sites, and then substituted these lysine residues with arginine residues. We identified the most effective substituent (K141R) to prevent ubiquitination and named it AUT-hGH. hGH was expressed and purified in the form of hGH-His, and ubiquitination was first verified at sites containing K141 in the blood stream. Through the study, we propose that AUT-hGH with an increased half-life could be used as a long-lasting hGH in the blood stream.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Ubiquitinação , Animais , Citoplasma/metabolismo , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Células HEK293 , Meia-Vida , Humanos , Masculino , Camundongos , Células NIH 3T3 , Ratos , Ratos Sprague-Dawley
9.
Anal Chem ; 93(28): 9771-9777, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34240861

RESUMO

Considering the expanding demand for nuclear waste management of the spent nuclear fuel materials in near future, a nondestructive analytical scheme applicable to one of the most difficult-to-measure nuclides 107Pd, which emits no decay γ-rays and whose half-life is too long to be decayed out during a human lifetime, was designed. The scheme consists of a sophisticated instrument capable of the detection of γ-rays by Ge detectors coupled with time-of-flight measurement of neutrons and a high-intensity pulsed neutron beam and can simultaneously perform time-of-flight-coupled prompt γ-ray analysis (TOF-PGA) as well as PGA and neutron resonance capture analysis (NRCA). The analytical capability for simulated samples of the Tc-platinum group metals (Tc-PGMs) obtained by the group-partitioning process of spent nuclear fuels, which contain not only 107Pd but also 99Tc and other difficult-to-measure fission products, was evaluated. It was confirmed that although PGA and NRCA can accurately analyze both nuclides in individual, single substances, only TOF-PGA can analyze 107Pd as well as 99Tc in the Tc-PGM-simulated sample. The TOF-PGA measurement technique can be widely used for the nondestructive analysis of 107Pd and 99Tc in nuclear wastes.


Assuntos
Nêutrons , Resíduos Radioativos , Raios gama , Meia-Vida , Humanos , Radioisótopos
10.
AAPS PharmSciTech ; 22(5): 198, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34195881

RESUMO

Chemical penetration enhancers (CPEs) are commonly added into transdermal patches to impart improved skin permeation of drug. However, significant unexplained variability in drug release kinetics in transdermal patches is possible as a result of the addition of CPEs; investigations into the underlying mechanisms are still limited. In the present study, a diverse set of CPEs was employed to draw broad conclusions. Solubility parameters of CPEs and acrylate pressure-sensitive adhesive were calculated by molecular dynamics simulation and Fedors group contribution method to evaluate drug-adhesive miscibility. CPE-adhesive interaction was characterized by FT-IR study, 13C NMR spectroscopy, and molecular docking simulation. Results showed that release enhancement ratio (ERR) of CPEs for zolmitriptan was rank ordered as isopropyl myristate > azone > Plurol Oleique® CC497 > Span® 80 > N-methylpyrrolidone > Transcutol® P. It was found that solubility parameter difference (Δδ) between CPE and adhesive was negatively related with ERR. It was proved that hydrogen bonding between CPE and adhesive would increase drug release rate, but only if the CPE showed good miscibility with adhesive. CPE like isopropyl myristate, which had good miscibility with adhesive, could decrease drug-adhesive interaction leading to the release of drug from adhesive.


Assuntos
Adesivos/química , Simulação de Acoplamento Molecular , Miristatos/química , Oxazolidinonas/metabolismo , Adesivo Transdérmico , Triptaminas/metabolismo , Administração Cutânea , Animais , Liberação Controlada de Fármacos , Meia-Vida , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Masculino , Oxazolidinonas/química , Ratos , Ratos Wistar , Absorção Cutânea , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , Triptaminas/química
11.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207956

RESUMO

This review is a survey of recent advances in studies concerning the impact of poly- and perfluorinated organic compounds in aquatic organisms. After a brief introduction on poly- and perfluorinated compounds (PFCs) features, an overview of recent monitoring studies is reported illustrating ranges of recorded concentrations in water, sediments, and species. Besides presenting general concepts defining bioaccumulative potential and its indicators, the biodistribution of PFCs is described taking in consideration different tissues/organs of the investigated species as well as differences between studies in the wild or under controlled laboratory conditions. The potential use of species as bioindicators for biomonitoring studies are discussed and data are summarized in a table reporting the number of monitored PFCs and their total concentration as a function of investigated species. Moreover, biomolecular effects on taxonomically different species are illustrated. In the final paragraph, main findings have been summarized and possible solutions to environmental threats posed by PFCs in the aquatic environment are discussed.


Assuntos
Organismos Aquáticos/metabolismo , Bioacumulação , Monitoramento Biológico , Fluorcarbonetos/metabolismo , Meia-Vida , Distribuição Tecidual
12.
Clin Drug Investig ; 41(7): 629-638, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34151413

RESUMO

BACKGROUND AND OBJECTIVES: Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. METHODS: Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. RESULTS: Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0-24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0-24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. CONCLUSION: These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection.


Assuntos
Desoxiadenosinas/administração & dosagem , Piridonas/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Desoxiadenosinas/efeitos adversos , Desoxiadenosinas/sangue , Desoxiadenosinas/farmacocinética , Método Duplo-Cego , Esquema de Medicação , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Piridonas/efeitos adversos , Piridonas/sangue , Piridonas/farmacocinética , Curva ROC , Sonolência , Triazóis/efeitos adversos , Triazóis/sangue , Triazóis/farmacocinética , Adulto Jovem
13.
Expert Opin Investig Drugs ; 30(8): 893-901, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34176392

RESUMO

BACKGROUND: Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported. RESEARCH DESIGN AND METHODS: Two Phase 1 studies (overall N = 93) assessed single- and multiple-dose balovaptan PK in healthy adults. One (N = 16) assessed absolute oral bioavailability (10 mg or 50 mg) vs a [13C]-balovaptan microdose. The other (N = 77) explored single- (0.5-76 mg) and multiple-dose (14 days; 12-52 mg/day) - randomized 6:2 balovaptan:placebo per dose - PK, dose proportionality, and the effect of food on single-dose (32 mg) Cmax and AUCinf. RESULTS: Absolute balovaptan bioavailability was high (103-116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45-47 hours, but single-dose Cmax increased more than dose proportionally and half-life was inversely dose-proportional - a discordance partially attributable to a dose-and-time-dependent volume of distribution. Accumulation (Day 1-Day 14) was inversely dose-proportional (~3.5 [12 mg] to ~1.8 [52 mg]). There was no relevant effect of a high-fat meal on single-dose balovaptan exposure. There were no safety signals: 2/93 subjects discontinued for adverse events. CONCLUSIONS: Balovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03764449; NCT01418963.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Interações Alimento-Droga , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Adolescente , Adulto , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Área Sob a Curva , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacocinética , Fatores de Tempo , Distribuição Tecidual , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto Jovem
14.
Cell Prolif ; 54(7): e13081, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34121240

RESUMO

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis. MATERIALS AND METHODS: SKLB-YTH-60 was developed through computer-aided drug design, de novo synthesis and high-throughput screening. We employed the bleomycin (BLM)-induced lung fibrosis animal models and used TGF-ß1 to induce the epithelial-mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α-smooth muscle actin (α-SMA), E-cadherin, p-FGFR1, p-PLCγ, p-Smad2/3 and p-Erk1/2 was detected by western blot. RESULTS: YTH-60 has obvious anti-proliferative activity on fibroblasts and A549 cells. Moreover, YTH-60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF-ß/Smad-dependent pathways. Intraperitoneal administration of preventive YTH-60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH-60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH-60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half-life time (T1/2  = 8.03 hours). CONCLUSIONS: Taken together, these preclinical evaluations suggested that YTH-60 could be a promising drug candidate for treating IPF.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Fibrose Pulmonar/patologia , Células A549 , Animais , Sítios de Ligação , Bleomicina/toxicidade , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Desenho de Fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Meia-Vida , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/farmacologia
15.
Cell Res ; 31(8): 847-860, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34112954

RESUMO

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Assuntos
Antivirais/metabolismo , COVID-19/patologia , Proteínas do Envelope de Coronavírus/metabolismo , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/química , Antivirais/uso terapêutico , Apoptose , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteínas do Envelope de Coronavírus/antagonistas & inibidores , Proteínas do Envelope de Coronavírus/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Meia-Vida , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidade , Baço/metabolismo , Baço/patologia , Carga Viral , Virulência
16.
Clin Drug Investig ; 41(7): 647-652, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34097256

RESUMO

BACKGROUND AND OBJECTIVE: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure with reduced ejection fraction. The objective of this study was to evaluate the potential for OM to affect the pharmacokinetics of metformin. METHODS: This was an open-label, fixed-sequence study in 14 healthy subjects. On Day 1, subjects received an 850 mg oral dose of metformin. From Days 4 to 9, subjects received twice-daily 25 mg oral doses of OM tablets. On Day 10, subjects received an 850 mg oral dose of metformin and a single 25 mg tablet of OM. Blood and urine samples were collected up to 36 h post-dose following administration of metformin on Days 1 and 10 to characterize concentrations of metformin in plasma and urine. RESULTS: The ratios of the geometric least square means of metformin coadministered with OM compared to metformin alone were 98.7%, 99.3%, and 110.2% for AUCinf, AUClast, and Cmax, respectively. The mean renal clearance of metformin was similar following metformin administered alone (34.2 L/h) compared to metformin coadministered with OM (32.9 L/h). All adverse events were mild in severity and resolved prior to the end of the study. No serious adverse events or treatment-emergent adverse events led to discontinuation from the study. CONCLUSIONS: There was no clinically relevant effect of OM on the pharmacokinetics of metformin in healthy subjects.


Assuntos
Metformina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ureia/análogos & derivados , Administração Oral , Adulto , Área Sob a Curva , Diarreia/etiologia , Interações Medicamentosas/fisiologia , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Análise dos Mínimos Quadrados , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Metformina/química , Pessoa de Meia-Idade , Curva ROC , Especificidade por Substrato , Comprimidos/química , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/química
17.
Clin Drug Investig ; 41(7): 639-645, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34110614

RESUMO

BACKGROUND AND OBJECTIVE: Omecamtiv mecarbil (OM) is a cardiac myosin activator under clinical development for the treatment of heart failure. Two modified-release (MR) novel OM minitablet formulations were developed to support the planned investigation of chronic heart failure in pediatric patients. The primary objective of this study was to determine the bioavailability of the minitablets relative to the adult matrix MR formulation tablets. METHODS: In a randomized, 5-period, crossover study, 20 healthy subjects received each of the following treatments orally: one 25-mg adult matrix MR tablet, 25 1-mg slow-release minitablets, 25 1-mg fast-release minitablets, six 1-mg slow-release minitablets, or six 1-mg fast-release minitablets after an overnight fast of at least 10 h with a minimum washout of 7 days between treatments. Blood samples were collected for up to 168 h. OM pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: When OM was administered as 25 1-mg OM slow-release minitablets, AUClast, AUCinf, and Cmax were 0.998-, 1.00-, and 1.29-fold of a single 25-mg OM matrix MR tablet, respectively. When OM was administered as 25 1-mg OM fast-release minitablets, AUClast, AUCinf, and Cmax were 1.26-, 1.25-, and 2.21-fold of a single 25-mg OM matrix MR tablet, respectively. The slow- and fast-release minitablets display approximately dose-proportional pharmacokinetics. There were no serious adverse events or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSIONS: Relative bioavailability of slow-release minitablets was demonstrated to be similar to the adult matrix MR formulation.


Assuntos
Preparações de Ação Retardada/química , Comprimidos/química , Ureia/análogos & derivados , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Composição de Medicamentos , Feminino , Meia-Vida , Voluntários Saudáveis , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Mialgia/etiologia , Ureia/efeitos adversos , Ureia/sangue , Ureia/farmacocinética , Ureia/uso terapêutico , Adulto Jovem
18.
J Am Vet Med Assoc ; 259(1): 84-87, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34125605

RESUMO

OBJECTIVE: To determine the pharmacokinetics of meloxicam in Wyandotte hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg [0.45 mg of meloxicam/lb]) and compare results with those previously published for White Leghorn hens. ANIMALS: 8 healthy adult Wyandotte hens. PROCEDURES: Hens were administered 1 mg of meloxicam/kg, PO, once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma and egg whites (albumen) and yolks were analyzed with high-performance liquid chromatography. RESULTS: Mean ± SD terminal half-life, maximum concentration, and time to maximum concentration were 5.53 ± 1.37 hours, 6.25 ± 1.53 µg/mL, and 3.25 ± 2.12 hours, respectively. Mean ± SD number of days meloxicam was detected in egg whites and yolks after drug administration was 4.25 ± 2 days and 9.0 ± 1.5 days, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with White Leghorn hens, meloxicam in Wyandotte hens had a longer terminal half-life, greater area under the plasma concentration-versus-time curve from time 0 to infinity, a smaller elimination rate constant, and a longer mean residence time-versus-time curve from time 0 to infinity, and drug persisted longer in their egg yolks. Therefore, the oral dosing interval of meloxicam may be greater for Wyandotte hens. Results may aid veterinarians on appropriate dosing of meloxicam to Wyandotte hens and inform regulatory agencies on appropriate withdrawal times.


Assuntos
Galinhas , Tiazinas , Administração Oral , Animais , Anti-Inflamatórios não Esteroides , Área Sob a Curva , Feminino , Meia-Vida , Meloxicam , Óvulo , Tiazóis
19.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066551

RESUMO

G-quadruplexes (G4s) are non-canonical structures formed by guanine-rich sequences of DNA or RNA that have attracted increased attention as anticancer agents. This systematic study aimed to investigate the anticancer potential of five G4-forming, sequence-related DNA molecules in terms of their thermodynamic and structural properties, biostability and cellular uptake. The antiproliferative studies revealed that less thermodynamically stable G4s with three G-tetrads in the core and longer loops are more predisposed to effectively inhibit cancer cell growth. By contrast, highly structured G4s with an extended core containing four G-tetrads and longer loops are characterized by more efficient cellular uptake and improved biostability. Various analyses have indicated that the G4 structural elements are intrinsic to the biological activity of these molecules. Importantly, the structural requirements are different for efficient cancer cell line inhibition and favorable G4 cellular uptake. Thus, the ultimate antiproliferative potential of G4s is a net result of the specific balance among the structural features that are favorable for efficient uptake and those that increase the inhibitory activity of the studied molecules. Understanding the G4 structural features and their role in the biological activity of G-rich molecules might facilitate the development of novel, more potent G4-based therapeutics with unprecedented anticancer properties.


Assuntos
Quadruplex G , Oligonucleotídeos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Endocitose/efeitos dos fármacos , Meia-Vida , Humanos , Oligonucleotídeos/sangue , Fosfoproteínas/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Termodinâmica
20.
Toxicon ; 190(Suupl 1): S72-S73, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34103769

RESUMO

Introduction and Objectives: Botulinum neurotoxin A (BoNT/A) is extremely toxic possessing an estimated intravenous LD50 of 1-2 ng/kg and as such has been designated a category A bioterrorism agent.1, 2 BoNT/A also possesses an extremely long half-life and persists within muscle neurons for months to >1 year.3 Because of BoNT/A longevity, we have utilized covalent inhibition as a means to abrogate BoNT/A's toxicity. To this end, we describe an approach to designing inhibitors that possess both electrophilic warheads and metal-binding groups for the bifunctional inhibition of BoNT/A. Methods: Small molecule inhibitors that possessed electrophilic moieties were designed, using X-ray crystallography as guidance, to target both the zinc metal-binding region and Cys165 within the active site of BoNT/A. Synthesized compounds were evaluated for covalent inhibition using a continuous SNAPtide FRET assay4 and exhaustive dialysis. Compounds were also evaluated against a C165A variant. Compound reactivity, stability, MMP selectivity and cellular efficacy/toxicity was also evaluated. Results: Several electrophilic warhead types were confirmed to inhibit BoNT/A LC covalently with substantial differences in time-dependent inhibition between the WT and C165A variant. A trend in warhead reactivity was reflected in inhibitor stability and toxicity. Compounds exhibited moderate potency in a BoNT/A neuronal cellular assay but were not further explored due to undesirable therapeutic potential. Conclusions: A fundamental framework for the bifunctional covalent inhibition of BoNT/A LC has been established. This approach has potential to be translated to other small molecule metal-binding inhibitors of BoNT/A LC with the vision that different pharmacophores, possessing improved physicochemical properties, will address BoNT/As toxicity and longevity within cells.


Assuntos
Toxinas Botulínicas Tipo A , Toxinas Botulínicas Tipo A/metabolismo , Toxinas Botulínicas Tipo A/toxicidade , Domínio Catalítico , Cristalografia por Raios X , Meia-Vida , Ligação Proteica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...