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1.
Int J Mol Sci ; 25(15)2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39125990

RESUMO

The terpolymers of N-vinylpyrrolidone (VP) with acrylic acid and triethylene glycol methacrylate were synthesized with more than 90% yield by radical copolymerization in ethanol from monomeric mixtures of different molar composition (98:2:2, 95:5: 2 and 98:2:5) and their monomer composition, absolute molecular masses and hydrodynamic radii in aqueous media were determined. Using the MTT test, these terpolymers were established to be low toxic for non-tumor Vero cells and HeLa tumor cells. Polymer compositions of hydrophobic dye methyl pheophorbide a (MPP) based on studied terpolymers and linear polyvinylpyrrolidone (PVP) were obtained and characterized in water solution. Quantum-chemical modeling of the MPP-copolymer structures was conducted, and the possibility of hydrogen bond formation between terpolymer units and the MPP molecule was shown. Using fluorescence microscopy, the accumulation and distribution of polymer particles in non-tumor (FetMSC) and tumor (HeLa) cells was studied, and an increase in the accumulation of MPP with both types of particles was found.


Assuntos
Acrilatos , Humanos , Animais , Chlorocebus aethiops , Acrilatos/química , Células Vero , Células HeLa , Sistemas de Liberação de Medicamentos , Pirrolidinonas/química , Metacrilatos/química , Polietilenoglicóis/química , Polímeros/química , Polímeros/síntese química , Sobrevivência Celular/efeitos dos fármacos
2.
J Med Chem ; 67(14): 11975-11988, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38981131

RESUMO

The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD. AVLX-144-based probes were labeled with the radioisotopes fluorine-18 and tritium, as well as a fluorescent tag. Tracer binding showed saturable, displaceable, and uneven distribution in rat brain slices, proving effective in quantitative autoradiography and cell imaging studies. Notably, we observed diminished tracer binding in human post-mortem Parkinson's disease (PD) brain slices, suggesting postsynaptic impairment in PD. We thus offer a suite of translational probes for visualizing and understanding PSD-related pathologies.


Assuntos
Encéfalo , Proteína 4 Homóloga a Disks-Large , Densidade Pós-Sináptica , Animais , Humanos , Proteína 4 Homóloga a Disks-Large/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Ratos , Densidade Pós-Sináptica/metabolismo , Imagem Molecular/métodos , Radioisótopos de Flúor/química , Doença de Parkinson/metabolismo , Doença de Parkinson/diagnóstico por imagem , Peptídeos/química , Peptídeos/metabolismo , Sondas Moleculares/química , Masculino , Autorradiografia , Ratos Sprague-Dawley , Trítio , Piridinas , Pirrolidinonas
3.
Chemosphere ; 362: 142585, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38866333

RESUMO

Manufacturing processes in semiconductor and photonics industries involve the use of a significant amount of organic solvents. Recycle and reuse of these solvents produce distillate residues and require treatment before being discharged. This study aimed to evaluate the performance of the biological treatment system in a full-scale wastewater treatment plant that treats wastewater containing distillate residues from the recycling of electronic chemicals. Batch experiments were conducted to investigate the optimal operational conditions for the full-scale wastewater treatment plant. To achieve good nitrogen removal efficiency with effluent ammonia and nitrate concentrations below 20 mg N/L and 50 mg N/L, respectively, it was suggested to control the ammonia concentration and pH of the influent below 500 mg N/L and 8.0, respectively. In addition, the biodegradability of N-methylpyrrolidone, diethylene glycol monobutyl ether, and cyclopentanone distillate residues from the electronic chemicals manufacturing process were evaluated under aerobic, anoxic, and anaerobic conditions. N-methylpyrrolidone and cyclopentanone distillate residues were suggested to be treated under anoxic condition. However, substrate inhibition occurred when using cyclopentanone distillate residue as a carbon source with chemical oxygen demand (COD) levels higher than 866 mg/L and nitrate levels higher than 415 mg N/L. Under aerobic condition, the COD from both N-methylpyrrolidone and cyclopentanone distillate residues could be easily degraded. Nevertheless, a negative effect on nitrification was observed, with a prolonged lag time for ammonia oxidation as the initial COD concentration increased. The specific ammonia oxidation rate and nitrate production rate decreased under high COD concentration contributed by N-methylpyrrolidone and cyclopentanone distillate residues. Furthermore, the biodegradability of diethylene glycol monobutyl ether distillate residue was found to be low under aerobic, anoxic, and anaerobic conditions. With respect to the abundance of nitrogen removal microorganisms in the wastewater treatment plant, results showed that Comammox may have an advantage over ammonia oxidizing bacteria under high pH conditions. In addition, Comammox may have higher resistance to environmental changes. Dominance of Comammox over ammonia oxidizing bacteria under high ammonia condition was first reported in this study.


Assuntos
Biodegradação Ambiental , Ciclopentanos , Etilenoglicóis , Nitrogênio , Pirrolidinonas , Eliminação de Resíduos Líquidos , Águas Residuárias , Poluentes Químicos da Água , Águas Residuárias/química , Eliminação de Resíduos Líquidos/métodos , Ciclopentanos/química , Pirrolidinonas/química , Etilenoglicóis/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , Amônia/química , Amônia/análise , Solventes/química
4.
Biomacromolecules ; 25(8): 5181-5197, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-38943659

RESUMO

Rapid proliferation and a faster rate of glycolysis in cancer cells often result in an elevated local temperature (40-43 °C) at the tumor site. Nanoparticles prepared from polymers with two lower critical solution temperatures (LCSTs) can be utilized to take advantage of this subtle temperature elevation to deliver anticancer drugs preferably to the cancer cells, thereby enhancing the overall therapeutic efficacy and reducing side effects. In this direction, we synthesized N-vinyl-2-pyrrolidone (NVP) and substituted NVP (sub-NVP: C2-NVP, C4-NVP)-based polymers with precisely controlled LCSTs by varying the ratio of NVP and sub-NVP. The first LCST (LCST1) was kept below 37 °C to promote self-assembly, drug loading, and structural stability in physiological conditions and the second LCST (LCST2) was in the range of 40-43 °C to ensure mild hyperthermia-induced drug release. Additionally, covalent attachment of tetraphenylethylene (TPE, AIEgen) resulted in aggregation-induced emission in thermoresponsive micellar nanoparticles in which TPE acted as a Förster Resonance Energy Transfer (FRET) pair with the loaded anticancer drug doxorubicin (DOX). Tracking of FRET-induced fluorescence recovery of TPE molecules was utilized to confirm the real-time thermoresponsive release of DOX from nanoparticles and eventual localization of TPE in the cytoplasm and DOX in the nucleus. In vitro cellular studies such as cytotoxicity, cellular uptake, and thermoresponsive drug release showed that the DOX-loaded polymeric nanoparticles were nontoxic to normal cells (HEK-293) but significantly more effective in cancer cells (MCF-7) at 40 °C. To our knowledge, this is the first report of preferential delivery of anticancer drugs only by exploiting the slightly elevated temperature of cancer cells.


Assuntos
Doxorrubicina , Liberação Controlada de Fármacos , Nanopartículas , Polímeros , Humanos , Nanopartículas/química , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Polímeros/química , Pirrolidinonas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Micelas , Temperatura , Sistemas de Liberação de Medicamentos/métodos , Células MCF-7 , Portadores de Fármacos/química , Transferência Ressonante de Energia de Fluorescência , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estilbenos
5.
Drug Deliv Transl Res ; 14(8): 2146-2157, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38822092

RESUMO

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system.


Assuntos
Trifosfato de Adenosina , Quitosana , Interações Hidrofóbicas e Hidrofílicas , Nanoestruturas , Animais , Trifosfato de Adenosina/administração & dosagem , Quitosana/química , Quitosana/administração & dosagem , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Liberação Controlada de Fármacos , Camundongos , Preparações de Ação Retardada/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Sistemas de Liberação de Medicamentos , Implantes de Medicamento , Injeções Subcutâneas , Nanogéis/química , Polietilenoglicóis/química , Polietilenoglicóis/administração & dosagem , Pirrolidinonas
6.
Adv Ther ; 41(7): 2682-2699, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38811492

RESUMO

One third of patients with epilepsy will continue to have uncontrolled seizures despite treatment with antiseizure medications (ASMs). There is therefore a need to develop novel ASMs. Brivaracetam (BRV) is an ASM that was developed in a major drug discovery program aimed at identifying selective, high-affinity synaptic vesicle protein 2A (SV2A) ligands, the target molecule of levetiracetam. BRV binds to SV2A with 15- to 30-fold higher affinity and greater selectivity than levetiracetam. BRV has broad-spectrum antiseizure activity in animal models of epilepsy, a favorable pharmacokinetic profile, few clinically relevant drug-drug interactions, and rapid brain penetration. BRV is available in oral and intravenous formulations and can be initiated at target dose without titration. Efficacy and safety of adjunctive BRV (50-200 mg/day) treatment of focal-onset seizures was demonstrated in three pivotal phase III trials (NCT00490035/NCT00464269/NCT01261325), including in patients who had previously failed levetiracetam. Efficacy and safety of adjunctive BRV were also demonstrated in adult Asian patients with focal-onset seizures (NCT03083665). In several open-label trials (NCT00150800/NCT00175916/NCT01339559), long-term safety and tolerability of adjunctive BRV was established, with efficacy maintained for up to 14 years, with high retention rates. Evidence from daily clinical practice highlights BRV effectiveness and tolerability in specific epilepsy patient populations with high unmet needs: the elderly (≥ 65 years of age), children (< 16 years of age), patients with cognitive impairment, patients with psychiatric comorbid conditions, and patients with acquired epilepsy of specific etiologies (post-stroke epilepsy/brain tumor related epilepsy/traumatic brain injury-related epilepsy). Here, we review the preclinical profile and clinical benefits of BRV from pivotal trials and recently published evidence from daily clinical practice.


One in three people with epilepsy continue to have seizures despite treatment. Brivaracetam is a medicine used to treat seizures in people with epilepsy. It binds to a protein in the brain (synaptic vesicle protein 2A) and is effective in many different animal models of epilepsy. Brivaracetam enters the brain quickly. It has few interactions with other medicines, which is important because people with epilepsy may be taking additional medicines for epilepsy or other conditions. Brivaracetam is available as tablets, oral solution, and solution for intravenous injection, can be started at the recommended target dose, and is easy to use. In three phase III trials, people with uncontrolled focal-onset seizures taking brivaracetam 50­200 mg each day had fewer seizures than people taking a placebo. Brivaracetam was tolerated well. It also worked well in many people who had previously not responded to antiseizure medications. The efficacy of brivaracetam treatment is maintained for up to 14 years. Brivaracetam treatment reduces seizures in the elderly (≥ 65 years old), in children (< 16 years old), in people with cognitive or learning disabilities, in people with additional psychiatric conditions, and in people with different causes of epilepsy (post-stroke epilepsy, brain-tumor related epilepsy, and traumatic brain injury-related epilepsy). Here, we review brivaracetam characteristics and the results when people with epilepsy received brivaracetam in key clinical trials and real-world studies in daily clinical practice.


Assuntos
Anticonvulsivantes , Epilepsia , Pirrolidinonas , Humanos , Pirrolidinonas/uso terapêutico , Pirrolidinonas/administração & dosagem , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Animais , Criança , Resultado do Tratamento , Avaliação Pré-Clínica de Medicamentos , Adulto
7.
Food Chem ; 450: 139328, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-38626712

RESUMO

N-Ethyl-2-pyrrolidinone-substituted flavan-3-ols (EPSFs) are a newly discovered compound class in tea with various bioactivities. This study aimed to develop a novel processing technique to enhance EPSF contents in white tea efficiently. Using optimal processing parameters of 125 °C and 30 min in a high-temperature sterilizing oven, total EPSF content significantly increased by 1.42-18.80-fold to 1.57-6.22 mg/g without impacting sensory characteristics. Metabolomics analysis revealed elevated levels of nucleosides, nucleotides, bases, theaflavins, flavonol aglycones, EPSFs, and most flavone-C-glycosides, as well as decreased levels of amino acids, procyanidins, theasinensins, several flavanols, and flavonol-O-glycosides after EPSF-enrichment treatment. Furthermore, the EPSF-enriched white tea exhibited notable anti-inflammatory effects, mitigating xylene-induced ear edema in mice and carrageenan-induced paw edema and cotton ball-induced granulomas in rats. This study developed a new processing technique for highly efficient enhancement of EPSFs in white tea and demonstrated that EPSF-enriched white tea has a potential to serve as effective anti-inflammatory dietary supplement.


Assuntos
Anti-Inflamatórios , Camellia sinensis , Flavonoides , Extratos Vegetais , Chá , Animais , Camundongos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ratos , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/análise , Masculino , Camellia sinensis/química , Chá/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Edema/tratamento farmacológico , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Ratos Sprague-Dawley , Humanos , Manipulação de Alimentos
8.
Acta Biomater ; 179: 130-148, 2024 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-38460932

RESUMO

Poor skin adhesion and mechanical properties are common problems of pressure-sensitive adhesive (PSA) in transdermal drug delivery system (TDDS). Its poor water compatibility also causes the patch to fall off after sweating or soaking in the application site. To solve this problem, poly (2-Ethylhexyl acrylate-co-N-Vinyl-2-pyrrolidone-co-N-(2-Hydroxyethyl)acrylamide) (PENH), a cross-linked pyrrolidone polyacrylate PSA, was designed to improve the adhesion and water resistance of PSA through electrostatic force and hydrogen bonding system. The structure of PENH was characterized by 1H NMR, FTIR, DSC, and other methods. The mechanism was studied by FTIR, rheological test, and molecular simulation. The results showed that the PENH patch could adhere to human skin for more than 10 days without cold flow, and it could still adhere after sweating or water contact. In contrast, the commercial PSA Duro-Tak® 87-4098 and Duro-Tak® 87-2852 fell off completely on the 3rd and 6th day, respectively, and Duro-Tak® 87-2510 showed a significant dark ring on the second day. Mechanism studies have shown that the hydrogen bond formed by 2-ethylhexyl acrylate (2-EHA), N-vinyl-2-pyrrolidinone (NVP), and N-(2-Hydroxyethyl)acrylamide (HEAA) enhances cohesion, the interaction with skin improves skin adhesion, and the electrostatic interaction with water or drug molecules enhances the ability of water absorption and drug loading. Due to the synergistic effect of hydrogen bonds and electrostatic force, PENH can maintain high cohesion after drug loading or water absorption. PENH provides a choice for the development of water-compatible patches with long-lasting adhesion. STATEMENT OF SIGNIFICANCE: Based on the synergistic effect of hydrogen bonding and electrostatic force, a hydrogen-bonded, cross-linked pyrrolidone acrylate pressure-sensitive adhesive for transdermal drug delivery was designed and synthesized, which has high adhesion and cohesive strength and is non-irritating to the skin. The patch can be applied on the skin surface continuously for more than 10 days without the phenomenon of "dark ring", and the patch can remain adherent after the patient sweats or bathes. This provides a good strategy for choosing a matrix for patches that require prolonged administration.


Assuntos
Adesivos , Administração Cutânea , Ligação de Hidrogênio , Pirrolidinonas , Eletricidade Estática , Água , Adesivos/química , Adesivos/farmacologia , Água/química , Humanos , Pirrolidinonas/química , Pressão , Animais , Acrilatos/química , Sistemas de Liberação de Medicamentos , Pele/efeitos dos fármacos , Pele/metabolismo , Reagentes de Ligações Cruzadas/química
9.
J Neurol ; 271(6): 3169-3185, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38436680

RESUMO

OBJECTIVE: To assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies. METHODS: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor-related epilepsy [BTRE], and traumatic brain injury-related epilepsy [TBIE]). RESULTS: At 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively. CONCLUSIONS: BRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE.


Assuntos
Anticonvulsivantes , Comorbidade , Epilepsia , Pirrolidinonas , Humanos , Pirrolidinonas/efeitos adversos , Pirrolidinonas/uso terapêutico , Masculino , Feminino , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Transtornos Mentais/epidemiologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Resultado do Tratamento , Adolescente
10.
Antiviral Res ; 224: 105842, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38417531

RESUMO

Enteroviruses are a significant global health concern, causing a spectrum of diseases from the common cold to more severe conditions like hand-foot-and-mouth disease, meningitis, myocarditis, pancreatitis, and poliomyelitis. Current treatment options for these infections are limited, underscoring the urgent need for effective therapeutic strategies. To find better treatment option we analyzed toxicity and efficacy of 12 known broad-spectrum anti-enterovirals both individually and in combinations against different enteroviruses in vitro. We identified several novel, synergistic two-drug and three-drug combinations that demonstrated significant inhibition of enterovirus infections in vitro. Specifically, the triple-drug combination of pleconaril, rupintrivir, and remdesivir exhibited remarkable efficacy against echovirus (EV) 1, EV6, EV11, and coxsackievirus (CV) B5, in human lung epithelial A549 cells. This combination surpassed the effectiveness of single-agent or dual-drug treatments, as evidenced by its ability to protect A549 cells from EV1-induced cytotoxicity across seven passages. Additionally, this triple-drug cocktail showed potent antiviral activity against EV-A71 in human intestinal organoids. Thus, our findings highlight the therapeutic potential of the pleconaril-rupintrivir-remdesivir combination as a broad-spectrum treatment option against a range of enterovirus infections. The study also paves the way towards development of strategic antiviral drug combinations with virus family coverage and high-resistance barriers.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Isoxazóis , Oxidiazóis , Oxazóis , Fenilalanina/análogos & derivados , Pirrolidinonas , Valina/análogos & derivados , Animais , Humanos , Infecções por Enterovirus/tratamento farmacológico , Enterovirus Humano B , Antivirais/farmacologia , Antivirais/uso terapêutico , Combinação de Medicamentos
11.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339112

RESUMO

A series of hydrazones, azoles, and azines bearing a 4-dimethylaminophenyl-5-oxopyrrolidine scaffold was synthesized. Their cytotoxic effect against human pancreatic carcinoma Panc-1 and triple-negative breast cancer MDA-MB-231 cell lines was established by MTT assay. Pyrrolidinone derivatives 3c and 3d, with incorporated 5-chloro and 5-methylbenzimidazole fragments; hydrazone 5k bearing a 5-nitrothien-2-yl substitution; and hydrazone 5l with a naphth-1-yl fragment in the structure significantly decreased the viability of both cancer cell lines. Compounds 3c and 5k showed the highest selectivity, especially against the MDA-MB-231 cancer cell line. The EC50 values of the most active compound 5k against the MDA-MB231 cell line was 7.3 ± 0.4 µM, which were slightly higher against the Panc-1 cell line (10.2 ± 2.6 µM). Four selected pyrrolidone derivatives showed relatively high activity in a clonogenic assay. Compound 5k was the most active in both cell cultures, and it completely disturbed MDA-MB-231 cell colony growth at 1 and 2 µM and showed a strong effect on Panc-1 cell colony formation, especially at 2 µM. The compounds did not show an inhibitory effect on cell line migration by the 'wound-healing' assay. Compound 3d most efficiently inhibited the growth of Panc-1 spheroids and reduced cell viability in MDA-MB-231 spheroids. Considering these different activities in biological assays, the selected pyrrolidinone derivatives could be further tested to better understand the structure-activity relationship and their mechanism of action.


Assuntos
Antineoplásicos , Neoplasias Pancreáticas , Neoplasias de Mama Triplo Negativas , Humanos , Antineoplásicos/uso terapêutico , Relação Estrutura-Atividade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Proliferação de Células , Hidrazonas/farmacologia , Pirrolidinonas/farmacologia , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
12.
J. appl. oral sci ; 28: e20190516, 2020. graf
Artigo em Inglês | LILACS, BBO - Odontologia | ID: biblio-1090775

RESUMO

Abstract This study investigated the effect of a calcium hydroxide (CH) paste (CleaniCal®) containing N-2-methyl pyrrolidone (NMP) as a vehicle on Enterococcus faecalis (E. faecalis) biofilms compared with other products containing saline (Calasept Plus™) or propylene glycol (PG) (Calcipex II®). Methodology Standardized bovine root canal specimens were used. The antibacterial effects were measured by colony-forming unit counting. The thickness of bacterial microcolonies and exopolysaccharides was assessed using confocal laser scanning microscopy. Morphological features of the biofilms were observed using field-emission scanning electron microscopy (FE-SEM). Bovine tooth blocks covered with nail polish were immersed into the vehicles and dispelling was observed. The data were analyzed using one-way analysis of variance and Tukey tests (p<0.05). Results CleaniCal® showed the highest antibacterial activity, followed by Calcipex II® (p<0.05). Moreover, NMP showed a higher antibacterial effect compared with PG (p<0.05). The thickness of bacteria and EPS in the CleaniCal® group was significantly lower than that of other materials tested (p<0.05). FE-SEM images showed the specimens treated with Calasept Plus™ were covered with biofilms, whereas the specimens treated with other medicaments were not. Notably, the specimen treated with CleaniCal® was cleaner than the one treated with Calcipex II®. Furthermore, the nail polish on the bovine tooth block immersed in NMP was completely dispelled. Conclusions CleaniCal® performed better than Calasept Plus™ and Calcipex II® in the removal efficacy of E. faecalis biofilms. The results suggest the effect might be due to the potent dissolving effect of NMP on organic substances.


Assuntos
Animais , Bovinos , Pirrolidinonas/farmacologia , Irrigantes do Canal Radicular/farmacologia , Hidróxido de Cálcio/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Antibacterianos/farmacologia , Cloreto de Potássio/farmacologia , Cloreto de Potássio/química , Pirrolidinonas/química , Irrigantes do Canal Radicular/química , Teste de Materiais , Cloreto de Cálcio/farmacologia , Cloreto de Cálcio/química , Hidróxido de Cálcio/química , Microscopia Eletrônica de Varredura , Cloreto de Sódio/farmacologia , Cloreto de Sódio/química , Contagem de Colônia Microbiana , Reprodutibilidade dos Testes , Análise de Variância , Bicarbonato de Sódio/farmacologia , Bicarbonato de Sódio/química , Estatísticas não Paramétricas , Microscopia Confocal , Combinação de Medicamentos
13.
J Antimicrob Chemother ; 70(3): 926-929, 2015.
Artigo em Inglês | LILACS, Sec. Est. Saúde SP, SESSP-IALPROD, Sec. Est. Saúde SP, SESSP-IALACERVO | ID: biblio-1022184

RESUMO

OBJECTIVES: Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity. PATIENTS AND METHODS: Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm. RESULTS: Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load. CONCLUSIONS: Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue.


Assuntos
Pirrolidinonas/uso terapêutico , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Terapia de Salvação/métodos , Falha de Tratamento , Análise de Sequência de DNA , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Adulto , Mutação de Sentido Incorreto , Farmacorresistência Viral , Adulto Jovem , Raltegravir Potássico , Genótipo , Compostos Heterocíclicos/farmacologia , Pessoa de Meia-Idade
14.
West Indian med. j ; 61(9): 932-936, Dec. 2012. ilus
Artigo em Inglês | LILACS | ID: lil-694370

RESUMO

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.


El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.


Assuntos
Adulto , Humanos , Masculino , Carbamatos/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Creatina Quinase/sangue , Cicloexanos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Fígado Gorduroso/induzido quimicamente , Inibidores da Fusão de HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Inibidores da Protease de HIV/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Organofosfatos/efeitos adversos , Pirrolidinonas/efeitos adversos , Sulfonamidas/efeitos adversos , Triazóis/efeitos adversos , Carbamatos/uso terapêutico , Cicloexanos/uso terapêutico , Substituição de Medicamentos , Quimioterapia Combinada , Fígado Gorduroso/diagnóstico , Inibidores da Fusão de HIV/uso terapêutico , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Cirrose Hepática/diagnóstico , Organofosfatos/uso terapêutico , Pirrolidinonas/uso terapêutico , Sulfonamidas/uso terapêutico , Triazóis/uso terapêutico
15.
Acta neurol. colomb ; 27(2): 129-133, abr.-jun. 2011. ilus
Artigo em Espanhol | LILACS | ID: lil-595205

RESUMO

El levetiracetam es un antiepileptico derivado de las pirrolidonas, altera los niveles de calcio intraneuronalreduciendo su liberacion de los depositos intracelulares, inhibe parcialmente los canales de calcio tipo N, y revierte parcialmente la reduccion en las corrientes de GABA y glicina inducidas porel Zinc y las beta-carbolinas, posee un perfil farmacocinetico y de seguridad favorable que lo han convertido en un medicamento de utilidad en el manejo adyuvante de crisis parciales no controladas. Se presentan 4 casos de pacientes manejados con levetiracetam innovador, que presentaron eventos adversos intolerables y fallo terapeutico al cambiar a levetiracetam generico, se concluye que se necesitan estudios locales adicionales para corroborar que cambio hacia el levetiracetam generico pueden afectar la adherencia al tratamiento por parte de los pacientes y generar situaciones potencialmente fatales como estado epileptico.


Levetiracetam an antiepileptic drug derived from pyrrolidones, alters intraneuronal calcium levels by reducing its release from intracellular stores, partially inhibits N-type calcium channels and partially reversed the reductionin GABA and glycine currents induced by Zinc and beta-carbolines. Levetiracetam has favorable pharmacokinetic and safety profiles that have made it a useful drug in the adjuvant management of uncontrolled partial seizures. This paper report 4 cases of patients managed with levetiracetam innovative, who presented intolerable adverse events and therapeutic failure by switching to generic levetiracetam, it is concluded that further local studies are required to corroborate the consequences of shift to generic levetiracetam that may affect treatment adherence and generate life-threatening situations such as status epilepticus.


Assuntos
Humanos , Colômbia , Pirrolidinonas
16.
Braz. j. med. biol. res ; 27(11): 2565-8, Nov. 1994. tab, graf
Artigo em Inglês | LILACS | ID: lil-153976

RESUMO

Tubular polymeric materials modified by radiation techniques can be used as vascular prosthesis and components of prosthetic devices. The biological interction between these materials and blood was studied by in vitro and ex vivo methods. Silicone rubber tubes were copolymerized with acrylamide and N-vinylpyrrolidone by radiation-grafting techniques. The irradiation was performed with y-rays from a 60Co source at a constant dose rate (0.2 kGy/h) for various time intervals (4-15 h). To evaluate the antithrombogenicity of the grafted tubes, the surface adsorption of 125I-albumin and 125I-fibrinogen was studied. All graft copolymers show a preference for albumin, and the degree of preference appears to correlate with antithrombogenic tendency. In the ex vivo experiment with animals, tubes were implanted in the carotid artery of dogs and the blood flow in the graft copolymers was detected with an ultrasonic flow meter. The blood flow rate in the ungrafted implants decreased more rapidly (stopped completely after 15 to 210 min) compared to the flow rate in the grafted ones (decreased slowly from 38 to 35 ml/min and 70 to 60 ml/min). There was a direct relationship between both methods in the study of blood compatibility of the materials. The results suggest that the graft copolymers can be used as biomaterials for long-term use in cardiovascular systems


Assuntos
Animais , Cães , Artérias Carótidas/fisiologia , Materiais Biocompatíveis , Prótese Vascular , Polímeros/efeitos da radiação , Acrilamidas/efeitos da radiação , Albuminas/metabolismo , Elastômeros de Silicone/efeitos da radiação , Fibrinogênio/metabolismo , Pirrolidinonas/efeitos da radiação , Fluxo Sanguíneo Regional , Propriedades de Superfície , Fatores de Tempo
17.
Folha méd ; 93(1): 39-41, jul. 1986. tab
Artigo em Português | LILACS | ID: lil-34074

RESUMO

Quarenta pacientes, abaixo dos 70 anos de idade, portadores de labirintopatias, foram tratados sob esquema duplo-cego com aniracetan (1 g/dia) ou placebo durante seis semanas. A avaliaçäo final da eficácia mostrou diferença estatisticamente significativa a favor do aniracetam (remissäo dos sintomas ou melhora acentuada em 55% dos pacientes tratados com aniracetam, contra 20% daqueles que receberam placebo). O sintoma que mostrou melhor resposta ao aniracetam foi o "zumbido" durante as crises. A tolerabilidade foi excelente tanto para o aniracetam quanto para o placebo, näo havendo diferença estatística significativa entre os dois grupos


Assuntos
Adulto , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Doenças do Labirinto/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Ensaios Clínicos como Assunto , Método Duplo-Cego , Placebos/uso terapêutico
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