RESUMO
OBJECTIVE: To explore whether early physical interventions, including neuromuscular retraining therapy, can minimize excessive movement or any unwanted co-contraction after a severe Bell's palsy. DATA SOURCES: From March 2021 to August 2022, the therapist treated Bell's palsy patients for the acute (<3 months, Group A), subacute (3-6 months, Group B) and chronic (> 6 months, Group C) stages of the condition. METHODS: We explored whether early physical interventions, including neuromuscular retraining therapy, can minimize facial synkinesis after a severe episode of Bell's palsy. Each patient was informed about the potential for synkinesis and the therapist explained that the main purpose of neuromuscular retraining therapy is to learn new patterns to minimize synkinesis. The facial function of Group A was compared to that of Groups B and C using the 'Synkinesis' scale of the Sunnybrook Facial Grading System. RESULTS: The final facial function score after neuromuscular retraining therapy was significantly associated with both the initial electroneuronographic degeneration rate and initial facial function. Early therapy did not prevent synkinetic movement in 84.7% of the patients. But, there was a significant difference between patients who started early neuromuscular retraining therapy and other groups in final facial function. CONCLUSION: Synkinesis in Bell's palsy patients can be minimized if physiotherapy commences before synkinesis develops; appropriate neuromuscular retraining therapy timing is essential. A patient with sudden severe Bell's palsy should receive oral steroids as soon as possible, along with physical therapy (including neuromuscular retraining therapy) within 3 months, to minimize synkinesis just before synkinesis onset.
Assuntos
Paralisia de Bell , Paralisia Facial , Sincinesia , Humanos , Paralisia de Bell/diagnóstico , Paralisia de Bell/terapia , Paralisia Facial/etiologia , Paralisia Facial/terapia , Movimento , Modalidades de Fisioterapia , Sincinesia/etiologiaRESUMO
A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak AChE and strong BuChE inhibitory activities. In particular, compound 8b and 8d were the most active compounds in the series against BChE with IC50 values of 45nM and 62nM, as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound 8b and 8d bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with better interaction energy values than AChE, in agreement with our experimental data. Furthermore, the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding nature in kinetic studies.
Assuntos
Inibidores da Colinesterase/farmacologia , Quinazolinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Quinazolinas/uso terapêuticoRESUMO
As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10µM concentration and exhibited cytotoxic effect (IC50=5.9µM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav3.2 channels.
Assuntos
Analgésicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Quinazolinas/química , Quinidina/análogos & derivados , Células A549 , Analgésicos/química , Analgésicos/toxicidade , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/toxicidade , Canais de Cálcio Tipo T/química , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Flúor/química , Células HEK293 , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Técnicas de Patch-Clamp , Quinazolinas/síntese química , Quinazolinas/toxicidade , Quinidina/síntese química , Quinidina/química , Quinidina/toxicidade , RatosRESUMO
Two new guaiane-type (2, 6) and one new furanogermacrane-type (11) sesquiterpenoids have been isolated along with twelve known compounds from an EtOAc-soluble extract of Curcuma phaeocaulis rhizomes. The structures of the isolated compounds were elucidated using a combination of NMR, MS, and circular dichroism (CD) spectra. The inhibitory effects of each compound on lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) activation in THP-1-Blue cells were assessed, and compound 4 showed more potent inhibitory activity against LPS-stimulated TLR4 activation.
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Curcuma/química , Lipopolissacarídeos/antagonistas & inibidores , Rizoma/química , Sesquiterpenos/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/farmacologia , Conformação Molecular , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Relação Estrutura-Atividade , Receptor 4 Toll-Like/metabolismoRESUMO
The objective of the present study is to investigate the catalytic performance of mesoporous alumina that were prepared via spray pyrolysis for double bond migration from 2-butene to 1-butene. The mesoporous alumina particles were prepared via spray pyrolysis by changing the types of organic surfactants and Al precursors. The texture and acidic properties of mesoporous alumina were analyzed through N2 adsorption, SEM, ammonia-temperature programmed desorption, and FT-IR of adsorbed pyridine. The morphologies and texture properties of the mesoporous alumina were found to have been strongly influenced by the combination of the Al precursor and the structure-directing agents. The mesoporous alumina samples had two kinds of acidic sites: a Lewis acid site and a H-bonded weak acid site. 1-Butene was produced selectively through double bond migration of 2-butene over all of the mesoporous alumina catalysts. The catalyst prepared by using a chloride compound as an aluminium precursor and CTAC as a structure-directing agent showed the highest activity in the double bond migration of 2-butene, which was attributed to its large surface area and an overall high amount of acid sites.
RESUMO
A novel, supersaturable self-microemulsifying drug delivery system (S-SMEDDS) was successfully formulated to enhance the dissolution and oral absorption of valsartan (VST), a poorly water-soluble drug, while reducing the total quantity for administration. Poloxamer 407 is a selectable, supersaturating agent for VST-containing SMEDDS composed of 10% Capmul® MCM, 45% Tween® 20, and 45% Transcutol® P. The amounts of SMEDDS and Poloxamer 407 were chosen as formulation variables for a 3-level factorial design. Further optimization was established by weighting different levels of importance on response variables for dissolution and total quantity, resulting in an optimal S-SMEDDS in large quantity (S-SMEDDS_LQ; 352 mg in total) and S-SMEDDS in reduced quantity (S-SMEDDS_RQ; 144.6 mg in total). Good agreement was observed between predicted and experimental values for response variables. Consequently, compared with VST powder or suspension and SMEDDS, both S-SMEDDS_LQ and S-SMEDDS_RQ showed excellent in vitro dissolution and in vivo oral bioavailability in rats. The magnitude of dissolution and absorption-enhancing capacities using quantity-based comparisons was in the order S-SMEDDS_RQ > S-SMEDDS_LQ > SMEDDS > VST powder or suspension. Thus, we concluded that, in terms of developing an effective SMEDDS preparation with minimal total quantity, S-SMEDDS_RQ is a promising candidate.
Assuntos
Emulsões/administração & dosagem , Valsartana/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Caprilatos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Emulsões/farmacocinética , Etilenoglicóis/química , Glicerídeos/química , Masculino , Polímeros , Polissorbatos/química , Ratos Sprague-Dawley , Solubilidade , Valsartana/administração & dosagemRESUMO
Though piperazine derivative BK10007S was known to induce apoptosis in pancreatic cancer xenograft model as a T-type CaV3.1 a1G isoform calcium channel blocker, its underlying antitumor mechanism still remains unclear so far. Thus, in the present study, the antitumor mechanism of BK10007S was elucidated in hepatocellular carcinoma cells (HCCs). Herein, BK10007S showed significant cytotoxicity by 3-[4,5-2-yl]-2,5-diphenyltetra-zolium bromide (MTT) assay and anti-proliferative effects by colony formation assay in HepG2 and SK-Hep1 cells. Also, apoptotic bodies and terminal deoxynucleotidyl transferase (TdT) dUTP Nick End Labeling (TUNEL) positive cells were observed in BK10007S treated HepG2 and SK-Hep1 cells by 4',6-diamidino-2-phenylinodole (DAPI) staining and TUNEL assay, respectively. Consistently, BK10007S increased sub G1 population in HepG2 and SK-Hep1 cells by cell cycle analysis. Furthermore, Western blotting revealed that BK10007S activated the caspase cascades (caspase 8, 9 and 3), cleaved poly (ADP-ribose) polymerase (PARP), and downregulated the expression of cyclin D1, survivin and for CUG-binding protein 1 (CUGBP1 or CELF1) in HepG2 and SK-Hep1 cells. Conversely, overexpression of CUGBP1 reduced cleavages of PARP and caspase 3, cytotoxicity and subG1 population in BK10007S treated HepG2 cells. Overall, these findings provide scientific evidences that BK10007S induces apoptosis via inhibition of CUGBP1 and activation of caspases in hepatocellular carcinomas as a potent anticancer candidate.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas CELF1/antagonistas & inibidores , Carcinoma Hepatocelular/patologia , Caspases/metabolismo , Neoplasias Hepáticas/patologia , Piperazinas/farmacologia , Quinazolinas/farmacologia , Proteínas CELF1/genética , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , HumanosRESUMO
A double layer-coated colon-specific drug delivery system (DL-CDDS) was developed, which consisted of chitosan (CTN) based polymeric subcoating of the core tablet containing citric acid for microclimate acidification, followed by an enteric coating. The polymeric composition ratio of Eudragit E100 and ethyl cellulose and amount of subcoating were optimized using a two-level factorial design method. Drug-release characteristics in terms of dissolution efficiency and controlled-release duration were evaluated in various dissolution media, such as simulated colonic fluid in the presence or absence of CTNase. Microflora activation and a stepwise mechanism for drug release were postulated. Consequently, the optimized DL-CDDS showed drug release in a controlled manner by inhibiting drug release in the stomach and intestine, but releasing the drug gradually in the colon (approximately 40% at 10 hours and 92% at 24 hours in CTNase-supplemented simulated colonic fluid), indicating its feasibility as a novel platform for CDD.
Assuntos
Quitosana/química , Colo/metabolismo , Sistemas de Liberação de Medicamentos , Modelos Biológicos , Colo/microbiologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Glicosídeo Hidrolases/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Especificidade de Órgãos , Fenilpropionatos/administração & dosagem , Fenilpropionatos/metabolismo , Polímeros/química , ComprimidosRESUMO
In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul® MCM (13.2 mg), Tween® 80 (59.2 mg), Transcutol® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite® PS-10 (119.1 mg) and Vivapur® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.
RESUMO
To improve the dissolution and oral bioavailability (BA) of atorvastatin calcium (ATV), we previously introduced an optimized self-microemulsifying drug delivery system (SMEDDS) using Capmul(®) MCM (oil), Tween(®) 20 (surfactant), and tetraglycol (cosurfactant). In this study, various solid carriers were employed to develop a solidified SMEDDS (S-SMEDDS): mannitol (M) and lactose (L) as water-soluble carriers, and Sylysia(®) 350 (S) and Aerosil(®) 200 (A) as water-insoluble carriers. Maximum solidifying capacities (SCmax) of water-insoluble carriers were significantly greater than those of water-soluble carriers were. The resultant powders were free flowing with an angle of repose <40° and Carr's index 5-20%, regardless of the solid carrier types. S-SMEDDS with mannitol (S(M)-SMEDDS) or lactose (S(L)-SMEDDS) had a smaller droplet size and greater dissolution than S-SMEDDS with Sylysia(®) 350 (S(S)-SMEDDS) or Aerosil(®) 200 (S(A)-SMEDDS). Following oral administration of various formulations to rats at a dose equivalent to 25mg/kg of ATV, plasma drug levels were measured by LC-MS/MS. The relative BAs (RBAs) of SMEDDS, S(M)-SMEDDS, and S(S)-SMEDDS were 345%, 216%, and 160%, respectively, compared to that of ATV suspension. Additionally, at a reduced dose of ATV equivalent to 5mg/kg, the RBAs of S(M)-SMEDDS and S(S)-SMEDDS compared to that of SMEDDS were 101% and 65%, respectively. These results suggest that S(M)-SEMDDS offers great potential for the development of solid dosage forms with improved oral absorption of drugs with poor water solubility.
Assuntos
Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Sistemas de Liberação de Medicamentos , Administração Oral , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacocinética , Atorvastatina/química , Atorvastatina/farmacocinética , Disponibilidade Biológica , Química Farmacêutica/métodos , Cromatografia Líquida , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Emulsões , Excipientes/química , Masculino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química , Espectrometria de Massas em TandemRESUMO
To develop a matrix-type, controlled-release tablet formulation of pelubiprofen (PLB), a recently developed non-steroidal anti-inflammatory drug, polymeric excipients including hypromellose, hydroxypropylcellulose, Eudragit(®) RS PO, and Kollidon(®) SR were screened. A formulation containing 12.4% w/w Kollidon(®) SR (K2 tablet) was found to be the most promising and stable for 6 months in an accelerated stability test. PLB release from K2 tablet was limited at pH 1.2, but gradually increased at pH 6.8 with a surface-erosion, resulting in the best fit to Hixson-Crowell equation. Comparative human PK studies were performed using a randomized, 2-way crossover design. LC-MS/MS assay revealed that the plasma level of PLB-transOH, an active metabolite, was significantly higher than that of PLB. After multiple dosing of immediate-release tablet (R) and K2 tablet (T), the T/R ratios of AUC were 1.02 and 1.04 for PLB and PLB-transOH, respectively. Level A in vitro-in vivo correlation was established for the K2 tablet-administered group. PK profile of PLB-transOH was not influenced by food intake, while that of PLB was altered. We suggest that K2 tablet could be administered twice a day without being affected by food intake, thereby enhancing patient compliance.
Assuntos
Fenilpropionatos/farmacocinética , Adulto , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ingestão de Alimentos , Excipientes/química , Excipientes/farmacocinética , Humanos , Fenilpropionatos/sangue , Fenilpropionatos/química , Solubilidade , Comprimidos/química , Comprimidos/farmacocinética , Adulto JovemRESUMO
A survey of reptile-associated ticks and their infection status with severe fever with thrombocytopenia syndrome (SFTS) virus was conducted to determine the relative abundance and distribution among lizards, skinks, and snakes in the Republic of Korea (ROK). In total, 132 reptiles, including 49 lizards (two species), 15 skinks (one species), and 68 snakes (eight species) were collected. In total, 84 ixodid ticks belonging to two genera (Ixodes and Amblyomma) were collected from 28/132 (21.2%) lizards, skinks, and snakes. Ixodes nipponensis Kitaoka & Saito was only collected from lizards and skinks, while Amblyomma testudinarium Koch was only collected from snakes. Takydromus wolteri had the highest tick index (0.7; total number ticks/total number collected hosts) among lizards and skinks, while Rhabdophis tigrinus had the highest tick index (2.2) among the snakes. Ixodes nipponensis larvae and nymphs accounted for 11.1% and 88.9%, respectively, of all ticks collected from lizards and skinks, while only A. testudinarium nymphs were collected from snakes. Nymphs of both species of ticks were collected from lizards and skinks from April to October, while I. nipponensis larvae were collected only from September to October. Ixodes nipponensis larvae and nymphs were preferentially attached to the lateral trunk (83.3%) and the foreleg axillae (16.7%) of lizards and skinks. SFTS virus was detected in both I. nipponensis and A. testudinarium collected from lizards and snakes. Phylogenetic analysis of SFTS viruses of ticks collected from two lizards and one snake demonstrated close relationships with SFTS virus strains observed from humans and ticks in the ROK, China, and Japan. These results implicate lizards and snakes as potential hosts of SFTS virus.