Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 69
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Mater Sci Eng C Mater Biol Appl ; 99: 919-928, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889766

RESUMO

The aim of this study was to determine the effect of bone morphogenetic protein-7 (BMP-7) and ornidazole (ORN) loaded Chitosan/ß-glycerophosphate (CS/ß-GP) thermosensitive hydrogels on periodontal regeneration. CS/ß-GP hydrogels with and without BMP-7 and ORN were compared with respect to physicochemical properties, release kinetics, and antimicrobial activity in vitro, and periodontal regeneration properties in class III furcation defects in beagles via radiography, histology including immunohistochemical staining of osteoblasts and osteoclasts, and histometric analysis. CS/ß-GP hydrogels with and without BMP-7 and ORN had comparable physicochemical properties and gelation kinetics. Release kinetics showed that the hydrogels were capable of stable and sustained release of BMP-7 and ORN. The hydrogels loaded with ORN exhibited obvious antimicrobial activity against P. gingivalis. Histometric analysis quantitatively showed significantly more new bone and cementum, and less connective tissue in defects implanted with BMP-7 loaded hydrogels compared with hydrogels without BMP-7. The number of osteoclasts reduced significantly in the CS/BMP-7/ORN and CS/BMP-7 groups, while the number of osteoblasts increased significantly in these groups. Our findings showed that BMP-7 and ORN conferred additional advantages to the CS/ß-GP hydrogel in periodontal regeneration and suggest potential consideration of this approach for periodontal therapy.


Assuntos
Proteína Morfogenética Óssea 7/uso terapêutico , Quitosana/química , Defeitos da Furca/tratamento farmacológico , Glicerofosfatos/química , Hidrogéis/química , Ornidazol/uso terapêutico , Periodonto/patologia , Cicatrização/efeitos dos fármacos , Animais , Anti-Infecciosos/farmacologia , Proteína Morfogenética Óssea 7/farmacologia , Preparações de Ação Retardada/farmacologia , Cães , Liberação Controlada de Fármacos , Defeitos da Furca/patologia , Injeções , Cinética , Masculino , Testes de Sensibilidade Microbiana , Ornidazol/farmacologia , Regeneração/efeitos dos fármacos , Temperatura Ambiente , Viscosidade
2.
Pharm Dev Technol ; 24(1): 118-126, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29334299

RESUMO

A bilayered mucoadhesive buccal film containing a combination of ornidazole (OD) and dexamethasone sodium phosphate (DEX) was prepared using solvent casting to treat oral ulcers. Films were systematically evaluated in vitro to obtain the optimum formulation. The therapeutic effects of these films were investigated in the rabbit oral ulcer model and the in vivo release of OD and DEX in the human oral cavity was also evaluated. The backing layer contained ethyl cellulose and an optimal mucoadhesive layer containing both OD and DEX was produced. Films from the optimum formulation were 0.427 ± 0.015 mm thick, weighed 55.89 ± 0.79 mg, and had a surface pH of 6.34 ± 0.01. The drug content of the optimum formulation approximated the theoretical value with good uniformity (2.959 ± 0.106 mg/cm2 for OD and 0.877 ± 0.031 mg/cm2 for DEX). The formulation showed favorable swelling characteristics and both drugs were released at >95% after 4 h. Moreover, the compound film had a statistically significant effect on mucosal repair and reduced ulcer inflammation without stimulating the human oral mucosa. Cmax of OD in saliva was 37.04 µg/ml and that of DEX was 9.737 µg/ml. Given promising therapeutic effects, the compound film developed here could become a local drug delivery device for treating oral ulcers.


Assuntos
Dexametasona/análogos & derivados , Mucosa Bucal/metabolismo , Úlceras Orais/tratamento farmacológico , Ornidazol/administração & dosagem , Adesividade , Administração Bucal , Adulto , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Celulose/análogos & derivados , Celulose/química , Química Farmacêutica/métodos , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Modelos Animais de Doenças , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Humanos , Masculino , Ornidazol/farmacologia , Coelhos , Suínos , Adulto Jovem
3.
Clin Ther ; 40(9): 1548-1555, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30146271

RESUMO

PURPOSE: The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole. METHODS: A single-center, open, multidose trial was conducted in 16 patients with intra-abdominal anaerobic infection. Patients received levornidazole at 500mg q12h by intravenous infusion for 3 to 7days. The plasma samples collected before and after the last dose were analyzed by the LC-MS/MS method to determine the concentration of levornidazole. The PK parameters of levornidazole were calculated, and the PK profiles of levornidazole after the dosing regimen of 750mg q24h for 7days were simulated based on the linear PK profile of levornidazole. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment (PTA) of both dosing regimens at steady-state against Bacteroides fragilis. FINDINGS: After administration of the last dose of 500mg of levornidazole, the mean (SD) Cmax_ss, AUC0-12, and t1/2 of levornidazole were 24.0 (5.37) µg/mL, 176.59 (29.22) µg·h/mL, and 11.03 (1.34) hours, respectively. The mean (SD) CLss and Vss of levornidazole were 2.90 (0.47) L/h and 45.90 (7.44) L, respectively. The mean (SD) distribution volume of central compartment (V1) and distribution volume of peripheral compartment (V2) were 26.71 (8.51) L and 19.21 (10.86) L, respectively. On the basis of simulation, the accumulation ratio of levornidazole in the 750mg q24h dosing regimen was 30.2% lower than the value in the 500mg q12h dosing regimen. Forthe 2 dosing regimens, the Cmax_ss, AUC0-τ, AUC0-∞, CLss, and Vss did not produce a significant difference between patients and healthy volunteers (P > 0.05). The cumulative fraction of response of levornidazole against B fragilis was >90%, and the probability of target attainment after both dosing regimens was >90%, when the MIC was ≤1 µg/mL. IMPLICATIONS: No significant differences were found in the PK profiles of levornidazole at steady state between the patients with intra-abdominal anaerobic infection and healthy volunteers. The clinical conventional 750mg q24h regimen can achieve similar clinical and microbiological efficacies against anaerobic in the patients after the 500mg q12h regimen.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Bacteroides fragilis/efeitos dos fármacos , Infecções Intra-Abdominais/tratamento farmacológico , Ornidazol/farmacologia , Ornidazol/farmacocinética , Adulto , Antibacterianos/uso terapêutico , Área Sob a Curva , Bactérias Anaeróbias , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Infecções Intra-Abdominais/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Ornidazol/uso terapêutico
4.
Int J Biol Macromol ; 116: 394-408, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29746970

RESUMO

Considering alarming projections in the prevalence of periodontitis, following study was undertaken to develop chitosan-vanillin crosslinked microspheres loaded in-situ gel (MLIG) implants containing ornidazole and doxycycline hyclate for the treatment of pocket infections. Firstly, microspheres were formulated and optimized using response surface methodology for particle size <50 µm, entrapment efficiency >80%, in-vitro drug release (T80%) >7 days and acceptable mucoadhesion. Further, MLIG were optimized for gelation temperature of 34-37 °C and viscosity <1000 cps respectively. FTIR, DSC and XRD graphs disclosed compatibility and alterations in crystallinity of drugs. In-vitro dissolution study demonstrated non-Fickian type of drug release mechanism for twelve days. Stability studies ascertained MLIG implants were sterilizable and stable for about 11.29 months on refrigeration. The formulations exhibited significant (p < 0.001) antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis, and were found biocompatible and biodegradable during preclinical studies. Ligature-induced periodontal rat model, corroborated significant growth (p < 0.05) of gingival tissue after two weeks. Clinical trials revealed, intra-pocket administration of MLIG along with SRP provided significant reduction in clinical parameters as compared to SRP alone. Conclusively, antimicrobials incorporated thermosensitive, biodegradable, mucoadhesive and syringeable MLIG implants appeared as better option for the treatment of periodontitis.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Periodontite/tratamento farmacológico , Implantes Absorvíveis , Animais , Química Farmacêutica/métodos , Quitosana/química , Doxiciclina/química , Doxiciclina/farmacologia , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Géis/química , Géis/farmacologia , Masculino , Microesferas , Ornidazol/química , Ornidazol/farmacologia , Tamanho da Partícula , Periodontite/microbiologia , Próteses e Implantes , Ratos , Solubilidade/efeitos dos fármacos , Viscosidade/efeitos dos fármacos
5.
Int J Biol Macromol ; 106: 775-783, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28818724

RESUMO

Molecular self-assembly of biodegradable amphiphilic polymers allows rational design of biocompatible nanomaterials for drug delivery. Use of substituted polysaccharides for such applications offers the ease of design and synthesis, and provides higher biofunctionality and biocompatibility to nanomaterials. The present work focuses on the synthesis, characterization and potential biomedical applications of self-assembled polysaccharide-based materials. We demonstrated that the synthesized amphiphilic inulin self-assembled in aqueous medium into nanostructures with average size in the range of 146-486nm and encapsulated hydrophobic therapeutic molecule, ornidazole. Hydrophophic dehydropeptide was conjugated with inulin via a biocompatible ester linkage. Dehydrophenylalanine, an unusual amino acid, was incorporated in the peptide to make it stable at a broader range of pH as well as against proteases. The resulting core-shell type of nanostructures could encapsulate ornidazole in the hydrophobic core and released it in a controlled fashion. By taking the advantage of inulin, which gets degraded in the colon by colonic bacteria, the effect of enzyme, inulinase, present in the microflora of the large intestine, on inulin-peptide degradation followed by drug release has been studied. Altogether, small peptide conjugated to inulin offers novel scaffold for the future design of nanostructures with potential applications in the field of targeted drug delivery.


Assuntos
Sistemas de Liberação de Medicamentos , Nanoestruturas/uso terapêutico , Ornidazol/farmacologia , Polissacarídeos/química , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/uso terapêutico , Liberação Controlada de Fármacos , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Inulina/síntese química , Inulina/química , Microscopia de Força Atômica , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Ornidazol/síntese química , Ornidazol/química , Peptídeos/síntese química , Peptídeos/química , Peptídeos/uso terapêutico , Fenilalanina/análogos & derivados , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Polissacarídeos/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier
6.
Clin Ther ; 39(7): 1336-1346, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28619503

RESUMO

PURPOSE: Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. METHODS: Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years). The PK profiles of levornidazole and its metabolites in elderly subjects were evaluated and compared with those in the young group. WinNonlin software was used for simulating the PK profile of levornidazole in the elderly population following the dosing regimens of 500 mg BID and 750 mg once daily for 7 days. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment of both dosing regimens against Bacteroides spp. RESULTS: The Cmax, AUC0-24, and AUC0-∞ values of levornidazole in the elderly group were 11.98 µg/mL, 131.36 µg·h/mL, and 173.61 µg·h/mL, respectively. The t1/2, CLt, and mean residence time from time 0 to infinity were 12.21 hours, 2.91 L/h, and 16.46 hours. The metabolic ratios of metabolites (M) 1, 2, 4, and 6 were <3.0%, and that of M16 was 17.70%. The urinary excretion values of levornidazole, M1, M2, M4, M6, and M16 over 96 hours were 10.21%, 0.92%, ~0%, 2.69%, 0.54%, and 41.98%. The PK properties of levornidazole and the urinary excretion of all metabolites were not statistically different between the 2 groups. The cumulative fraction of response was >90% against B fragilis and other Bacteroides spp, and the probability of target attainment was >90% when the minimum inhibitory concentration was ≤1 µg/mL, in both groups. IMPLICATIONS: No dosing regimen adjustment is suggested when levornidazole is used in elderly patients with normal hepatic functioning and mild renal dysfunction. The findings from the PK/PD analysis imply that both regimens may achieve satisfactory clinical and microbiological efficacy against anaerobic infections in elderly patients. Chinese Clinical Trial Registry (http://www.chictr.org.cn) identifier: ChiCTR-OPC-16007938.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Infecciosos/farmacocinética , Bacteroides/efeitos dos fármacos , Ornidazol/farmacologia , Ornidazol/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/sangue , Anti-Infecciosos/urina , Bacteroides/crescimento & desenvolvimento , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Ornidazol/sangue , Ornidazol/urina , Adulto Jovem
7.
Clin Ther ; 39(4): 828-836, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28363695

RESUMO

PURPOSE: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. METHODS: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body. The device of 2-compartment PK/PD model was constructed by using digital control of flow rate to simulate 4 regimens of single-dose intravenous infusion of levornidazole to determine the bactericidal activity of levornidazole against the 3 strains of B fragilis within 72 hours. PD parameters such as reduction of colony count within 24 hours (∆Log24h), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid Emax model of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect. FINDINGS: PK and PD validation proved the stability of the model in simulating levornidazole against B fragilis and the precision and accuracy in the results of PK modeling. Cmax and AUC0-24h found only -1.46% and -6.72% differences from the values in vivo. Our study found that ∆Log24h, AUBC, and IKR were more correlated with AUC0-24h/MIC and Cmax/MIC than with %T>MIC. According to ∆Log24h, the PK/PD target values of AUC0-24h/MIC, Cmax/MIC, and %T>MIC of levornidazole against B fragilis were 157.6%, 14.1%, and 56.4%, respectively. IMPLICATIONS: Our findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Bacteroides fragilis/efeitos dos fármacos , Modelos Biológicos , Ornidazol , Anaerobiose , Área Sob a Curva , Infecções Bacterianas/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Ornidazol/análogos & derivados , Ornidazol/farmacocinética , Ornidazol/farmacologia
8.
Biochem J ; 473(23): 4413-4426, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27647935

RESUMO

Ornidazole of the 5-nitroimidazole drug family is used to treat protozoan and anaerobic bacterial infections via a mechanism that involves preactivation by reduction of the nitro group, and production of toxic derivatives and radicals. Metronidazole, another drug family member, has been suggested to affect photosynthesis by draining electrons from the electron carrier ferredoxin, thus inhibiting NADP+ reduction and stimulating radical and peroxide production. Here we show, however, that ornidazole inhibits photosynthesis via a different mechanism. While having a minute effect on the photosynthetic electron transport and oxygen photoreduction, ornidazole hinders the activity of two Calvin cycle enzymes, triose-phosphate isomerase (TPI) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Modeling of ornidazole's interaction with ferredoxin of the protozoan Trichomonas suggests efficient electron tunneling from the iron-sulfur cluster to the nitro group of the drug. A similar docking site of ornidazole at the plant-type ferredoxin does not exist, and the best simulated alternative does not support such efficient tunneling. Notably, TPI was inhibited by ornidazole in the dark or when electron transport was blocked by dichloromethyl diphenylurea, indicating that this inhibition was unrelated to the electron transport machinery. Although TPI and GAPDH isoenzymes are involved in glycolysis and gluconeogenesis, ornidazole's effect on respiration of photoautotrophs is moderate, thus raising its value as an efficient inhibitor of photosynthesis. The scarcity of Calvin cycle inhibitors capable of penetrating cell membranes emphasizes on the value of ornidazole for studying the regulation of this cycle.


Assuntos
Bactérias Anaeróbias/efeitos dos fármacos , Ornidazol/farmacologia , Fotossíntese/efeitos dos fármacos , Cianobactérias/efeitos dos fármacos , Ferredoxinas/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Glicólise , Metronidazol/farmacologia , Modelos Biológicos , Synechocystis/efeitos dos fármacos , Trichomonas/efeitos dos fármacos , Trichomonas/metabolismo , Triose-Fosfato Isomerase/metabolismo
9.
Clin Lab ; 62(5): 793-800, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27349003

RESUMO

BACKGROUND: Nitroimidazoles, which are drugs that are used to effectively treat Trichomonas vaginalis, alter the structure of the T. vaginalis cell membrane, penetrate into its cytoplasm and nucleus and block cellular metabolism. In this study, we observed the morphological changes that occurred in T. vaginalis during in vitro exposure to 1.3 µg/mL of ornidazole at various time intervals ranging from 10 minutes to 10 hours. METHODS: Vaginal and urethral secretion samples from suspected T. vaginalis cases were inoculated into Cysteine Peptone Liver Maltose medium. In 18 sterile tubes, 9.5 mL of this solution were mixed with 0.5 mL of ornidazole. The periods of contact between ornidazole and T. vaginalis ranged from 10 minutes to 10 hours. RESULTS: The first change was vacuolization, which started in the 10th minute of exposure. The glycogen particles started to diminish in the 20th minute. CONCLUSIONS: During exposure to 1.3 mg/L of ornidazole, cell lysis began in the 30th minute and accelerated towards the 60th minute (p < 0.001). Cytoplasmic matrix integrity was impaired in the 60th minute (p < 0.001).


Assuntos
Antitricômonas/farmacologia , Ornidazol/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Fatores de Tempo , Trichomonas vaginalis/ultraestrutura
10.
Mikrobiyol Bul ; 50(1): 133-9, 2016 Jan.
Artigo em Turco | MEDLINE | ID: mdl-27058337

RESUMO

The current treatment of trichomoniasis is based on the use of 5-nitroimidazole derivatives. Although metronidazole is reliable, inexpensive and highly effective against anaerobic microorganisms and protozoa, the development of metronidazole-resistant T.vaginalis strains pose to an increasing problem. Nitroimidazoles are compounds having azomycin (2-nitroimidazole) chemical structure and are obtained from Streptomyces strains. Benzimidazole, which is found in the structure of proton pump inhibitors, is also present in the other components that have antiprotozoal activity. In this study, the in vitro susceptibility of T.vaginalis against metronidazole, ornidazole, and the proton pump inhibitors which are tested recently as antiprotozoal agents; pantoprazole and esomeprazole was investigated. For this purpose a clinical T.vaginalis strain which was formerly isolated and stored after cryopreservation process in our laboratory was used. Minimum inhibitory concentration (MIC) and minimum lethal concentration (MLC) values of those agents against to this strain were determined in vitro by dilution method in 24-well cell culture plates. Trypticase yeast extract maltose medium, horse serum and antibiotic (penicillin + streptomycin) were distributed to each well of cell culture plates and after metronidazole, ornidazole, pantoprazole and esomeprazole solutions were added to two wells for each as 800, 400, 200, 100, 50 and 25 µg/ml, followed by the addition of 1 ml 5x10(3) T.vaginalis trophozoites into each well. Plates were incubated at 37°C, and viability and motility of the trophozoites were evaluated under light microscope at 24, 48 and 72 hours after incubation. MIC and MLC values of metronidazole/ornidazole in the 72(th) hour were found as 50 µg/ml and 100 µg/ml, respectively. MIC and MLC values for pantoprazole in the 72th hour were 200 µg/ml and 400 µg/ml, while the values for esomeprazole were 400 µg/ml ve 800 µg/ml, respectively. As a result, T.vaginalis strain used in the study was susceptible to metronidazole and ornidazole, besides, it was considered that pantoprazole and esomeprazole were also effective to the parasite and could be used as alternative drugs. However, further in vitro and clinical studies are clearly needed on the antiprotozoal effects of proton pump inhibitors. To our knowledge, this study was the first in literature, which esomeprazole's susceptibility on T.vaginalis was investigated in vitro.


Assuntos
Antitricômonas/farmacologia , Metronidazol/farmacologia , Ornidazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Criopreservação , Resistência a Medicamentos , Esomeprazol/farmacologia , Humanos , Pantoprazol , Testes de Sensibilidade Parasitária , Fatores de Tempo
11.
Chem Biol Interact ; 242: 163-9, 2015 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-26415617

RESUMO

This is the preliminary study of the sedative and muscle relaxation activity of ornidazole enantiomers, which are widely used in the treatment of susceptible protozoal infections and anaerobic bacterial infections. Adverse effects on the central nervous system (CNS) are the main side effects of ornidazole during its clinical application. The aim of this study was to compare the different central inhibitory effects between S-(-) ornidazole and R-(+) ornidazole in mice and clarify the possible mechanisms. In the present study, central effects of ornidazole were evaluated by open-field test and rota-rod test, and such effects were reversed by pre-treatment with flumazenil (i.p., 10 mg/kg) suggesting that ornidazole exhibits such action by interacting with the GABAergic system. Then, the functional difference between S-(-) ornidazole and R-(+) ornidazole was further explored by evaluating the contents of glutamate (Glu) and γ-aminobutyric acid (GABA) in the brain, and Western blot was used to measure glutamic acid decarboxylase (GAD65/67) expression in the mice cerebral cortex. We found that R-(+) ornidazole mediated an increase in GABA level while decreased the level of glutamate through upregulation of GAD65/67 in the cerebral cortex. Taken together, our study suggests that R-(+) ornidazole mediate stronger central inhibitory effects than S-(-) ornidazole through interaction with the GABAergic system.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Ornidazol/química , Ornidazol/farmacologia , Receptores de GABA-A/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Flumazenil/farmacologia , Glutamato Descarboxilase/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Camundongos Endogâmicos ICR , Ornidazol/sangue , Ornidazol/farmacocinética , Teste de Desempenho do Rota-Rod , Estereoisomerismo , Ácido gama-Aminobutírico/metabolismo
12.
Biochem Pharmacol ; 97(2): 178-88, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26212544

RESUMO

Levornidazole, which was originally used to inhibit anaerobic and protozoal infections, is currently known to possess a novel pharmacological effect. In this study, we investigated the possible modulation by levornidazole of NOD-like receptor protein 3 (NLRP3) inflammasome-mediated IL-1ß and IL-18 release from macrophages. The NLRP3 inflammasome could be activated by lipopolysaccharide (LPS) plus ATP or monosodium urate (MSU) in PMA-pretreated THP-1 macrophages. Surprisingly, an in vitro study showed that levornidazole suppressed IL-1ß and IL-18 secretion by blocking the activation of the NLRP3 inflammasome. However, dextrornidazole barely suppressed the NLRP3 inflammasome. Levornidazole displays activity similar to that of dextrornidazole against clinical anaerobic bacteria, and they possess the same pharmacokinetic properties. Moreover, both of these compounds were unable to ameliorate T cell-mediated inflammation. Therefore, we used the widely applied NLRP3 inflammasome-related models of dextran sodium sulfate (DSS)-induced colitis and LPS-induced endotoxin shock to confirm the novel pharmacological effect of levornidazole in vivo. The in vivo studies verified the novel activity of levornidazole because the inhibition of NLRP3 inflammasome by levornidazole contributed to a better ameliorating effect than that of dextrornidazole in the in vivo models tested. Furthermore, this inhibitory effect of levornidazole was found to be at least partially achieved by decreasing the mitochondrial ROS generation without inhibiting NF-κB activation. In summary, these data describe a new pharmacological effect of levornidazole as an inhibitor of NLRP3 inflammasome activation.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Ornidazol/análogos & derivados , Ornidazol/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR
13.
Dalton Trans ; 44(4): 1992-2000, 2015 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25502216

RESUMO

An acetate-bridged binuclear Cu((II)) complex of the antiparasitic drug ornidazole was synthesized and characterized by different techniques. Single crystal X-ray diffraction revealed that the complex had a paddle wheel structure. Enzymatic assay experiments performed under anaerobic conditions on ornidazole and its Cu((II))-complex using xanthine oxidase as a model nitro-reductase showed that complex formation is able to cause a significant decrease in the reduction of the nitro group on the imidazole ring. Reduction products of 5-nitroimidazoles interact with DNA, causing destruction of the double helical structure and strands, leading to the inhibition of protein synthesis. Although not directly coordinated to the metal center, such a decrease in the generation of nitro radical anion through complex formation would result in decreased cytotoxicity of the complex, which could be a disadvantage from the standpoint of drug efficacy. For this reason, other aspects associated with the drug action of 5-nitroimidazoles, such as DNA binding, were studied. Experiments using cyclic voltammetry revealed that the binding of the complex was almost comparable to ornidazole. Bactericidal activity of ornidazole and the complex was studied on two separate bacterial strains, showing that the complex was comparable to ornidazole. Nitro radical anions are known to adversely affect the central nervous system, and this study showed that the Cu((II)) complex has the ability to decrease the generation of NO2˙(-) to an extent that struck the correct balance for beneficial activity, as cytotoxicity due to ornidazole was not affected.


Assuntos
Antibacterianos/química , Antiparasitários/química , Complexos de Coordenação/química , Cobre/química , Radicais Livres/química , Ornidazol/química , Antibacterianos/farmacologia , Antiparasitários/farmacologia , Complexos de Coordenação/farmacologia , Cobre/farmacologia , DNA/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ornidazol/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Difração de Raios X , Xantina Oxidase/química
14.
Int J Antimicrob Agents ; 44(6): 514-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25301712

RESUMO

This study evaluated the in vitro anti-anaerobic activity and spectrum of levornidazole, its metabolites and comparators against 375 clinical isolates of anaerobic bacteria, including Gram-negative bacilli (181 strains), Gram-negative cocci (11 strains), Gram-positive bacilli (139 strains) and Gram-positive cocci (44 strains), covering 34 species. Minimum inhibitory concentrations (MICs) of levornidazole, its five metabolites and three comparators against these anaerobic isolates were determined by the agar dilution method. Minimum bactericidal concentrations (MBCs) of levornidazole and metronidazole were measured against 22 strains of Bacteroides fragilis. Levornidazole showed good activity against B. fragilis, other Bacteroides spp., Clostridium difficile, Clostridium perfringens and Peptostreptococcus magnus, evidenced by MIC90 values of 0.5, 1, 0.25, 2 and 1mg/L, respectively. The activity of levornidazole and the comparators was poor for Veillonella spp. Generally, levornidazole displayed activity similar to or slightly higher than that of metronidazole, ornidazole and dextrornidazole against anaerobic Gram-negative bacilli, Gram-positive bacilli and Gram-positive cocci, especially B. fragilis. Favourable anti-anaerobic activity was also seen with levornidazole metabolites M1 and M4 but not M2, M3 or M5. For the 22 clinical B. fragilis strains, MBC50 and MBC90 values of levornidazole were 2mg/L and 4mg/L, respectively. Both MBC50/MIC50 and MBC90/MIC90 ratios of levornidazole were 4, similar to those of metronidazole. Levornidazole is an important anti-anaerobic option in clinical settings in terms of its potent and broad-spectrum in vitro activity, bactericidal property, and the anti-anaerobic activity of its metabolites M1 and M4.


Assuntos
Antibacterianos/farmacologia , Bactérias Anaeróbias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Bactérias Gram-Positivas/efeitos dos fármacos , Cocos Gram-Positivos/efeitos dos fármacos , Ornidazol/farmacologia , Infecções Bacterianas/microbiologia , Bacteroides fragilis/efeitos dos fármacos , Clostridium difficile/efeitos dos fármacos , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana
15.
Colloids Surf B Biointerfaces ; 82(2): 325-32, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20889316

RESUMO

In view of the antidiarrheal properties of sterculia gum and ornidazole, an attempt has been made to synthesize novel hydrogels by functionalization of sterculia gum with poly(vinylpyrrolidone) (PVP) for release of the model antidiarrheal drug ornidazole. These hydrogels were characterized with FTIR, SEM, TGA and swelling behavior. Swelling kinetics of the hydrogels and in vitro release dynamics of ornidazole from the drug loaded hydrogels have been studied to determine the mechanism of swelling and drug release from the drug loaded hydrogels. A Fickian diffusion mechanism has been observed for the release of drug from the hydrogels. These hydrogels may have dual actions for the treatment of diarrhea.


Assuntos
Antidiarreicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Sterculia/química , Calibragem , Difusão , Humanos , Hidrogéis/química , Concentração de Íons de Hidrogênio , Cinética , Microscopia Eletrônica de Varredura/métodos , Ornidazol/farmacologia , Polímeros/química , Povidona/farmacologia , Cloreto de Sódio/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Termogravimetria/métodos
16.
Exp Parasitol ; 127(2): 600-3, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20875410

RESUMO

The aim of this study was to develop a simple and reliable method to determine the viability of Giardia intestinalis after incubation with an anti-giardial agent by using a colorimetric method. Factors that may affect the optical density value were systematically evaluated. The most suitable conditions were obtained when G. intestinalis trophozoites, 5 × 10(5)cells/ml were incubated with the anti-giardial agent for 48 h. The culture medium was removed and trophozoites were immediately fixed by immersing the whole plate in absolute methanol for 2 min. The fixed trophozoites were then stained with 0.1% w/v methylene blue for 10 min, washed once by immersing the whole plate into distilled water. The dye was released by adding 0.1M hydrochloric acid solution (300 µl) and the optical density was read at 655 nm. The 50% inhibitory concentration values (IC(50)) of metronidazole, ornidazole and furazolidone obtained from our proposed method (0.41 ± 0.06, 0.18 ± 0.01, 0.26 ± 0.13 µg/ml, respectively) were comparable to the IC(50) values obtained by the current conventional method (0.14 ± 0.05, 0.15 ± 0.04, 0.14 ± 0.02 µg/ml, respectively). This new method did provide a convenient and reliable way to screen for potential anti-giardial agents.


Assuntos
Antiprotozoários/farmacologia , Colorimetria/métodos , Giardia lamblia/efeitos dos fármacos , Testes de Sensibilidade Parasitária/métodos , Corantes , Furazolidona/farmacologia , Metronidazol/farmacologia , Ornidazol/farmacologia
17.
J Biomed Mater Res A ; 85(2): 566-72, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17806112

RESUMO

To create a moist environment for rapid wound healing, a new C-P-A film with sustained antibacterial capacity had been developed by the casting/solvent evaporation method. This new type of C-P-A film consists of a chitosan top layer and sodium alginate sublayer separated by an ornidazole-incorporated poly(vinyl alcohol) layer, exhibited perfect binding characteristics among the three layers. Physical characterization of the C-P-A film showed that the triple-layerd film had excellent light transmittance, control of water vapor transmission rate, and fluid drainage ability promotion, compared with the single-layer film. From the in vitro release studies, about 90% of OD was released from the composite films within 60 min, and no significant difference was observed in cumulative release percentage with increases in the drug content. The composite film at low concentration of OD (1.0 mg/cm2) showed effective antimicrobial activity in the cultures of Staphylococcus aureus and Escherichia coli in agar plates. The results obtained in this work indicated that the new type of C-P-A composite film incorporated with ornidazole has the potential for wound dressing application.


Assuntos
Alginatos/química , Antitricômonas/química , Quitosana/química , Escherichia coli/crescimento & desenvolvimento , Ornidazol/química , Álcool de Polivinil/química , Staphylococcus aureus/crescimento & desenvolvimento , Antitricômonas/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Ornidazol/farmacologia
18.
Pharmacol Rep ; 59(5): 580-7, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18048959

RESUMO

In this study, we determined the in vitro inhibitory effects of ceftriaxone sodium, imipenem and ornidazole on hydratase and esterase activities of human erythrocyte carbonic anhydrase-I and II isozymes (CA I and II). Human erythrocyte CAI and II isozymes were purified by Sepharose-4B L-tyrosine affinity chromatography column with a yield of 30% and 40%, a specific activity of 920 and 8,000 EU/mg protein, respectively. In the overall purification procedure, human carbonic anhydrase (hCA)-I and (hCA)-II were purified 104 and 900-fold, respectively. In order to determine the purity of the enzymes, SDS-PAGE was performed. Inhibitory effects of the drugs on hCA-I and hCA-II were determined by using colorimetric method for CO2-hydratase activity assay and spectrophotometric method for esterase activity assay. P-Nitrophenyl acetate was used as a substrate in the spectrophotometric esterase activity assay. The obtained IC50 values (inhibitor concentrations which cause 50% inhibition of in vitro enzyme activity) for esterase activity were 1.900, 0.008, 0.318 mM for hCA-I and 2.542, 0.0258, 0.343 mM for hCA-II for ceftriaxone sodium, imipenem and ornidazole, respectively. IC50 values for CO2-hydratase activity were 0.864, 0.00354, 0.131 mM for hCA-I and 1.118, 0.0214, 0.263 mM for hCA-II for ceftriaxone sodium, imipenem and ornidazole, respectively. In conclusion, ceftriaxone sodium, imipenem and ornidazole showed inhibitory effects on human erythrocte carbonic anhydrase-I and II isozyme activities under in vitro conditions.


Assuntos
Anti-Infecciosos/farmacologia , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Esterases/antagonistas & inibidores , Animais , Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Anidrase Carbônica I/química , Anidrase Carbônica II/química , Ceftriaxona/farmacologia , Eritrócitos/enzimologia , Esterases/química , Humanos , Imipenem/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Ornidazol/farmacologia , Ratos
19.
Eur J Nucl Med Mol Imaging ; 34(9): 1348-54, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17334763

RESUMO

PURPOSE: The 2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)acetamide (EF3) is a 2-nitroimidazole derivative which undergoes bioreductive activation under hypoxic conditions. Using the PET tracer [18F]EF3 in mice, tumour-to-muscle ratios ranging from 1.3 to 3.5 were observed. This study investigated the impact of various interventions aimed at increasing [18F]EF3 elimination, thus potentially increasing the tumour-to-noise ratio in mice, by increasing the renal filtration rate (spironolactone, furosemide), decreasing tubular re-absorption (metronidazole, ornidazole, amino acid solution) or stimulating gastro-intestinal elimination (phenobarbital). METHODS: C3H mice were injected i.v. with an average of 12.95 MBq of [18F]EF3. Drugs were injected i.v. 15 min before the tracer or daily 4 days prior to the experiment (phenobarbital). Anaesthetised mice were imaged from 30 to 300 min with a dedicated animal PET (Mosaic, Philips). Regions of interest were delineated around the tumour, bladder, heart, liver and leg muscle. Radioactivity was expressed as a percentage of injected activity per gram of tissue. RESULTS: Ornidazole decreased the urinary excretion and increased the liver uptake of [18F]EF3, but without causing any changes in the other organs. Phenobarbital significantly increased the liver concentration and decreased radioactivity in blood and muscle without affecting the tracer uptake in tumour. Consequently, a small but non-significant increase in tumour-to-noise ratio was observed. Although some effects were observed with other drugs, they did not modify the tumour-to-noise ratio. CONCLUSION: Only phenobarbital induced a trend toward an increased tumour-to-noise ratio that could possibly be tested in the clinical situation.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nitroimidazóis/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Animais , Área Sob a Curva , Hipóxia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Ornidazol/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Espironolactona/farmacologia , Fatores de Tempo , Distribuição Tecidual , Resultado do Tratamento
20.
J Mater Sci Mater Med ; 18(6): 1125-33, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17268861

RESUMO

The distinguishable films composed of poly(vinyl alcohol) (PVA) and carboxymethyl-chitosan (CMCS) were prepared by blending/casting method, and loaded with ornidazole (OD) as local drug delivery system. In vitro test, the blend films showed pH-responsive swelling behavior and moderate drug release action, and also exhibited a little antimicrobial activity against E. coli and S. aureus strains. Those characteristics of CMCS/PVA blend films were essentially governed by the weight ratio of CMCS and PVA. Increasing the content of PVA in blend film would decrease swelling and decelerated the drug release. However, increasing the content of CMCS would enhance the antimicrobial activity. The biocompatibility and bioactivity of the blend film were also evaluated using rabbit blood and Wister rats. This blend drug system was of no hemolysis, no toxicity to rat periodontia and no cytotoxicity to the rat muscle. After subcutaneously implanting the blend drug films in Wister rat, the systems kept a good retention at the application site and maintained high drug concentration in long time (5 days) which was longer than the period of drug released in vitro (160 min).


Assuntos
Quitosana/análogos & derivados , Quitosana/química , Álcool de Polivinil/química , Animais , Antitricômonas/administração & dosagem , Antitricômonas/química , Antitricômonas/farmacologia , Quitosana/efeitos adversos , Sistemas de Liberação de Medicamentos , Inflamação/tratamento farmacológico , Membranas Artificiais , Ornidazol/administração & dosagem , Ornidazol/química , Ornidazol/farmacologia , Doenças Periodontais/induzido quimicamente , Álcool de Polivinil/efeitos adversos , Ratos , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA