RESUMO
We have previously obtained compelling proof-of-principle evidence for COX2 gene therapy for fracture repair using integrating retroviral vectors. For this therapy to be suitable for patient uses, a suitable vector with high safety profile must be used. Accordingly, this study sought to evaluate the feasibility of AAV as the vector for this COX2 gene therapy, because AAV raises less safety issues than the retroviral vectors used previously. However, an appropriate AAV serotype is required to provide early increase in and adequate level of COX2 expression that is needed for fracture repair. Herein, we reported that AAV-DJ, an artificial AAV pseudoserotype, is highly effective in delivering COX2 gene to fracture sites in a mouse femoral fracture model. Compared with AAV-2, the use of AAV-DJ led to ~5-fold increase in infectivity in mesenchymal stem cells (MSCs) and provided an earlier and significantly higher level of transgene expression at the fracture site. Injection of this vector at a dose of 7.5 × 10(11) genomic copies led to high COX2 level at the fracture site on day 3 after injections and significantly promoted fracture union at 21 days, as analyzed by radiography and µ-CT. The therapeutic effect appears to involve enhanced osteoblastic differentiation of MSCs and remodeling of callus tissues to laminar bone. This interpretation is supported by the enhanced expression of several key genes participating in the fracture repair process. In conclusion, AAV-DJ is a promising serotype for the AAV-based COX2 gene therapy of fracture repair in humans.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Dependovirus/metabolismo , Consolidação da Fratura , Tíbia/lesões , Transgenes , Animais , Modelos Animais de Doenças , Terapia Genética , Vetores Genéticos/administração & dosagem , Masculino , Camundongos Endogâmicos C57BLRESUMO
Multiple drug resistance is a common problem in the treatment of epilepsy, and approximately 30% of patients continue to have seizures despite all therapeutic interventions. Among various classes of drug transporters, genetic variants of P-glycoprotein (P-gp) encoded by the ABCB1 (ATP-binding cassette subfamily B member 1) gene have been associated with drug-refractory epilepsy. Our aim was to investigate the effect of the 1236C>T(rs1128503), 2677G>T/A(rs2032582), and 3435C>T(rs1045642) single-nucleotide polymorphisms of ABCB1 (or MDR1) on drug resistance in north Indian patients with epilepsy. Genotyping was performed in 101 control subjects and 325 patients with epilepsy, of whom 94 were drug resistant and 231 drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital, and valproate was also performed to confirm compliance in 20% of the patients. Genotype and haplotype frequencies of these polymorphisms did not differ between drug-resistant and drug-responsive patients. Our results demonstrate ABCB1 polymorphisms are not associated with drug resistance in north Indian epileptic patients.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Anticonvulsivantes/uso terapêutico , Epilepsia/epidemiologia , Epilepsia/genética , Polimorfismo Genético/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Alelos , DNA/genética , Resistência a Medicamentos/genética , Epilepsia/tratamento farmacológico , Feminino , Frequência do Gene , Variação Genética , Genótipo , Haplótipos , Humanos , Índia/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores Sexuais , Adulto JovemRESUMO
The synthesis of fifteen new 1-aryl-2-amino-3-(4-arylthiazol-2-yl)/(benzothiazol-2-yl)gua nidines is described. They were screened for their antimicrobial susceptibility by the standard disc diffusion method of the World Health Organization (WHO) and the activities compared with that of standard strain of Escherichia coli NCTC 10418. The sensitive aminoguanidines were further subjected to the minimum inhibitory concentration (MIC) test.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Guanidinas/síntese química , Guanidinas/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Guanidinas/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
A series of p-nitrophenyl substituted semicarbazones has been synthesised and their anticonvulsant activity was screened against MES, scPTZ and scSTY. 4(4'-Nitrophenyl)-o-nitrobenzaldehyde semicarbazone has been found to be the most active in all these tests. The studies revealed that a primary amino function is not essential for anticonvulsant activity in the semicarbazone series of compounds. Presumably these compounds could further act on glycine receptors.
Assuntos
Anticonvulsivantes/síntese química , Semicarbazonas/síntese química , Animais , Anticonvulsivantes/farmacologia , Fenômenos Químicos , Físico-Química , Convulsivantes , Eletrochoque , Espectroscopia de Ressonância Magnética , Camundongos , Pentilenotetrazol , Equilíbrio Postural/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Semicarbazonas/farmacologia , Espectrofotometria Infravermelho , EstricninaRESUMO
Some new 2-carbamoylmethylthio- and 2-(omega-dimethylamino-alkyl)thio-3-aryl-7-chloro-4(3H)-quinazolinones have been prepared from 2-thio-3-aryl-7-chloro-4(3H)-quinazolinones as the key intermediate. Five of the synthetic compounds were screened for their CNS activities on mice and found to be either CNS depressants or stimulants.
Assuntos
Fármacos do Sistema Nervoso Central/síntese química , Quinazolinas/síntese química , Animais , Camundongos , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Synthesis is described of eleven new 2-(N-substituted or N,N-disubstituted aminoacetamido)-4- or -4,5-substituted thiazoles (I). Their hydrochlorides were screened for local anaesthetic activity on frogs by the sciatic plexus method and the activity compared with that of procaine.