RESUMO
BACKGROUND: Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).METHODS: This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.RESULTS: By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).CONCLUSIONS: While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Feminino , Humanos , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Rifampina/farmacologia , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
The present work describes the synthesis of polyvinylpyrrolidone (PVP) assisted Fe-BiOI based Fe/Bi-povidoneiodine (Fe/Bi-P-I) micro-flowers based composite and its photocatalytic and antibacterial applications. The Fe/Bi-P-I micro-flowers-based composite material was synthesized using a simple co-precipitation method. The prepared Fe/Bi-P-I micro-flowers-based composite materials were characterized using various characterization techniques and tested against photocatalytic degradation of rhodamine B (RhB) dye and antibacterial analysis. The PVP or povidoneiodine provides more exposure of reactive sites and oxygen vacancies, which leads to a high separation rate of photoinduced charge carriers, and migration, thereby 100% of photodegradation efficiency at 1 mg/L initial concentration of RhB dye towards the synthesized P-Fe-BiOI based micro-flowers composite. Interestingly, Povidone-Iodine in Fe/Bi-P-I micro-flowers-based composite might be advantageous for antimicrobial activity against both gram-negative (E. coli), and gram-positive (S. aureus) bacterial strains. Therefore, the prepared Fe/Bi-P-I micro-flowers-based composite improved both photocatalytic degradation of organic pollutants as well as high antimicrobial activity. The method of synthesizing the Bi/Fe-P-I micro flower composite in the present study is novel, facile, and economically viable.
Assuntos
Antibacterianos/química , Bismuto/química , Ferro/química , Luz , Fotólise/efeitos da radiação , Povidona-Iodo/química , Antibacterianos/farmacologia , Catálise , Escherichia coli/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Rodaminas/química , Staphylococcus aureus/efeitos dos fármacosRESUMO
Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the in vivo efficacy. Meropenem generics were compared with the innovator in vitro by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and in vivo with the neutropenic guinea pig soleus infection model (Pseudomonas aeruginosa) and the neutropenic mouse thigh (P. aeruginosa), brain (P. aeruginosa), and lung (Klebisella pneumoniae) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient, in vitro susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.
Assuntos
Antibacterianos/farmacocinética , Dipeptidases/metabolismo , Medicamentos Genéricos/farmacocinética , Infecções por Klebsiella/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Tienamicinas/farmacocinética , Animais , Antibacterianos/metabolismo , Biotransformação , Encéfalo/efeitos dos fármacos , Encéfalo/microbiologia , Cilastatina/farmacologia , Dipeptidases/antagonistas & inibidores , Estabilidade de Medicamentos , Medicamentos Genéricos/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Cobaias , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Meropeném , Camundongos , Testes de Sensibilidade Microbiana , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/microbiologia , Inibidores de Proteases/farmacologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Equivalência Terapêutica , Tienamicinas/metabolismo , Coxa da Perna/microbiologia , Resultado do TratamentoAssuntos
Arte , Síndrome de Down/história , Colômbia , Equador , História Antiga , Humanos , Indígenas Sul-AmericanosRESUMO
The reducing activity on the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, z.rad;OH radical scavenging potential, in vitro inhibition of lipid peroxidation and modulation of mutagenicity induced by ter-butyl hydroperoxide (TBH) in Escherichia coli were sequentially screened in 45 species of plants used with medicinal purposes in Cuba, in a search for antioxidant agents which protect DNA against oxidative stress.Five species, e.g. Tamarindus indica L., Lippia alba L., Pimenta dioica (L.) Merr, Rheedia aristata Griseb. and Curcuma longa L. displayed IC(50)<30 micro g/ml in the DPPH radical reduction assay and IC(50)<32 micro g/ml in lipid peroxidation inhibition testing. Pimenta dioica and Curcuma longa L. showed also a 20% inhibition of the in vitro induced z.rad;OH attack to deoxyglucose. Further antimutagenesis assay in Escherichia coli IC 188 evidenced that only Pimenta dioica prevents DNA damage by TBH to the test bacteria. A role of antioxidant enzymes is presumed in this case, as judged by a different response in the isogenic Escherichia coli IC 203 deficient in catalase and alkyl hydroperoxide reductase and the discrete inhibition of oxidative mutagenesis also observed when pre-treatment of the extract was assayed. Eugenol, the main constituent of the essential oil of Pimenta dioica, also inhibited oxidative mutagenesis by TBH in Escherichia coli, at concentrations ranging from 150 to 400 micro g/plate.
Assuntos
Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Plantas Medicinais/química , Compostos de Bifenilo , Cuba , Dano ao DNA , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Sequestradores de Radicais Livres/farmacologia , Radicais Livres/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Medicina Tradicional , Picratos/farmacologia , Extratos Vegetais/farmacologia , Estruturas Vegetais/químicaRESUMO
The object of the present study was to determine the c-fos gene expression pattern in the hypothalamus (HYP) and the preoptic area (POA) after estradiol and testosterone priming during the critical period of sexual differentiation of the rat brain. Three-day-old female rats were injected s.c. with a single dose of 17beta-estradiol (200 microg), testosterone enantate (200 microg) or vehicle (corn oil). HYP and POA were dissected 2 h, 24 h and 14 days after treatments and on the day of vaginal opening (VO). Other animals, previously treated as above, were acutely injected with 17beta-estradiol (5 microg) on the day of VO; HYP and POA were obtained 3 h later. Total RNA was extracted and processed for semiquantitative RT-PCR. We observed that c-fos gene expression was markedly increased in POA of the animals treated with estradiol or testosterone 2 h after treatments, while a non-significant increase in c-fos gene expression was observed in the HYP of these animals. We found a significant increase in c-fos expression in HYP and POA on the day of VO in both estradiol and testosterone defeminized rats. Interestingly, the acute estradiol administration on the day of VO did not induce c-fos gene expression in either HYP or POA of defeminized animals, instead a diminution in its expression was observed in animals treated with testosterone in POA. The overall results suggest that estradiol and testosterone imprinting during critical postnatal period of sexual differentiation of the brain permanently modifies the regulation of c-fos gene expression.
Assuntos
Hipotálamo/fisiologia , Área Pré-Óptica/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Diferenciação Sexual/fisiologia , Animais , Período Crítico Psicológico , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hormônios Esteroides Gonadais/farmacologia , Hipotálamo/crescimento & desenvolvimento , Área Pré-Óptica/crescimento & desenvolvimento , Ratos , Ratos Wistar , Diferenciação Sexual/efeitos dos fármacos , Testosterona/farmacologiaRESUMO
c-fos gene expression in the hypothalamus, the preoptic area, the hippocampus and the frontal cerebral cortex of the rat was determined every two hours from 09:00 h to 19:00 h on the day of proestrus by using reverse transcription coupled to polymerase chain reaction. Rats under a 14:10 h light-dark cycle, with lights on at 06:00 h were used. We found a marked increase in c-fos gene expression in the studied regions but the hippocampus at 13:00 h, followed by a significant diminution in the subsequent hours of proestrus day. The high expression of c-fos gene at 13:00 could be associated to the increase in estradiol seric levels observed both at 11:00 h and at 13:00 h. Our results correlate with the increase in the number of FOS immunoreactive cells in some forebrain areas in proestrus afternoon related to gonadotropin releasing hormone secretion.
Assuntos
Genes fos , Hipotálamo/metabolismo , Área Pré-Óptica/metabolismo , Proestro/metabolismo , Animais , Córtex Cerebral/metabolismo , Feminino , Expressão Gênica , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos , Transcrição GênicaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversosRESUMO
Cisplatin-based induction chemotherapy has been extensively tested in nasopharyngeal carcinoma for the improvement of local and systemic control and survival of this disease. In this study, we report the results of the treatment with induction chemotherapy in 40 patients with locally advanced carcinoma of the nasopharynx (LANPC) with four courses of cisplatin (P) 25 mg/m2 per day and 5-fluorouracil (F) 1000 mg/m2 per day both in a 4-days continuous infusion, with or without leucovorin (L) 250 mg/m2 per day in 2-hour infusion at the beginning of daily administration of PF, followed by sequential radiotherapy. All except one were in stage IV. The overall response after induction chemotherapy was 93%, with 55% CR and 38% PR. Definitive overall response after radiotherapy was 98%, with 80% CR and 18% PR. At a maximum follow up of 11 years, the overall survival rate is 55%. Induction chemotherapy with continuous infusion of PF with or without leucovorin followed by radiotherapy is a highly active regimen for the treatment of locally advanced nasopharyngeal carcinoma with response and survival rates comparable to other combinations of sequential or simultaneous chemotherapy and radiotherapy.