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OBJECTIVES: This study was aimed to develop dual-purpose natamycin (NAT)-loaded niosomes in ketorolac tromethamine (KT) gels topical ocular drug delivery system to improve the clinical efficacy of natamycin through enhancing its penetration through corneal tissue and reducing inflammation associated with Fungal keratitis (FK). SIGNIFICANCE: Nanosized carrier systems, as niosomes would provide great potential for improving NAT ocular bioavailability.NAT niosomal dispersion formulae were prepared and then incorporated in 0.5%KT gels using different mucoadhesive viscosifying polymers. METHODS: Niosomes were prepared using the reverse-phase evaporation technique. In vitro experimental, and in vivo clinical evaluations for these formulations were done for assessment of their safety and efficacy for treatment of Candida Keratitis in Rabbits. In vitro release study was carried out by the dialysis method. In vivo and histopathological studies were performed on albino rabbits. RESULTS: NAT niosomes exhibited high entrapment efficiency percentage (E.E%) up to96.43% and particle size diameter ranging from 181.75 ± 0.64 to 498.95 ± 0.64 nm, with negatively charged zeta potential (ZP). NAT niosomal dispersion exhibited prolonged in vitro drug release (40.96-77.49% over 24h). NAT-loaded niosomes/0.5%KT gel formulae revealed retardation in vitro release, compared to marketed-product (NATACYN®) and NAT-loaded niosomes up to57.32% (F8). In vivo experimental studies showed the superiority for F8 in treatment of candida keratitis and better results on corneal infiltration and hypopyon level. These results were consistent with histopathological examination in comparison with F5 and combined marketed products (NATACYN® and Ketoroline®). CONCLUSIONS: This study showed that F8 has the best results from all pharmaceutical in vitro evaluations and a better cure percent in experimental application and enhancing the prolonged delivery of NAT and penetrating the cornea tissues.
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Candida/efectos de los fármacos , Composición de Medicamentos/métodos , Queratitis/tratamiento farmacológico , Ketorolaco Trometamina/farmacología , Natamicina/farmacología , Administración Oftálmica , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Disponibilidad Biológica , Córnea/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Modelos Animales de Enfermedad , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Liberación de Fármacos , Geles , Humanos , Queratitis/microbiología , Ketorolaco Trometamina/uso terapéutico , Liposomas , Masculino , Pruebas de Sensibilidad Microbiana , Nanopartículas/química , Natamicina/uso terapéutico , Tamaño de la Partícula , Permeabilidad , Polímeros/química , ConejosRESUMEN
INTRODUCTION: The effectiveness and safety of long-acting insulin glargine U300 (Gla-300), in patients with type 2 diabetes mellitus (T2DM) requiring insulin, has not been reported in the Gulf region. METHODS: Insulin-naïve patients with T2DM, uncontrolled on OADs, and prescribed Gla-300 were followed up in a 12-month prospective observational study. Gla-300 was titrated to glycemic targets. The primary endpoint (achieving glycemic targets) was evaluated at month 6 of treatment. The need for treatment intensification, safety, and patient-reported outcomes (PRO) were also reported. RESULTS: The study included 412 patients (61.7% men; age 52.2 ± 11.1 years and T2DM duration 10.7 ± 6.8 years). Almost 50% were on more than 3 OADs, mostly biguanides, sulfonylureas, and dipeptidyl-peptidase-4 inhibitors. Baseline HbA1c level was 9.2% ± 1.1% and targets were set at 6.9% ± 0.4%. Baseline fasting plasma glucose was 11.5 ± 3.8 mmol/l. Fifty-seven patients (13.8%) achieved glycemic targets at month 6, hindered by baseline HbA1c ≥ 10%, frequent co-morbidities, older age, suburban/rural residence, and full-time employment. Levels of HbA1c dropped progressively by 0.96% ± 0.07% (month 3), 1.29% ± 0.08% (month 6), and 1.76% ± 0.06% (month 12). Gla-300 dose was 17.0 ± 9.0 IU/day at baseline, 24.6 ± 9.6 IU/day at month 3, 28.5 ± 9.9 IU/day at month 6, and 30.7 ± 10.7 IU/day at month 12. Three patients experienced non-severe hypoglycemia and a slight decrease in body weight and PROs improved. CONCLUSIONS: In the Gulf, Gla-300 in patients with T2DM uncontrolled on OADs improved glycemic control, with low rates of hypoglycemia and improved PROs. Gla-300 dose up-titration from baseline to month 6 did not, however, result in a vast proportion of patients achieving their pre-determined HbA1c targets. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03703869.
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Aim of the study: Non-alcoholic fatty liver disease (NAFLD) is regarded as the most relevant liver disease of the twenty-first century, affecting at least one third of the general population. NAFLD is associated with increased mortality due to cardiovascular disease (CVD) and cancer. The carotid intimal media thickness (CIMT), mean platelet volume (MPV) and endocan level could be markers for generalised atherosclerotic burden and endothelial dysfunction. The aims of the study were to evaluate the association between non-alcoholic fatty liver disease and early atherosclerosis by measuring CIMT, MPV and endocan level, as markers of endothelial dysfunction, in NAFLD patients. Material and methods: This cross-sectional study included 50 patients who were divided into two groups: group I included 25 subjects with NAFLD and group II included 25 healthy subjects. Complete blood count with MPV, liver profile, lipid profile, fasting blood glucose level, 2-hour postprandial kidney function test, and serum concentrations of endocan were measured for all patients. NAFLD fibrosis score (NFS) was calculated. Abdominal ultrasonography and carotid ultrasound scan for measurement of CIMT were performed. Results: Serum endocan levels, MPV and CIMT were significantly higher (p < 0.005) in NAFLD patients (0.6, 9.3 ±1.2 and 0.9 ±0.3 respectively) than healthy subjects (0.1, 8.1 ±0.6 and 0.6 ±0.1 respectively). The analysis of diagnostic performance of these factors revealed that they have good sensitivity and specificity in prediction of endothelial dysfunction with AUC (0.950, 0.844 and 0.849 respectively). Conclusions: Serum endocan levels, MPV and CIMT could be considered as good predictors of endothelial dysfunction and therefore early detection of subclinical atherosclerosis in NAFLD patients.
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BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common cancer arising from the nasopharynx with a poor prognosis. Targeting immune checkpoint is one of the new promising lines in cancer treatment. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1) are immune checkpoints that regulate T-cell immune function. AIM: This work aimed to assess the immunohistochemical expression of PD-L1 and CTLA-4 in NPC and their ability to predict survival and response therapy and to check their validity as immunotherapy targets. Twenty-six cases of NPC were studied by immunohistochemistry for PD-L1 and CTLA-4 and by nested polymerase chain reaction followed by DNA sequencing for the presence of EBNA-1 gene of Epstein-Barr virus (EBV). All investigated cases were diagnosed and treated in the Zagazig University Hospital in the period from August 2015 to July 2018. EBNA-1 gene was identified in 84.6% of the cases. Whereas the expression of PD-L1 was noted in 46.2% of all cases studied, 54.6% of EBV-associated NPCs were found to express PD-L1. There was a significant association between PD-L1 expression and the advanced stage of the tumor (P<0.001). CTLA-4 expression was observed in 88.4% of all NPC cases as cytoplasmic staining in both tumor cells and tumor-infiltrating lymphocytes. CTLA-4 expression in lymphocytes was associated with the presence of EBV. A significant association was detected between CTLA-4 and tumor-infiltrating lymphocyte expression on one side and the stage of the tumor on the other. High expression of CTLA-4 was significantly associated with disease progression and worse overall survival. CONCLUSION: PD-L1 and CTLA-4 are adverse prognostic markers in NPC. The authors propose that targeted therapy against PD-L1 and CTLA-4 will be a hopeful therapy for cases of NPC with resistance to concurrent chemoradiation treatment in Egypt, especially EBV-associated cases.
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Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Antígeno CTLA-4/metabolismo , Infecciones por Virus de Epstein-Barr/metabolismo , Herpesvirus Humano 4/fisiología , Inhibidores de Puntos de Control Inmunológico/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/mortalidad , Antígenos Nucleares del Virus de Epstein-Barr/genética , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/inmunología , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/mortalidad , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND/AIM: Evaluation of liver fibrosis in chronic hepatitis C patients (CHC) provides a high value, not only for the diagnosis of the disease, but also for the therapeutic decision. The aim of the current study is the construction of simple non-invasive and more accurate score for liver fibrosis staging in CHC patients and estimating its performance against three published non-invasive indexes. MATERIAL AND METHODS: CHC patients were divided into two groups: an estimated group (n = 75) and validated group (n = 50). Liver fibrosis was tested in biopsies by Metavair score system. Fas/CD95, hepatocyte growth factor (HGF) and endostatin were assayed by enzyme linked immunosorbent assay (ELISA). Statistical analysis was performed by stepwise linear discriminate analysis and area under-receiver operating curves (AUCs). RESULTS: The multivariate discriminate analysis (MDA) selects a function based on absolute values of five biochemical markers; FHEPA (Fas/CD95, HGF, Endostatin, Platelets&Albumin)-Test score = 1.2 × Fas/CD95 (ng/mL) + 0.006 × HGF (pg/mL) + 0.03 × Endostatin (ng/mL) - 0.007 × platelets count(109/L)-3.6 × Albumin (g/dL) - 8.6.FHEPA-Test producesAUCs 0.99, 0.877 and 0.847 to discriminate patients with significant fibrosis (F2-F4), advanced fibrosis (F3-F4) and cirrhosis (F4), respectively. CONCLUSION: FHEPA-Test is considered a novel non-invasive test which could be applied in assessment of liver fibrosis in HCV infected patients. Our novel score was more efficient than Immune Fibrosis Index, Fibrosis Index and FibroQ and thus it could be more applicable, feasible & economic for Egyptian HCV patients. Our Novel Scoring system could be globalized to other populations to confirm its advantageous use in early diagnosis of liver fibrosis.
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Biomarcadores/sangre , Endostatinas/sangre , Hepatitis C Crónica/sangre , Hepatitis C Crónica/fisiopatología , Factor de Crecimiento de Hepatocito/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/fisiopatología , Adulto , Biopsia/métodos , Egipto , Femenino , Humanos , Cirrosis Hepática/sangre , Masculino , Persona de Mediana Edad , Curva ROC , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Colorectal cancer (CRC) has high morbidity and mortality rates. Invasive techniques and other laboratory tests with variable sensitivity and specificity are currently used in diagnosis. Micro ribonucleic acids (miRNAs) have bio vital roles in cell proliferation and apoptosis. Dys-regulation of miRNAs is linked to tumour genesis. The objective of this study was to evaluate the specificity and sensitivity of serum non-invasive biomarkers (micro-RNAs), miR-1246, miR-23a, and miR-451in CRC patients. METHODS: Peripheral expression of three miRNAs (miR-1246, miR-23a and miR-451) was investigated in sera of 37 CRC Egyptian patients and 30 healthy controls, using quantitative real-time polymerase chain reaction trying to reach the optimal non-invasive combination of miRNAs. RESULTS: Serum miR-1246 was up-regulated in sera of CRC patients compared to normal controls (fold change = 3.55; P<0.001) and showed 100% sensitivity and 80% specificity in diagnosis of CRC. Serum miR-451 was significantly down-regulated in CRC patients (fold change = -4.86; p= 0.014), whereas, miR-23a was down-regulated but this was not statistically significant. CONCLUSION: Up-regulation of miR-1246 and down-regulation of miR-451 in the sera of primary CRC Egyptian patients were confirmed with high sensitivity and specificity. Large-scale studies on a wider spectrum of miRNAs in Egyptian CRC patients are needed.
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Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , MicroARNs/sangre , Adulto , Anciano , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Neoplasias del Colon/sangre , Neoplasias del Colon/patología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Egipto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
Purpose: Formulation of new drug delivery system as Natamycin (NT)-loaded nanoparticle niosomal formulae mixed in different polymer gel, with the addition of ketorolac tromethamine (KETR). Pharmaceutical and experimental assessments to evaluate their safety and efficacy in treating Aspergillus keratitis. Methods: NT nanoparticle niosomes prepared by reverse-phase evaporation technique were mixed in different polymers, with the addition of KETR. Two formulae are evaluated in this study: F1 [NT-loaded nanoparticle niosomes/0.5% KETR 4% carboxymethyl cellulose (Na.CMC) gel], F2 [NT-loaded nanoparticle niosomes/0.5% KETR 2% hydroxypropylmethyl cellulose (HPMC)-E4 gel], and mixed marketed products (MMP), namely Natamet® and Ketoroline® suspension eye drops. NT-loaded nanoparticle niosomes/0.5% KETR were evaluated through viscosity determination, mucoadhesive attractive force, and in vitro NT release studies. The in vivo antifungal evaluation was performed on 45 albino rabbits, Aspergillus species were inoculated in right corneas of all rabbits, and then rabbits were subdivided into 3 groups, 15 rabbits each: Group A: received F1, Group B: received F2, and Group C: received MMP. Daily examination of rabbits was performed for evaluation of corneal infiltration, and signs of iritis. Two weeks later, rabbits were euthanized; their corneas were dissected at the limbus and sent for histopathological evaluation. Results: F1 had a higher viscosity and more mucoadhesive power than F2, and showed better results on corneal infiltration, and level of hypopyon. These results were consistent with the histopathological examination. Conclusion: The formula of NT-loaded nanoparticle niosomes/0.5% KT 4% Na.CMC gel has the best results from all pharmaceutical in vitro evaluations and a better cure percent in experimental application.
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Aspergilosis/tratamiento farmacológico , Queratitis/tratamiento farmacológico , Ketorolaco/farmacología , Natamicina/farmacología , Administración Oftálmica , Animales , Antiinfecciosos Locales/administración & dosificación , Antiinfecciosos Locales/farmacología , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Aspergilosis/microbiología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Queratitis/microbiología , Ketorolaco/administración & dosificación , Liposomas , Nanopartículas , Natamicina/administración & dosificación , Polímeros , ConejosRESUMEN
INTRODUCTION: Colorectal cancer (CRC) incidence is increasing globally. It is ranked as the second most common cancer in women and the third most in men. Angiogenesis plays a significant role in the development and spread of colorectal cancer. Angiogenesis has been proposed as a prognostic marker in a variety of human neoplasms. In this regard, markers of angiogenic endothelial cells are emerging as targets for cancer therapy. AIM OF THE WORK: The aim of this study is to evaluate the prognostic impact of tumor angiogenesis assessed by microvessel density (MVD) counting using CD31 and CD105 along with VEGF immunostaining in colorectal cancer patients. METHODS: VEGF, CD31, and CD105 expressions were evaluated using immunohistochemical staining in 50 patients with colorectal cancer. The relationship between their expressions and clinicopathological factors and outcome of patients were analyzed. RESULTS: The VEGF expression (70% of the cases) correlated significantly with larger tumor size, higher grade, and advanced tumor stage (p = 0.006, p < 0.001, p < 0.001), respectively. The mean MVD was 24.2 ± VMD by CD105 (p = 0.10.65 019 for CD105, 19.2 ± 8.41 for CD31, respectively. MVD by CD31 (p = 0.023)) and was significant predictive factors for overall survival. Furthermore, the VEGF expression (p = < 0.001) was a significant predictive factor for DFS. There was a statistically significant association between the recurrence rates with both VEGF and CD105 (p < 0.001) but not significant with CD31. CONCLUSION: CRC patients with high VEGF, CD105, and CD31 expression showed poor prognosis. The immunohistochemical markers could be used for stratification of patients into low-risk and high-risk groups.