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1.
Medicine (Baltimore) ; 99(1): e18569, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895800

RESUMO

An adverse drug reactions avoidability tool called the Liverpool ADR avoidability assessment tool (LAAT) was recently developed (for research purposes), and subsequently validated with mixed interrater reliability (IRR). We investigated the comparative IRR of this tool in an inpatient cohort to ascertain its practical application in this setting.The patient population was comprised of 44 ADR drug pairs drawn from an observational prospective cohort of patents with ADR attending a Weill Cornell Medicine-affiliated tertiary medical Centre in Doha Qatar (Hamad General Hospital). Using the LAAT, and modified Hallas tools, 4 independent raters (2 Clinical Pharmacologists, and 2 General Physicians) assessed and scored the 44 ADR-drug pairs. Agreement proportions between the rating pairs were evaluated as well individual/overall kappa statistics and intraclass correlation coefficients. We evaluated the weight of each of the 7 questions on the LAAT tool to ascertain its determinative role.Across 44 ADR-drug pairs, the overall median Fleiss kappa using the LAAT, and modified Hallas tools were 0.67 (interquartile range (IQR) 0.55, 0.76), 0.36 (IQR, 0.23-0.71) respectively. The overall percentage pairwise agreement with the LAAT and modified Hallas tools were 78.5%, and 62.2% respectively. Exact pairwise agreement occurred in 37 out of 44 (range 0.71-1), and 27 of 44 (0.53-0.77) ADR-drug pairs using the LAAT and modified Hallas tools respectively. Using the LAAT tool, the overall intraclass correlation coefficient was 0.68 (CI 0.55, 0.79), and 0.37 (CI 0.22, 0.53) with the modified Hallas tool.We report a higher proportion of "possible" and "definite" avoidability outcomes of adverse drug reactions compared with the modified Hallas, or that reported by developers of the LAAT tool. Although initially developed for research purposes, our report has suggested for the first time a potential applicability of this tool in clinical environment as well.


Assuntos
Rotas de Resultados Adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Adulto , Algoritmos , Feminino , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Catar , Reprodutibilidade dos Testes
2.
Medicine (Baltimore) ; 98(50): e18322, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852121

RESUMO

BACKGROUND: Drug induced liver injury (DILI) is an increasing cause of acute liver injury especially with increasing need for pharmacotherapy of widening comorbidities amongst our ever-aging population. Uncertainty however remains regarding both acceptable and widely agreeable diagnostic algorithms as well a clear understanding of mechanistic insights that most accurately underpins it. In this review, we have explored the potential role of emerging novel markers of DILI and how they could possibly be integrated into clinical care of patients. METHODS: We explored PUBMED and all other relevant databases for scientific studies that explored potential utility of novel biomarkers of DILI, and subsequently carried out a narrative synthesis of this data. As this is a narrative review with no recourse to patient identifiable information, no ethics committee's approval was sought or required. RESULTS: Novel biomarkers such as microRNA-122 (miR-122) profiles, high mobility group box-1 (HMGB1), glutamate dehydrogenase (GLDH), and cytokeratin-18 (K-18), amongst others do have the potential for reducing diagnostic uncertainties associated with DILI. CONCLUSION: With the increasing validation of some of the novel liver biomarkers such as K-18, mir-122, HMGB-1, and GLDH, there is the potential for improvement in the diagnostic uncertainty commonly associated with cases of DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Glutamato Desidrogenase/análise , Proteína HMGB1/análise , Queratina-18/análise , MicroRNAs/análise , Medição de Risco/métodos , Biomarcadores/análise , Humanos
3.
Semin Cancer Biol ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31562954

RESUMO

Neuroblastoma (NB) is a widely diagnosed cancer in children, characterized by amplification of the gene encoding the MYCN transcription factor, which is highly predictive of poor clinical outcome and metastatic disease. microRNAs (a class of small non-coding RNAs) are regulated by MYCN transcription factor in neuroblastoma cells. The current research is focussed on identifying differential role of miRNAs and their interactions with signalling proteins, which are intricately linked with cellular processes like apoptosis, proliferation or metastasis. However, the therapeutic success of miRNAs is limited by pharmaco-technical issues which are well counteracted by nanotechnological advancements. The nanoformulated miRNAs unload anti-cancer drugs in a controlled and prespecified manner at target sites, to influence the activity of target protein in amelioration of NB. Recent advances and developments in the field of miRNAs-based systems for clinical management of NBs and the role of nanotechnology to overcome challenges with drug delivery of miRNAs have been reviewed in this paper.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31025282

RESUMO

Empowering role of nanoinformatics in design and elucidation of nanoparticles for effective cancer treatment has made this field a fascinating area for researchers, inspiring them to enhance up the quality and efficacy of existing anticancer medicines. Theoretical and computational modeling is being seen as a forefront solution for problems related to surface chemistry, optimized geometry, or other properties in nanoparticle designing and drug delivery. The current review aims to acquaint with the insight story of the incubation of in silico tools and techniques in nanotechnology to develop better anticancer nanomedicines. The review also recapitulates the assets and liabilities of this field and present an outline of existing inventiveness and endeavors of nanoinformatics. We propose how nanoinformatics could hasten up the advancements in anticancer nanomedicines through use of computational tools, nanoparticles repositories & various modeling and simulation methods.

5.
Semin Cancer Biol ; 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31891780

RESUMO

Breast cancer is one of the most prevalent and reoccurring cancers and the second most common reason of death in women. Despite advancements in therapeutic strategies for breast cancer, early tumor recurrence and metastasis in patients indicate resistance to chemotherapeutic medicines, such as paclitaxel due to the abnormal expression of ER and EGF2 in breast cancer cells. Therefore, the development of alternatives to paclitaxel is urgently needed to overcome challenges involving drug resistance. An increasing number of studies has revealed miRNAs as novel natural alternative substances that play a crucial role in regulating several physiological processes and have a close, adverse association with several diseases, including breast cancer. Due to the therapeutic potential of miRNA and paclitaxel in cancer research, the current review focuses on the differential roles of various miRNAs in breast cancer development and treatment. miRNA delivery to a specific target site, the development of paclitaxel and miRNA formulations, and nanotechnological strategies for the delivery of nanopaclitaxel in the management of breast cancer are discussed. These strategies involve improving the cellular uptake and bioavailability and reducing the toxicity of free paclitaxel to achieve accumulation tumor site. Furthermore, a molecular docking study was performed to ascertain the enhanced anticancer activity of the nanoformulation of ANG1005 and Abraxane. An in silico analysis revealed that ANG1005 and Abraxane nanoformulations have superior and significantly enhanced interactions with the proteins α-tubulin and Bcl-2. Therefore, ANG1005 and Abraxane may be more suitable in the therapeutic management of breast cancer than the existing free paclitaxel. miRNAs can revert abnormal gene expression to normalcy; since miRNAs serve as tumor suppressors. Therefore, restoration of particular miRNAs levels as a replacement therapy may be an effective endocrine potential strategy for treating ER positive/ negative breast cancers.

6.
Saudi J Biol Sci ; 25(8): 1546-1551, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30581316

RESUMO

Japanese encephalitis (JE), a viral disease has seen a drastic and fatal enlargement in the northern states of India in the current decade. The better and exact cure for the disease is still in waiting. For the cause an in silico strategy in the development of the peptide vaccine has been taken here for the study. A computational approach to find out the Major Histocompatibility Complex (MHC) binding peptide has been implemented. The prediction analysis identified MHC class I (using propred I) and MHC class II (using propred) binding peptides at an expectable percent predicted IC (50) threshold values. These predicted Human leukocyte antigen [HLA] allele binding peptides were further analyzed for potential conserved region using an Immune Epitope Database and Analysis Resource (IEDB). This analysis shows that HLA-DRB1*0101, HLA-DRB3*0101, HLA-DRB1*0401, HLA-DRB1*0102 and HLA-DRB1*07:01% of class II (in genotype 2) and HLA-A*0101, HLA-A*02, HLA-A*0301, HLA-A*2402, HLA-B*0702 and HLA-B*4402% of HLA I (in genotype 3) bound peptides are conserved. The predicted peptides MHC class I are ILDSNGDIIGLY, FVMDEAHFTDPA, KTRKILPQIIK, RLMSPNRVPNYNLF, APTRVVAAEMAEAL, YENVFHTLW and MHC class II molecule are TTGVYRIMARGILGT, NYNLFVMDEAHFTDP, AAAIFMTATPPGTTD, GDTTTGVYRIMARGI and FGEVGAVSL found to be top ranking with potential super antigenic property by binding to all HLA. Out of these the predicted peptide FVMDEAHFTDPA for allele HLA-A*02:01 in MHC class I and NYNLFVMDEAHFTDP for allele HLA-DRB3*01:01 in MHC class II was observed to be most potent and can be further proposed as a significant vaccine in the process. The reported results revealed that the immune-informatics techniques implemented in the development of small size peptide is useful in the development of vaccines against the Japanese encephalitis virus (JEV).

7.
In Silico Pharmacol ; 5: 12, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29098138

RESUMO

Pseudomonas aeruginosa an opportunistic pathogen regulates its virulence through Quorum sensing (QS) mechanism comprising of Las and Rhl system. Targeting of QS mechanism could be an ideal strategy to combat infection caused by P. aeruginosa. Silver nanoparticles (AgNPs) have been broadly applied as antimicrobial agents against a number of pathogenic bacterial and fungal strains, but have not been reported as an anti-QS agent. Therefore, the aim of present work was to show the computational analysis for the interaction of AgNPs with the QS system using an In silico approach. In silico studies showed that AgNPs got 'locked' deeply into the active site of respective proteins with their surrounding residues. The molecular docking analysis clearly demonstrated that AgNPs got bound to the catalytic cleft of LasI synthase (Asp73-Ag = 3.1 Å), RhlI synthase (His52-Ag = 2.8 Å), transcriptional receptor protein LasR (Leu159-Ag = 2.3 Å) and RhlR (Trp10-Ag = 3.1 Å and Glu34-Ag = 3.2 Å). The inhibition of LasI/RhlI synthase by AgNPs blocked the biosynthesis of AHLs, thus no AHL produced, no QS occurred. Further, interference with transcriptional regulatory proteins led to the inactivation of LasR/RhlR system that finally blocked the expression of QS-controlled virulence genes. Our findings clearly demonstrate the anti-QS property of AgNPs in P. aeruginosa which could be an alternative approach to the use of traditional antibiotics for the treatment of P. aeruginosa infection.

8.
PLoS One ; 9(9): e107068, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25215666

RESUMO

Polycyclic aromatic hydrocarbons (PAH), like Benzo[alpha]Pyrene (BaP) are known to cause a number of toxic manifestations including lung cancer. As Titanium dioxide Nanoparticles (TiO2 NPs) have recently been shown to adsorb a number of PAHs from soil and water, we investigated whether TiO2 NPs could provide protection against the BaP induced toxicity in biological system. A549 cells when co-exposed with BaP (25 µM, 50 µM and 75 µM) along with 0.1 µg/ml,0.5 µg/ml and 1 µg/ml of TiO2 NPs, showed significant reduction in the toxic effects of BaP, as measured by Micronucleus Assay, MTT Assay and ROS Assay. In order to explore the mechanism of protection by TiO2 NP against BaP, we performed in silico studies. BaP and other PAHs are known to enter the cell via aromatic hydrocarbon receptor (AHR). TiO2 NP showed a much higher docking score with AHR (12074) as compared to the docking score of BaP with AHR (4600). This indicates a preferential binding of TiO2 NP with the AHR, in case if both the TiO2 NP and BaP are present. Further, we have done the docking of BaP with the TiO2 NP bound AHR-complex (score 4710), and observed that BaP showed strong adsorption on TiO2 NP itself, and not at its original binding site (at AHR). TiO2 NPs thereby prevent the entry of BaP in to the cell via AHR and hence protect cells against the deleterious effects induced by BaP.


Assuntos
Benzo(a)pireno/toxicidade , Carcinógenos Ambientais/toxicidade , Nanopartículas/química , Titânio/farmacologia , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Endocitose/efeitos dos fármacos , Humanos , Testes para Micronúcleos , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/química , Receptores de Hidrocarboneto Arílico/metabolismo , Reprodutibilidade dos Testes , Software
9.
World J Cardiol ; 6(3): 107-11, 2014 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-24669292

RESUMO

AIM: To assess current practice of United Kingdom cardiologists with respect to patients with reported shellfish/iodine allergy, and in particular the use of iodinated contrast for elective coronary angiography. Moreover we have reviewed the current evidence-base and guidelines available in this area. METHODS: A questionnaire survey was send to 500 senior United Kingdom cardiologists (almost 50% cardiologists registered with British Cardiovascular Society) using email and first 100 responses used to analyze practise. We involved cardiologists performing coronary angiograms routinely both at secondary and tertiary centres. Three specific questions relating to allergy were asked: (1) History of shellfish/iodine allergy in pre-angiography assessment; (2) Treatments offered for shellfish/iodine allergy individuals; and (3) Any specific treatment protocol for shellfish/iodine allergy cases. We aimed to establish routine practice in United Kingdom for patients undergoing elective coronary angiography. We also performed comprehensive PubMed search for the available evidence of relationship between shellfish/iodine allergy and contrast media. RESULTS: A total of 100 responses were received, representing 20% of all United Kingdom cardiologists. Ninety-three replies were received from consultant cardiologists, 4 from non-consultant grades and 3 from cardiology specialist nurses. Amongst the respondents, 66% routinely asked about a previous history of shellfish/iodine allergy. Fifty-six percent would pre-treat these patients with steroids and anti-histamines. The other 44% do nothing, or do nonspecific testing based on their personal experience as following: (1) Skin test with 1 mL of subcutaneous contrast before intravenous contrast; (2) Test dose 2 mL contrast before coronary injection; (3) Close observation for shellfish allergy patients; and (4) Minimal evidence that the steroid and anti-histamine regime is effective but it makes us feel better. CONCLUSION: There is no evidence that allergy to shellfish alters the risk of reaction to intravenous contrast more than any other allergy and asking about such allergies in pre-angiogram assessment will not provide any additional information except propagating the myth.

10.
Med Sci Monit ; 13(8): CS101-5, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17660729

RESUMO

BACKGROUND: Takayasu disease is a giant cell arteritis, primarily affecting the aorta and its main branches, particularly over the first 1.5 cm. It is more common in South-East Asian countries and in young females, whose clinical manifestations range from asymptomatic to catastrophic neurological impairment. CASE REPORT: We report on a Pakistani family in which five of seven siblings, aged 12 to 19 years, are affected with atypical Takayasu arteritis. The proband is a 14-year-old male who presented with sudden, painless loss of vision. He was found to have absent pulses, retinal changes and magnetic resonance angiography (MRA) findings diagnostic of Takayasu arteritis. In addition, though, he had decreased intraocular pressure, murmur of mitral valve prolapse, as well as atypical involvement of the aorta as visualized in MRA and decreased renal blood flow; these last three findings are not usual features of the disease. The unique involvement in the aorta indicates that this patient corresponds to yet another sub-type in the angiographic classification of TA. Four siblings of the proband are asymptomatic but fulfill the diagnostic criteria of the American College of Rheumatology. This is the first reported multiplex family with Takayasu arteritis, in which more than two members meet the diagnostic criteria. CONCLUSIONS: Previous reports indicate possible HLA associations of Takayasu disease in Japanese patients. Our present study indicates both that there may be clinical and etiological heterogeneity in Takayasu disease, and the possibility that an autosomal recessive form of the disease exists.


Assuntos
Arterite de Takayasu/diagnóstico , Arterite de Takayasu/genética , Adolescente , Adulto , Cegueira/genética , Criança , Saúde da Família , Feminino , Genes Recessivos , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Masculino , Doenças do Sistema Nervoso/metabolismo , Paquistão , Linhagem , Irmãos , Arterite de Takayasu/patologia
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