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排序方式: 共有273条查询结果,搜索用时 234 毫秒
11.
Harun M. Patel Malleshappa N. Noolvi Poonam Sharma Varun Jaiswal Sumit Bansal Sandeep Lohan Suthar Sharad Kumar Vikrant Abbot Saurabh Dhiman Varun Bhardwaj 《Medicinal chemistry research》2014,23(12):4991-5007
Drug design is a process which is driven by technological breakthroughs implying advanced experimental and computational methods. Nowadays, the techniques or the drug design methods are of paramount importance for prediction of biological profile, identification of hits, generation of leads, and moreover to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. From decades to recent research, QSAR methods have been applied in the development of relationship between properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. Classical QSAR studies include ligands with their binding sites, inhibition constants, rate constants, and other biological end points, in addition molecular to properties such as lipophilicity, polarizability, electronic, and steric properties or with certain structural features. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free–Wilson approaches, which exploit the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, and ANN. This paper provides an overview of 1-6 dimension-based developed QSAR methods and their approaches. In particular, we present various dimensional QSAR approaches, such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis, Topomer CoMFA, self-organizing molecular field analysis, comparative molecule/pseudo receptor interaction analysis, comparative molecular active site analysis, and FLUFF-BALL, 4D-QSAR, and G-QSAR approaches. 相似文献
12.
An eleven-year-old clinically dysmorphic and devel-opmentally retarded male child presenting with com-plaints of 5 episodes of recurrent cholestatic jaundice since 3 years of age was evaluated. Imaging revealed features consistent with congenital extrahepatic porto-caval shunt(Abernethy type 1b), multiple regenerative liver nodules and intrahepatic biliary radical dilatation. The presence of ductal paucity and trisomy 8 were con-firmed on liver biopsy and karyotyping. The explanation for unusual and previously unreported features in the present case has been proposed. 相似文献
13.
Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy. 相似文献
14.
Archana Rastogi Narendra Krishnani Surender Kumar Yachha Vikrant Khanna Ujjal Poddar Richa Lal 《Journal of gastroenterology and hepatology》2009,24(1):97-102
Background and Aim: A major challenge in neonatal cholestasis (NC) is to differentiate biliary atresia (BA) from other non-atretic causes. In developing countries there are considerable problems of late referral of NC cases and performing surgery without prelaparotomy liver biopsy that contributes to a high proportion of negative laparotomy and increased morbidity. We evaluated the hepatic histopathology for presence of features that correlate best with the diagnosis of BA and assessed the accuracy of percutaneous liver biopsy.
Methods: Fifty-five cases of NC that fulfilled the selection criteria and had liver biopsy available were analyzed. Among the 49 adequate liver biopsies, 28 cases were diagnosed as BA, 15 neonatal hepatitis (NH) and 6 were due to other causes. Validity of percutaneous liver biopsy diagnoses was compared with confirmed cases by laparotomy findings and 1-year follow up. Twelve histological parameters of confirmed cases of BA and NH were evaluated by logistic regression analyses.
Results: Ductular proliferation ( P = 0.0002), bile duct and ductular bile plugs ( P = 0.009), and portal fibrosis ( P = 0.002) were the best indicators of BA and among them ductular proliferation was the most important in distinguishing BA from NH. Ductal plate malformation was observed in 17.9% cases of BA. Sensitivity and specificity of percutaneous liver biopsy for diagnosing BA was 88.2% each.
Conclusion: Percutaneous liver biopsy is highly accurate (88.2%) in diagnosing BA. In developing countries. This investigation should be done to decrease the frequency of negative laparotomy and to achieve cost–benefit with reduced morbidity. 相似文献
Methods: Fifty-five cases of NC that fulfilled the selection criteria and had liver biopsy available were analyzed. Among the 49 adequate liver biopsies, 28 cases were diagnosed as BA, 15 neonatal hepatitis (NH) and 6 were due to other causes. Validity of percutaneous liver biopsy diagnoses was compared with confirmed cases by laparotomy findings and 1-year follow up. Twelve histological parameters of confirmed cases of BA and NH were evaluated by logistic regression analyses.
Results: Ductular proliferation ( P = 0.0002), bile duct and ductular bile plugs ( P = 0.009), and portal fibrosis ( P = 0.002) were the best indicators of BA and among them ductular proliferation was the most important in distinguishing BA from NH. Ductal plate malformation was observed in 17.9% cases of BA. Sensitivity and specificity of percutaneous liver biopsy for diagnosing BA was 88.2% each.
Conclusion: Percutaneous liver biopsy is highly accurate (88.2%) in diagnosing BA. In developing countries. This investigation should be done to decrease the frequency of negative laparotomy and to achieve cost–benefit with reduced morbidity. 相似文献
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The advent of safe and effective hypolipidemic therapy has revolutionized the ability of the clinician to optimize abnormalities
in the lipid profile. The advent of statin therapy has provided a potent option to decrease low-density lipoprotein and frequently
allows achievement of National Cholesterol Education Program target lipid levels with monotherapy. However, lipid goals are
frequently not achieved due to inadequate response to therapy or side effects. The role of combination therapy in the optimization
of the lipid profile provides a means by which the implementation of pharmacologic agents with synergistic mechanisms of action
allows further improvement in circulating levels of low-density lipoprotein cholesterol. Statins have been combined with bile
acid resins, fibric acid derivatives, and nicotinic acid. However, bile acid resins, although not systemically absorbed, have
significant problems with patient compliance and drug interactions. The implementation of therapy with fibric acid derivatives
or nicotinic acid increases the risk of significant side effects such as rhabdomyolysis or liver toxicity. Ezetimibe is a
prototype of a new class of agents that specifically block the absorption of cholesterol from the gastrointestinal tract.
Ezetimibe has minimal systemic absorption and a metabolic pathway involving enterohepatic circulation that allows for once
a day administration due to a prolonged half-life. Ezetimibe lacks the drug interactions that are common with the bile acid
resins and it may be utilized as either monotherapy or in combination with other pharmacologic agents. Ezetimibe has a relatively
flat dose-response curve and titration is not required. This review centers on the role of pharmacologic agents that act predominantly
by the reduction of cholesterol absorption, including colesevelam and ezetimibe. 相似文献
19.
Molecular targets in cerebral ischemia for developing novel therapeutics 总被引:20,自引:0,他引:20
Cerebral ischemia (stroke) triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. These intricate processes lead to activation of signalling mechanisms involving calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The distribution of these transducers bring them in contact with appropriate molecular targets leading to altered gene expression, e.g. ERK and JNK mediated early gene induction, responsible for activation of cell survival/damaging mechanisms. Moreover, inflammatory reactions initiated at the neurovascular interface and alterations in the dynamic communication between the endothelial cells, astrocytes and neurons are thought to substantially contribute to the pathogenesis of the disease. The damaging mechanisms may proceed through rapid nonspecific cell lysis (necrosis) or by active form of cell demise (apoptosis or necroptosis), depending upon the severity and duration of the ischemic insult. A systematic understanding of these molecular mechanisms with prospect of modulating the chain of events leading to cellular survival/damage may help to generate the potential strategies for neuroprotection. This review briefly covers the current status on the molecular mechanisms of stroke pathophysiology with an endeavour to identify potential molecular targets such as targeting postsynaptic density-95 (PSD-95)/N-methyl-d-aspartate (NMDA) receptor interaction, certain key proteins involved in oxidative stress, CaMKs and MAPKs (ERK, p38 and JNK) signalling, inflammation (cytokines, adhesion molecules, etc.) and cell death pathways (caspases, Bcl-2 family proteins, poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor (AIF), inhibitors of apoptosis proteins (IAPs), heat shock protein 70 (HSP70), receptor interacting protein (RIP), etc., besides targeting directly the genes itself. However, selecting promising targets from various signalling cascades, for drug discovery and development is very challenging, nevertheless such novel approaches may lead to the emergence of new avenues for therapeutic intervention in cerebral ischemia. 相似文献
20.
Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development. 相似文献