Chlamydia Trachomatis (C.T.) is one of the most common pathogens of human sexually transmitted diseases. Treatment of C.T. infection primarily depends on Tetracyclines, Macrolides and Quinolones, but with the wide use...Chlamydia Trachomatis (C.T.) is one of the most common pathogens of human sexually transmitted diseases. Treatment of C.T. infection primarily depends on Tetracyclines, Macrolides and Quinolones, but with the wide use of antibiotics an increasing number of drug-resistant Chlamydia trachomatis cases have been reported. This review summarizes the resistant conditions and the possible resistance mechanisms of C.T..展开更多
In the past,there has been considerable focus on a host of drugs and chemicals that may produce colonic toxicity.Now,a variety of new biological monoclonal antibody agents,usually administered by infusion,have appeare...In the past,there has been considerable focus on a host of drugs and chemicals that may produce colonic toxicity.Now,a variety of new biological monoclonal antibody agents,usually administered by infusion,have appeared in the clinical realm over the last decade or so to treat different chronic inflammatory or malignant disorders.For some of these agents,adverse effects have been documented,including apparently new forms of immune-mediated inflammatory bowel disease.In some,only limited symptoms have been recorded,but in others,severe colitis with serious complications,such as bowel perforation has been recorded.In others,adverse effects may have a direct vascular or ischemic basis,while other intestinal effects may be related to a superimposed infection.Some new onset cases of ulcerative colitis or Crohn's disease may also be attributed to the same agents used to treat these diseases,or be responsible for disease exacerbation.Dramatic and well documented side effects have been observed with ipilimumab,a humanized monoclonal antibody developed to reduce and overcome cytotoxic T-lymphocyte antigen 4,a key negative feedback regulator of the T-cell anti-tumor response.This agent has frequently been used in the treatment of different malignancies,notably,malignant melanoma.Side effects with this agent occur in up to 40% and these are believed to be largely immune-mediated.One of these is a form of enterocolitis that may be severe,and occa-sionally,fatal.Other agents include rituximab(an antiCD20 monoclonal antibody),bevacizumab(a monoclonal antibody against the vascular endothelial growth factor) and anti-tumor necrosis factor agents,including infliximab,adalimumab and etanercept.展开更多
Receptor tyrosine kinases(RTKs)such as the epidermal growth factor receptor(EGFR)regulate cellular homeostatic processes.EGFR activates downstream signaling cascades that promote tumor cell survival,proliferation and ...Receptor tyrosine kinases(RTKs)such as the epidermal growth factor receptor(EGFR)regulate cellular homeostatic processes.EGFR activates downstream signaling cascades that promote tumor cell survival,proliferation and migration.Dysregulation of EGFR signaling as a consequence of overexpression,amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes.Consequently,concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR.However,limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies.A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses.Here,we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs(miRs)as downstream effector molecules utilized by EGFR to promote tumor initiation,progression and that play a role in resistance to EGFR inhibitors.We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.展开更多
An extension of the authors＇ previous discovery of in vitro antitumor activity of substituted thino [2,3-d] prymidine derivatives is reported. The synthesis of some new spirothino [2,3-d] prymidine （4a-f）, imidazol...An extension of the authors＇ previous discovery of in vitro antitumor activity of substituted thino [2,3-d] prymidine derivatives is reported. The synthesis of some new spirothino [2,3-d] prymidine （4a-f）, imidazolidin, substituted prymidinyl and substituted thiazolidine thino [2,3-d] prymidine derivatives have been described. Thirteen of the obtained compounds were selected by the NCI and evaluated for their in vitro anticancer activity. Seven of the investigated compounds, 4a, 8a, 9a, （12a, b）, 14a and 15a, displayed high anticancer activity in the primary assay. These compounds have been selected for a full anticancer screening against a 60-cell panel assay where they showed non-selective broad spectrum and promising activity against all cancer cell lines. Compounds 12a and 12b proved to be the active members in this study compared to 5-fluorouracil and cyclophosphamide as reference drugs, respectively. Compounds 12a and 12b were identified as promising lead compounds, evaluated for their in-vitro antitumor activity.展开更多
Target-mediated drug disposition (TMDD)model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK)ofmonoclonal antibodies.However,there are too many parameters in full TMDD model to be esti...Target-mediated drug disposition (TMDD)model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK)ofmonoclonal antibodies.However,there are too many parameters in full TMDD model to be estimated based on limited clinical data,leading to instability of the final model.In the present study,we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS)model with the assumption that the total target concentration was a constant parameter during treatment with monoelonal antibody in clinical data modeling.Based on the parameters of a published TMDD model of denosumab,simulations were performed at population and individual levels.Then,a simplified TMDD model,QSS model, was used to examine the effects of hypotheses,in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation.Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses,the total receptor concentration had little influence on changes in drug concentration,and the model with constant total receptor concentration had the same predictive power.The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.展开更多
文摘Chlamydia Trachomatis (C.T.) is one of the most common pathogens of human sexually transmitted diseases. Treatment of C.T. infection primarily depends on Tetracyclines, Macrolides and Quinolones, but with the wide use of antibiotics an increasing number of drug-resistant Chlamydia trachomatis cases have been reported. This review summarizes the resistant conditions and the possible resistance mechanisms of C.T..
文摘In the past,there has been considerable focus on a host of drugs and chemicals that may produce colonic toxicity.Now,a variety of new biological monoclonal antibody agents,usually administered by infusion,have appeared in the clinical realm over the last decade or so to treat different chronic inflammatory or malignant disorders.For some of these agents,adverse effects have been documented,including apparently new forms of immune-mediated inflammatory bowel disease.In some,only limited symptoms have been recorded,but in others,severe colitis with serious complications,such as bowel perforation has been recorded.In others,adverse effects may have a direct vascular or ischemic basis,while other intestinal effects may be related to a superimposed infection.Some new onset cases of ulcerative colitis or Crohn's disease may also be attributed to the same agents used to treat these diseases,or be responsible for disease exacerbation.Dramatic and well documented side effects have been observed with ipilimumab,a humanized monoclonal antibody developed to reduce and overcome cytotoxic T-lymphocyte antigen 4,a key negative feedback regulator of the T-cell anti-tumor response.This agent has frequently been used in the treatment of different malignancies,notably,malignant melanoma.Side effects with this agent occur in up to 40% and these are believed to be largely immune-mediated.One of these is a form of enterocolitis that may be severe,and occa-sionally,fatal.Other agents include rituximab(an antiCD20 monoclonal antibody),bevacizumab(a monoclonal antibody against the vascular endothelial growth factor) and anti-tumor necrosis factor agents,including infliximab,adalimumab and etanercept.
基金supported by An American Brain Tumor Association Basic Research grant to G.G.G. in memory of Keith Powers, P01-CA95616, R01-NS080939James S. McDonnell Foundation
文摘Receptor tyrosine kinases(RTKs)such as the epidermal growth factor receptor(EGFR)regulate cellular homeostatic processes.EGFR activates downstream signaling cascades that promote tumor cell survival,proliferation and migration.Dysregulation of EGFR signaling as a consequence of overexpression,amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes.Consequently,concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR.However,limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies.A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses.Here,we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs(miRs)as downstream effector molecules utilized by EGFR to promote tumor initiation,progression and that play a role in resistance to EGFR inhibitors.We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.
文摘An extension of the authors＇ previous discovery of in vitro antitumor activity of substituted thino [2,3-d] prymidine derivatives is reported. The synthesis of some new spirothino [2,3-d] prymidine （4a-f）, imidazolidin, substituted prymidinyl and substituted thiazolidine thino [2,3-d] prymidine derivatives have been described. Thirteen of the obtained compounds were selected by the NCI and evaluated for their in vitro anticancer activity. Seven of the investigated compounds, 4a, 8a, 9a, （12a, b）, 14a and 15a, displayed high anticancer activity in the primary assay. These compounds have been selected for a full anticancer screening against a 60-cell panel assay where they showed non-selective broad spectrum and promising activity against all cancer cell lines. Compounds 12a and 12b proved to be the active members in this study compared to 5-fluorouracil and cyclophosphamide as reference drugs, respectively. Compounds 12a and 12b were identified as promising lead compounds, evaluated for their in-vitro antitumor activity.
文摘Target-mediated drug disposition (TMDD)model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK)ofmonoclonal antibodies.However,there are too many parameters in full TMDD model to be estimated based on limited clinical data,leading to instability of the final model.In the present study,we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS)model with the assumption that the total target concentration was a constant parameter during treatment with monoelonal antibody in clinical data modeling.Based on the parameters of a published TMDD model of denosumab,simulations were performed at population and individual levels.Then,a simplified TMDD model,QSS model, was used to examine the effects of hypotheses,in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation.Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses,the total receptor concentration had little influence on changes in drug concentration,and the model with constant total receptor concentration had the same predictive power.The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.
