Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （...Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （NSAIDs）, or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic （intraperitoneal） administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.展开更多
OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel m...OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel multifunctional agonist for opioid and neuropeptide FF(NPFF) receptors named DN-9.The present study was conducted to evaluate the pharmacological activities of DN-9 after peripheral administration.METHODS Antinociceptive activities of subcutaneous DN-9 were investigated in mouse models of acute inflammatory and neuropathic pain.Furthermore,the side-effects of DN-9 were evaluated after peripheral injection in rotarod,antinociceptive tolerance,abuse and gastrointestinal transit tests.RESULTS Subcutaneous DN-9 dose-dependently produced antinociception via peripheral mu-and kappa-opioid receptors,independent of delta-opioid and NPFF receptors,in the tail-flick assay.Similarly,a dose-dependent antinociceptive effect of DN-9 was mediated via peripheral opioid receptors in other inflammatory and neuropathic pain models.Repeated treatment with DN-9 produced antinociceptive effects without a loss of potency in various models of acute,inflammatory and neuropathic pain.DN-9 maintained potent analgesia in morphine-tolerant mice.The gastrointestinal motility inhibition and abuse properties of DN-9 were significantly reduced after subcutaneous injection compared to morphine.DN-9 did not significantly influence the motor coordination of mice.CONCLUSION Subcutaneous administration of DN-9 produces potent analgesic activities with minimal side effects.These data strengthen the therapeutic potential of peripherally acting opioids with multifunctional agonistic properties that are active in a broad range of experimental pain models after peripheral delivery.展开更多
Objective To analyze the change in drug resistance of staphylococcus aureus(SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics...Objective To analyze the change in drug resistance of staphylococcus aureus(SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics for clinical applications. Methods The SAU strains isolated from clinical samples in the hospital were collected and subjected to the Kirby-Bauer disk diffusion test. The results were assessed based on the 2002 American National Committee for Clinical Laboratory Standards(NCCLS) guidelines. Results SAU strains were mainly isolated from sputum, urine, blood and wound excreta and distributed in penology, neurology wards, orthopedics and surgery ICU wards. Except for glycopeptide drugs, methicillinresistant staphylococcus aureus(MRSA) had a higher drug resistance rate than those of the other drugs and had significantly more resistance than methicillin-sensitive staphylococcus aureus(MSSA)(P<0.05). In the dynamic observation of drug resistance, we discovered a gradual increase in drug resistance to fourteen test drugs during the last five years. Conclusion Drug resistance rate of SAU stayed at a higher level over the last five years; moreover, the detection ratio of MRSA keeps rising year by year. It is crucial for physicians to use antibiotics rationally and monitor the change in drug resistance in a dynamic way.展开更多
目的:分析医院2012-2021年住院病区甲氧西林耐药的金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus,MRSA)的检出率与抗菌药物使用强度(antibiotics use density,AUD)的相关性,为临床细菌耐药的防控和抗菌药物的合理使用提...目的:分析医院2012-2021年住院病区甲氧西林耐药的金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus,MRSA)的检出率与抗菌药物使用强度(antibiotics use density,AUD)的相关性,为临床细菌耐药的防控和抗菌药物的合理使用提供参考。方法:选取2012年1月-2021年12月玉林市第一人民医院病区送检标本的病原学结果和抗菌药物的使用数据作为研究资料,统计革兰阳性菌及其中金黄色葡萄球菌(Staphylococcus aureus,SA)的检出数据和SA对各种抗菌药物的耐药率,计算历年各抗菌药物的AUD,分析MRSA的检出率与AUD的相关性。结果:2012-2021年,医院住院病区革兰阳性菌中SA的检出率从26.70%升至50.70%,变化显著(P<0.01);而SA中MRSA的检出率在38.20%至57.04%之间浮动,平均检出率为48.27%;药敏结果显示,SA对环丙沙星、复方磺胺甲噁唑、红霉素、克林霉素、四环素、庆大霉素的耐药率呈逐年下降之势,并且变化显著(P<0.01),此外SA对万古霉素、利奈唑胺的耐药率始终为0.00%;2012-2021年,青霉素、头孢唑林、红霉素、克林霉素、左氧氟沙星和总喹诺酮类药物的AUD均呈下降趋势(P<0.05),而氨苄西林-舒巴坦钠、哌拉西林-他唑巴坦钠、万古霉素、利奈唑胺、替加环素和莫西沙星的AUD呈升高趋势(P<0.05);相关性分析显示,MRSA的检出率与青霉素、头孢呋辛、红霉素、阿奇霉素、左氧氟沙星、总喹诺酮类的AUD呈正相关(P<0.05),而与氨苄西林-舒巴坦钠、环丙沙星、万古霉素、利奈唑胺、替加环素的AUD呈负相关(P<0.05);线性回归分析结果显示,MRSA的检出率与阿奇霉素、左氧氟沙星、环丙沙星、总喹诺酮类药物的AUD相关性的确定系数R2均大于0.7,具有临床意义。结论:医院MRSA的检出率常年维持在较高水平,而其又与阿奇霉素、左氧氟沙星、环丙沙星、总喹诺酮类药物的使用关系密切,故临床开展抗感染治疗时应适当调整此类高相关性药物的使用习惯,以降低MRSA的产生。展开更多
Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant...Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance.The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli,which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal,ultimately leading to treatment resistance and cancer recurrence.Therefore,targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients,although our current knowledge of these DTP cells in treatment resistance remains limited.In this review,we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells,investigate the potential drugs for DTP(including preclinical drugs,novel use for old drugs,and natural products)based on different medicine models,and discuss the necessity and feasibility of anti-DTP therapy,related application forms,and future issues that will need to be addressed to advance this emerging field towards clinical applications.Nonetheless,understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.展开更多
Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive thera...Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.展开更多
基金supported by the grant from Georgian National Science Foundation,No.GNSF/ST07/6-234
文摘Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （NSAIDs）, or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic （intraperitoneal） administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.
基金National Natural Science Foundation of China(8167328281273355).
文摘OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel multifunctional agonist for opioid and neuropeptide FF(NPFF) receptors named DN-9.The present study was conducted to evaluate the pharmacological activities of DN-9 after peripheral administration.METHODS Antinociceptive activities of subcutaneous DN-9 were investigated in mouse models of acute inflammatory and neuropathic pain.Furthermore,the side-effects of DN-9 were evaluated after peripheral injection in rotarod,antinociceptive tolerance,abuse and gastrointestinal transit tests.RESULTS Subcutaneous DN-9 dose-dependently produced antinociception via peripheral mu-and kappa-opioid receptors,independent of delta-opioid and NPFF receptors,in the tail-flick assay.Similarly,a dose-dependent antinociceptive effect of DN-9 was mediated via peripheral opioid receptors in other inflammatory and neuropathic pain models.Repeated treatment with DN-9 produced antinociceptive effects without a loss of potency in various models of acute,inflammatory and neuropathic pain.DN-9 maintained potent analgesia in morphine-tolerant mice.The gastrointestinal motility inhibition and abuse properties of DN-9 were significantly reduced after subcutaneous injection compared to morphine.DN-9 did not significantly influence the motor coordination of mice.CONCLUSION Subcutaneous administration of DN-9 produces potent analgesic activities with minimal side effects.These data strengthen the therapeutic potential of peripherally acting opioids with multifunctional agonistic properties that are active in a broad range of experimental pain models after peripheral delivery.
文摘Objective To analyze the change in drug resistance of staphylococcus aureus(SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics for clinical applications. Methods The SAU strains isolated from clinical samples in the hospital were collected and subjected to the Kirby-Bauer disk diffusion test. The results were assessed based on the 2002 American National Committee for Clinical Laboratory Standards(NCCLS) guidelines. Results SAU strains were mainly isolated from sputum, urine, blood and wound excreta and distributed in penology, neurology wards, orthopedics and surgery ICU wards. Except for glycopeptide drugs, methicillinresistant staphylococcus aureus(MRSA) had a higher drug resistance rate than those of the other drugs and had significantly more resistance than methicillin-sensitive staphylococcus aureus(MSSA)(P<0.05). In the dynamic observation of drug resistance, we discovered a gradual increase in drug resistance to fourteen test drugs during the last five years. Conclusion Drug resistance rate of SAU stayed at a higher level over the last five years; moreover, the detection ratio of MRSA keeps rising year by year. It is crucial for physicians to use antibiotics rationally and monitor the change in drug resistance in a dynamic way.
文摘Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance.The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli,which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal,ultimately leading to treatment resistance and cancer recurrence.Therefore,targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients,although our current knowledge of these DTP cells in treatment resistance remains limited.In this review,we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells,investigate the potential drugs for DTP(including preclinical drugs,novel use for old drugs,and natural products)based on different medicine models,and discuss the necessity and feasibility of anti-DTP therapy,related application forms,and future issues that will need to be addressed to advance this emerging field towards clinical applications.Nonetheless,understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.
文摘Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.
