Drugs related to morphine represent not only large range of important therapeutic applications for the relief of moderate to severe pain but also give rise to a relatively large series of novel opioids that mimic the ...Drugs related to morphine represent not only large range of important therapeutic applications for the relief of moderate to severe pain but also give rise to a relatively large series of novel opioids that mimic the action of this naturally occurring analgesic.Most of these are based on fentanyl structures that are much more potent,and dangerous,than fentanyl itself.This publication reviews reports of fatalities attributed to 15 novel opioids with the view to assessing mortality associated with their misuse as well as reviewing published analytical procedures that would be able to detect these and other novel opioids.These drugs include reports of deaths to acetylfentanyl,acrylfentanyl,butr(yl)fentanyl,carfentanil,2-and 4-fluorofentanyls,4-fluorobutyrfentanyl,4-fluoroisobutyrfentanyl,furanylfentanyl,a-and 3-methylfentanyls,4-methoxyfentanyl,ocfentanil,as well as AH-7921,U-47700 and MT-45.Most of these cases reporting a drug-caused death involved other drugs in addition to the opioid.No obvious minimum fatal concentration was discerned for any of the opioids for which details were provided,however,the more potent members required detection limits well under 1 ng/mL and often even well below 0.1 ng/mL requiring use of the most sensitive mass spectral detection procedures,particularly when screening specimens using a non-targeted mode.Four other novel opioids have been reported in admissions to hospitals include 4-chloroisobutryfentanyl,cyclopentylfentanyl and tetrahydrofuranfentanyl,all of which are likely to have the potential to cause death.It is also likely that other analogues will appear with time.展开更多
Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.Novel approaches to combating the disease have emerged in recent years and several drug candidates are ...Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically.However,it is long before these novel drugs can hit the market,especially due to a scarcity of safety and efficacy data.To reduce the malaria burden,the Medicines for Malaria Venture(MMV)was established in 1999 to develop novel medicines through industry and academic partners’collaboration.However,no reviews were focused following various preclinical and clinical studies published since the MMV initiation(2000)to till date.We identify promising approaches in the global portfolio of antimalarial medicines,and highlight challenges and patient specific concerns of these novel molecules.We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies.Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further,especially for use in pregnant women.Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads.Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy.AQ-13 induced electrocardiac events,which led to prolonged QTc intervals.Tafenoquine,the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency,has raised significant concerns due to its hemolytic activity.Other compounds,including methylene blue(potential transmission blocker)and fosmidomycin(DXP reductoisomerase inhibitor),are available but cannot be used in children.At this stage,we are unable to identify a single magic bullet against malaria.Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission.Newer medicines have also raised concerns in terms of efficacy and safety.Overall,more evidence is needed to effectively reduce the current malaria burden.Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.展开更多
Cancer Drug Resistance publishes contributions to understanding the biology and consequences of mechanisms that interfere with successful treatment of cancer. Since virtually all patients who die of metastatic cancer ...Cancer Drug Resistance publishes contributions to understanding the biology and consequences of mechanisms that interfere with successful treatment of cancer. Since virtually all patients who die of metastatic cancer have multidrug-resistant tumors, improved treatment will require an understanding of the mechanisms of resistance to design therapies that circumvent these mechanisms, exploit these mechanisms, or inactivate these multidrug resistance mechanisms. One example of a resistance mechanism is the expression of ATP-binding cassette efflux pumps, but unfortunately, inhibition of these transporters has not proved to be the solution to overcome multidrug resistance in cancer. Other mechanisms that confer multidrug resistance, and the confluence of multiple different mechanisms (multifactorial multidrug resistance) have been identified, and it is the goal of this Special Collection to expand this catalog of potential multidrug resistance mechanisms, to explore novel ways to overcome resistance, and to present thoughtful reviews on the problem of multidrug resistance in cancer.展开更多
A survey of the current literature on natural isoflavones and their biological activity is presented.This subcategory of a large group of plant polyphenolics has particular characteristics,structural as well as pharma...A survey of the current literature on natural isoflavones and their biological activity is presented.This subcategory of a large group of plant polyphenolics has particular characteristics,structural as well as pharmacological,which makes it suitable for discussion of pleiotropic activities of phytochemicals and their exploitation in healthcare,beyond the concept of selectively targeted new drugs for narrow therapeutic indication.展开更多
文摘Drugs related to morphine represent not only large range of important therapeutic applications for the relief of moderate to severe pain but also give rise to a relatively large series of novel opioids that mimic the action of this naturally occurring analgesic.Most of these are based on fentanyl structures that are much more potent,and dangerous,than fentanyl itself.This publication reviews reports of fatalities attributed to 15 novel opioids with the view to assessing mortality associated with their misuse as well as reviewing published analytical procedures that would be able to detect these and other novel opioids.These drugs include reports of deaths to acetylfentanyl,acrylfentanyl,butr(yl)fentanyl,carfentanil,2-and 4-fluorofentanyls,4-fluorobutyrfentanyl,4-fluoroisobutyrfentanyl,furanylfentanyl,a-and 3-methylfentanyls,4-methoxyfentanyl,ocfentanil,as well as AH-7921,U-47700 and MT-45.Most of these cases reporting a drug-caused death involved other drugs in addition to the opioid.No obvious minimum fatal concentration was discerned for any of the opioids for which details were provided,however,the more potent members required detection limits well under 1 ng/mL and often even well below 0.1 ng/mL requiring use of the most sensitive mass spectral detection procedures,particularly when screening specimens using a non-targeted mode.Four other novel opioids have been reported in admissions to hospitals include 4-chloroisobutryfentanyl,cyclopentylfentanyl and tetrahydrofuranfentanyl,all of which are likely to have the potential to cause death.It is also likely that other analogues will appear with time.
文摘Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically.However,it is long before these novel drugs can hit the market,especially due to a scarcity of safety and efficacy data.To reduce the malaria burden,the Medicines for Malaria Venture(MMV)was established in 1999 to develop novel medicines through industry and academic partners’collaboration.However,no reviews were focused following various preclinical and clinical studies published since the MMV initiation(2000)to till date.We identify promising approaches in the global portfolio of antimalarial medicines,and highlight challenges and patient specific concerns of these novel molecules.We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies.Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further,especially for use in pregnant women.Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads.Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy.AQ-13 induced electrocardiac events,which led to prolonged QTc intervals.Tafenoquine,the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency,has raised significant concerns due to its hemolytic activity.Other compounds,including methylene blue(potential transmission blocker)and fosmidomycin(DXP reductoisomerase inhibitor),are available but cannot be used in children.At this stage,we are unable to identify a single magic bullet against malaria.Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission.Newer medicines have also raised concerns in terms of efficacy and safety.Overall,more evidence is needed to effectively reduce the current malaria burden.Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.
基金This publication was funded by the Intramural Research Program of the National Institutes of Health,the National Cancer Institute,Center for Cancer Research.
文摘Cancer Drug Resistance publishes contributions to understanding the biology and consequences of mechanisms that interfere with successful treatment of cancer. Since virtually all patients who die of metastatic cancer have multidrug-resistant tumors, improved treatment will require an understanding of the mechanisms of resistance to design therapies that circumvent these mechanisms, exploit these mechanisms, or inactivate these multidrug resistance mechanisms. One example of a resistance mechanism is the expression of ATP-binding cassette efflux pumps, but unfortunately, inhibition of these transporters has not proved to be the solution to overcome multidrug resistance in cancer. Other mechanisms that confer multidrug resistance, and the confluence of multiple different mechanisms (multifactorial multidrug resistance) have been identified, and it is the goal of this Special Collection to expand this catalog of potential multidrug resistance mechanisms, to explore novel ways to overcome resistance, and to present thoughtful reviews on the problem of multidrug resistance in cancer.
文摘A survey of the current literature on natural isoflavones and their biological activity is presented.This subcategory of a large group of plant polyphenolics has particular characteristics,structural as well as pharmacological,which makes it suitable for discussion of pleiotropic activities of phytochemicals and their exploitation in healthcare,beyond the concept of selectively targeted new drugs for narrow therapeutic indication.
