Detailed ADME (absorption, distribution, metabolism and excretion) evaluation is required in the preclinical stage of drug development. The preclinical ADME data may be extrapolated to humans and some predictions may ...Detailed ADME (absorption, distribution, metabolism and excretion) evaluation is required in the preclinical stage of drug development. The preclinical ADME data may be extrapolated to humans and some predictions may be made with the application of proper pharmacokinetic and pharmacodynamic principles. Novel drugs with validated drug targets and favorable ADME properties are being sought by drug scientists, and oral administration is becoming a major delivery approach for many drugs due to its great safety, reduced cost, improved quality of life, and the potential for improved efficacy. The incorporation of herbal therapy into the main stream medical-care system has been encouraged by World Health Organization (WHO). Chinese herbal medicines may represent an important group of multi-component therapeutics suitable for the management of diseases with networked abnormalities such as cancer and diabetes. However, the disposition pathways, pharmacological targets and safety profiles of most Chinese herbal medicines are unknown or not well characterized. The evidence for the use of Chinese herbal medicines as effective and safe multi-component therapeutics is not established. The quality control and standardization of these natural products still constitute a major challenge in their evidence-based clinical application. Recently, there is an increased interest in the incorporation of systems biology approaches and combined use of preclinical and clinical models in understanding the complex disposition pathways, multiple targets and toxicities of Chinese herbal medicines. Like synthetic drugs, Chinese herbal medicines are subject to similar ADME processes in the body like synthetic drugs. However, data are scant on the ADME of most Chinese herbal medicines. Thus, it is important to characterize ADME for both drugs and Chinese herbal medicines. My research team and collaborators have synthesized several small molecule novel compounds for cancer treatment, including 5,6-dimethylxanthenone-4-acetic acid (DMXAA, an antiangiogenic agent and TNF-( inducer) and SYUIQ-5, a novel telomerase inhibitor. The metabolic pathways and transport properties of both DMAA and SYUIQ-5 have been characterized. We have also investigated the metabolism and transport of the major active components of several commonly used Chinese herbal medicines, such as Danshen (Salvia miltiorrhiza) and ginkgo (Ginkgo biloba) using a combination of in vitro and in vivo models. It is believed that ADME studies are necessary and important for both synthetic drugs and Chinese herbal medicines in an attempt to establish their efficacy and safe-ty profiles.展开更多
BACKGROUND The treatment of hepatocellular carcinoma(HCC)≥10 cm remains a challenge.AIM To consolidate the role of surgical resection for HCC larger than 10 cm.METHODS Eligible HCC patients were identified from the C...BACKGROUND The treatment of hepatocellular carcinoma(HCC)≥10 cm remains a challenge.AIM To consolidate the role of surgical resection for HCC larger than 10 cm.METHODS Eligible HCC patients were identified from the Chang Gung Research Database,the largest multi-institution database,which collected medical records of all patients from Chang Gung Memorial Foundation.The surgical outcome of HCC≥10 cm(L-HCC)was compared to that of HCC<10 cm(S-HCC)(model 1).The survival of L-HCC after either liver resection or transarterial chemoembolization(TACE)was also analyzed(model 2).The long-term risks of all-cause mortality and recurrence were assessed to consolidate the role of surgery for L-HCC.RESULTS From January 2004 to July 2015,a total of 32403 HCC patients were identified from the Chang Gung Research Database.Among 3985 patients who received liver resection,3559(89.3%)had S-HCC,and 426 had L-HCC.The L-HCC patients had a worse disease-free survival(0.27 for L-HCC vs 0.40 for S-HCC)and overall survival(0.18 for L-HCC vs 0.45 for S-HCC)than the S-HCC after liver resection(both P<0.001).However,the surgical and long-term outcome of resected L-HCC had improved dramatically in the recent decades.After adjusting for covariates,surgery could provide a better outcome for L-HCC than TACE(adjusted hazard ratio of all-cause mortality:0.46,95%confidence interval:0.38-0.56 for surgery).Subgroup analysis stratified by different stages showed similar trend of survival benefit among L-HCC patients receiving surgery.CONCLUSION Our study demonstrated an improving surgical outcome for HCC larger than 10 cm.Under selected conditions,surgery is better than TACE in terms of disease control and survival and should be performed.Due to inferior survival,a subclassification within T1 stage should be considered.Future studies are mandatory to confirm our findings.展开更多
文摘Detailed ADME (absorption, distribution, metabolism and excretion) evaluation is required in the preclinical stage of drug development. The preclinical ADME data may be extrapolated to humans and some predictions may be made with the application of proper pharmacokinetic and pharmacodynamic principles. Novel drugs with validated drug targets and favorable ADME properties are being sought by drug scientists, and oral administration is becoming a major delivery approach for many drugs due to its great safety, reduced cost, improved quality of life, and the potential for improved efficacy. The incorporation of herbal therapy into the main stream medical-care system has been encouraged by World Health Organization (WHO). Chinese herbal medicines may represent an important group of multi-component therapeutics suitable for the management of diseases with networked abnormalities such as cancer and diabetes. However, the disposition pathways, pharmacological targets and safety profiles of most Chinese herbal medicines are unknown or not well characterized. The evidence for the use of Chinese herbal medicines as effective and safe multi-component therapeutics is not established. The quality control and standardization of these natural products still constitute a major challenge in their evidence-based clinical application. Recently, there is an increased interest in the incorporation of systems biology approaches and combined use of preclinical and clinical models in understanding the complex disposition pathways, multiple targets and toxicities of Chinese herbal medicines. Like synthetic drugs, Chinese herbal medicines are subject to similar ADME processes in the body like synthetic drugs. However, data are scant on the ADME of most Chinese herbal medicines. Thus, it is important to characterize ADME for both drugs and Chinese herbal medicines. My research team and collaborators have synthesized several small molecule novel compounds for cancer treatment, including 5,6-dimethylxanthenone-4-acetic acid (DMXAA, an antiangiogenic agent and TNF-( inducer) and SYUIQ-5, a novel telomerase inhibitor. The metabolic pathways and transport properties of both DMAA and SYUIQ-5 have been characterized. We have also investigated the metabolism and transport of the major active components of several commonly used Chinese herbal medicines, such as Danshen (Salvia miltiorrhiza) and ginkgo (Ginkgo biloba) using a combination of in vitro and in vivo models. It is believed that ADME studies are necessary and important for both synthetic drugs and Chinese herbal medicines in an attempt to establish their efficacy and safe-ty profiles.
文摘BACKGROUND The treatment of hepatocellular carcinoma(HCC)≥10 cm remains a challenge.AIM To consolidate the role of surgical resection for HCC larger than 10 cm.METHODS Eligible HCC patients were identified from the Chang Gung Research Database,the largest multi-institution database,which collected medical records of all patients from Chang Gung Memorial Foundation.The surgical outcome of HCC≥10 cm(L-HCC)was compared to that of HCC<10 cm(S-HCC)(model 1).The survival of L-HCC after either liver resection or transarterial chemoembolization(TACE)was also analyzed(model 2).The long-term risks of all-cause mortality and recurrence were assessed to consolidate the role of surgery for L-HCC.RESULTS From January 2004 to July 2015,a total of 32403 HCC patients were identified from the Chang Gung Research Database.Among 3985 patients who received liver resection,3559(89.3%)had S-HCC,and 426 had L-HCC.The L-HCC patients had a worse disease-free survival(0.27 for L-HCC vs 0.40 for S-HCC)and overall survival(0.18 for L-HCC vs 0.45 for S-HCC)than the S-HCC after liver resection(both P<0.001).However,the surgical and long-term outcome of resected L-HCC had improved dramatically in the recent decades.After adjusting for covariates,surgery could provide a better outcome for L-HCC than TACE(adjusted hazard ratio of all-cause mortality:0.46,95%confidence interval:0.38-0.56 for surgery).Subgroup analysis stratified by different stages showed similar trend of survival benefit among L-HCC patients receiving surgery.CONCLUSION Our study demonstrated an improving surgical outcome for HCC larger than 10 cm.Under selected conditions,surgery is better than TACE in terms of disease control and survival and should be performed.Due to inferior survival,a subclassification within T1 stage should be considered.Future studies are mandatory to confirm our findings.
