Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms

Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.

Emodin Inhibits Lipopolysaccharide-Induced Inflammation by Activating Autophagy in RAW 264.7 Cells

Objective:To investigate the effects of emodin on inflammation and autophagy in lipopolysaccharide(LPS)-induced RAW 264.7 macrophages and reveal its underlying mechanism.Methods:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium(MTS)assay was conducted to find the appropriate dose for emodin.RAW264.7 cells pretreated with different concentrations(0–50μmol/L)of emodin or vehicle for 2 h prior to exposure to LPS for 16 h.Cell morphology was examined and propidium iodide staining was used to examine cell cycle.Expressions of inflammation-related proteins[nuclear factor-kappa B(NF-κB)and I-kappa B(IκB)α]and autophagy-related proteins[light chain(LC)3,P62/sequestosome 1,mammalian target of rapamycin(m TOR),and p-m TOR]were examined using Western blot analysis.Expression of inflammation-related cytokines including tumor necrosis factor(TNF)-α,interleukin(IL)-1βand IL-6 were detected by enzyme-linked immunosorbent assay.Autophagy was examined with LC3 B fluorescence intensity and aggregation.The effect of emodin on autophagy was conducted with an autophagy inhibitor,3-methyladenine(3-MA).Results:The expression of NF-κB in LPS-induced cells was significantly increased(P<0.01)and simultaneously IκBαdecreased compared with the normal cell(P<0.05).The expressions of TNF-α,IL-1β,and IL-6 proteins in the LPS-induced RAW264.7 cells were significantly higher than in the normal cell(P<0.05 or P<0.01).LPS increased the percentage of cells in the G0/G1 phase,which was recovered by emodin at different doses(12.5,25,and 50μmol/L,P<0.05 or P<0.01).The mediumdose(25μml/L)emodin decreased the expressions of NF-κB,P62 and p-m TOR(P<0.01)and increased IκBαexpression,LC3 BⅡ/Ⅰratio as well as LC3 B fluorescence intensity(P<0.05 or P<0.01).Meanwhile,the enhanced autophagic effects of emodin,such as the increment of LC3 BⅡ/ratio and the decrement of P62 expression,were suppressed by autophagy inhibitor 3-MA.Conclusion:Emodin could inhibit inflammation of mice RAW264.7 macrophages induced by LPS,possibly through activating autophagy.

Spectrum-Toxicity Correlation Study Revealed the Influence of the Nine-Time Steaming and Sun Drying Method on Hepatotoxic Components of Polygoni Multiflori Radix

Objective:Polygoni Multiflori Radix(PM)is a traditional herbal medicine with repeated reports of liver injury events in recent years.We wondered whether the classical processing method,namely,nine-time steaming and sun drying(NSSD),had toxicity-attenuating effects on PM and the relationships between toxicity and times of processing,as well as with the alteration trends of its compounds.Materials and Methods:The chemical fingerprints of different PM extracts were developed using ultra-high-performance liquid chromatography.The spectrum-toxicity correlation between the chemical fingerprints and hepatocellular toxicity was analyzed with multiple correlation analysis.Results:The results suggested that the hepatotoxicity of NSSD processing products markedly decreased with the repeated steaming and sun drying,which was obviously superior to the product processed by the modern method.Comprehensive analysis revealed that the contents of cis-stilbene glycoside and emodin-8-O-β-D-glucoside related to liver injury susceptibility were reduced with the times of NSSD processing,which was consistent with the decreased trend of hepatocellular toxicity.After the five times of NSSD,the contents of them as well as the hepatotoxicity of PM were steady.Moreover,we found that the contents of catechin and physcion declined rapidly after the one time of NSSD and then remained stable until the nine times of NSSD.Based on the fact,they could be utilized to indicate whether PM products were processed by steaming and sun drying.Conclusions:This paper confirmed that the NSSD had a good influence on the toxicity attenuating to PM and found four compounds which could apply for the quality control of PM.

Disease-based Toxicology on Safety Assessment Strategy and Application for Herbal and Traditional Medicines

The safety issue on herbal and traditional medicines(H&TM) is one of the most challenging problems and serious concern worldwide. With scientific endeavor and further exploration, we came to realize that there are great differences between H&TM and synthetic drugs in many aspects, such as medical theory, medication experience, compatibility, processing, toxicological characteristics, and safety evaluating requirements. In the current preclinical models for synthetic drugs, the safety assessment results of some conventional deemed 'nontoxic' H&TM were not well consistent with clinical situations, which resulted in major difficulties to understand the mechanisms and guide the safe and rational uses of these H&TM. Thus, based on the traditional Chinese medicine toxicity theory called You Gu Wu Yun, this paper introduces a novel safety assessment strategy for H&TM, named as disease-based toxicology. It aims to cognize the relativity and susceptibility of the toxicity of H&TM, and then to enhance controllability in new drug development and clinical applications. It also provides a theoretical practice for the traditional Chinese medicine toxicity theory and a methodological promotion for the future development of the precision toxicology for H&TM.