OBJECTIVE To evaluate the long-term toxicity of fully human anti-human tumor necrosis factor-α monoclonal antibody(anti-hTNF-α FHMA)for injection in cynomolgus monkeys. METHODS Forty cynomolgus monkeys were randomly divided into 5 groups (4 males and 4 females in each group):negative control group,adalimumab 10 mg·kg-1 group,anti-hTNF-αFHMA 2,10 and 50 mg·kg-1 groups. Cynomolgus monkeys in each group were injected sc once a week for 5 consecutive times, followed by 4 weeks of recovery. During the test,general clinical observation,body mass,body temperature,electrocardiogram(ECG),hematology,coagulation function,blood biochemistry,urine, ophthalmology,immune index,and pathological changes in organs and tissues were observed. At the same time,plasma drug concentrations were detected and the toxicokinetics parameters were analyzed. RESULTS No significant toxicological changes related to drugs were observed in general clinical observation,body mass,body temperature,ECG,ophthalmic examination,blood cell counts,coagu?lation function,blood biochemistry,urine analysis,lymphocyte subsets,cytokines,serum immuno?globulin,serum complement. Neutralizing anti-drug antibody(ADA)could be detected in adalimumab group and anti-hTNF-αFHMA groups. Anti-hTNF-αFHMA showed linear dynamic characteristics in cyno?molgus monkeys. At the same dose(10 mg·kg-1),anti-hTNF-αFHMA had similar immunogenicity and kinetics characteristics to adalimumab. CONCLUSION The level of anti-hTNF-α FHMA at which no adverse effect was observed was 50 mg · kg-1,which is equivalent to 75 times clinical dosage of quasi (0.67 mg·kg-1),which suggests that anti-hTNF-αFHMA be safe in clinical use.

As a novel fluorescent nanomaterial,quantum dots (QDs) have a prospect for wide application. However , the adverse effects of QDs have become a concern among and more researchers. The toxic actions of QDs in vivo are closely associated with the biotransport and bio?transformation of QDs,which can be affected by the exposure pathways,exposure dose,surface modification and the particle size. Among them,the exposure pathways can affect the absorption and distribution of QDs in vivo,the exposure dose can affect the metabolism and excretion,thus influencing the distribution of QDs in vivo ,the surface modification can affect the distribution ,metabolism and excretion of QDs in vivo,the particle size can affect the absorption,distribution and excretion of QDs in vivo,and larger QDs are more likely to remain in the body and difficult to remove. QDs can enter the body through the circulatory system,get accumulated and degraded in the liver,kidney and other organs. The degraded products can be excerted through excrement and urine under the metabolism in the liver,spleen and kidneys. In addition,QDs can interact with biological macromolecules in the body,causing DNA damage,affecting the function and gene expression level of the liver,kidney,nervous system and other organs,and resulting in pathological and functional damage to tissues and organs.

Cadmium is one of the important heavy metal pollutants with strong toxicity and wide distribution. It poses a threat to human health and invertebrates,especially to insects. It has been demonstrated that cadmium can infiltrate into insects through respiration ,food intake and so on. It can affect their development,and even induce apoptosis via oxidative damage. Insects can gradually develop defense mechanisms against cadmium with the help of metallothionein,antioxidant enzymes, excretion and heat shock protein. Toxicity effect varies among different species. This paper reviewsed the effect of cadmium on development,cell apoptosis mechanism and defense mechanism in insects.

Currently,a physiologically based pharmacokinetic(PBPK)model plays a key role in pharmaceutical research,which has been widely used at each stage of drug discovery and develop?ment. In the process of drug discovery,the selection of drug candidates is finished using the PBPK model to predict the pharmacokinetic properties of the drugs. In the process of preclinical development , through a combination of in vitro and physiological data amplification coefficient,the PBPK model can be used to predict not only the overall pharmacokinetic behavior of drug candidates in humans and animals and in vitro metabolism experiments,but also drug-drug interactions(DDI). In the course of clinical development,the PBPK model can help predict the difference between reference populations (age,different disease state,and polymorphism),especially the dosage and sampling time of the children. At present,the input parameters of PBPK model are mostly the mean values of the population,making it difficult to serve individuals. It is hoped that the input parameters of the model can reflect more of the individual characters according to the individual requirement,and that the time parameters of the input accord more with the actual physiological condition. In this article ,we briefly introduced the characteristics of common PBPK software,and reviewd the principle and feature of the PBPK model,as well as its application to drug discovery,preclinical development and clinical development,DDI,and individualized medication.

The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition,cancer cells have other metabolic characteristics,such as increasing fatty acid synthesis and glutamine metabolism. Emerging evidences show that many key enzymes in dysregulated Warburg-like glucose metabolism,fatty acid synthesis and glutaminolysis are linked to drug resistance in cancer treatment. For example, lactate dehydrogenase A contributes to paclitaxel/trastuzuma resistance in breast cancer, fatty acid synthase is linked to docetaxel/trastuzumab/adriamycin resistance in breast cancer, and glutaminolysis is linked to cisplatin resistance in gastric cancer. Therefore,targeting cellular metabolism may improve the response to cancer therapeutics,and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may overcome drug resistance in cancer therapy. This review discussed the relationship between dysregulated cellular metabolism and chemotherapy resistance, and the way in which targeting of metabolic enzymes can help overcome the resistance to cancer therapy or enhance the efficacy of common therapeutic agents.

γ-Secretase is aⅠtransmembrane protease associated with Alzheimer disease(AD), and including four subunits:presenilin,presenilin enhancer-2,anterior-pharynx-defective1 and nicastrin. In recent studies,the ultra-high-resolution cryo-electron microscope has been used for the first time, revealing the humanγ-secretase″horseshoe″,the three-dimensional structure and the arrangement of the subunits. This technique has shed light on the regulation of the enzyme pathway and mechanism. In addition,the γ-secretase modulators,including non-steroidal anti-inflammatory drugs,have been shown in vitro to inhibit γ-secretase activity and selectively reduce the level of Aβ42 against AD. They have provided an effective approach,with broad prospects for development. Studies in this area have become a hot topic in recent years. Here we summarized the γ-secretase subunits regulatory pathways, humanγ-secretase fine three-dimensional structure andγ-secretase modulators .

Traditional Chinese medicine(TCM)compatibility is related to the safety of clinical use of drugs and embodies the essence of interactions between drugs and organisms. This is a scientific problem thatr has attracted more attention. Currently, most of the knowledge on TCM compatibility is from predecessors′ experience. The corresponding molecular biology mechanism is poorly understood. As a powerful tool to identify a large number of proteins simultaneously,proteomics technology has the potential to reveal the protein alterations under certain conditions,and to provide more direct insights into biological processes during TCM compatibility. In this paper,we introduced the main technology of proteomics,including two dimensional gel electrophoresis,2D-DIGE,iTRAQ, QconCAT/MRM and chemical proteomics. Also,the applications of these technologies in the field of TCMM compatibility study were reviewed.

The incompatibility of traditional Chinese medicine is an important part of traditional Chinese medicine compatibility theory,while early toxicity predetermination of traditional Chinese medi?cine is an important component of drug safety evaluation. Once a simple and reliable method to predict the compatibility of Chinese medicine and Chinese traditional medicine is established,it is possible to obtain the data of toxic reaction of Chinese herbal medicine quickly and early. Pregnane X receptor (PXR)is a ligand dependent transcription factor,acting as a ligand or activator of a large number of clinical drugs and of cytochrome P-450 CYP3A (CYP3A) gene expression induced by PXR. In the course of treatment of diseases,the activation of PXR may increase the risk of drug interactions and adverse reactions,resulting in decreased efficacy and even toxicity. This paper may provide a new method of drug toxicity predetermination depending on the PXR-CYP3A pathway.

Currently,the toxicity study of traditional Chinese medicine is faced with the following problems. Firstly,the evaluation in vitro cannot fully reflect the true state of the body. Secondly,the traditional method is not sensitive enough to the early toxicity. Lastly,the toxicity evaluation indexes cannot determine whether the compatibility of traditional Chinese medicine produces toxicity or increases toxicity systematically. The paper proposed a synthesized early evaluation research method for target organ toxicity induced by traditional Chinese medicine:screening,validation,optimization and application. This method mainly inoolves early target organ toxicity biomarkers in screening,optimi?zation,validation,biological significance explanation,and application to the traditional Chinese medicine incompatibility based on the metabolic dynamic fingerprint spectrum in order to obtain biomarkers of target organ toxicity that are sensitive and precede conventional biochemical indices for early evaluation . We attempted to analyze the pattern of chang of the biomarkers for animals acted by″18 incompatible medicaments″compatibility combination. We found that Radix Aconiti Lateralis Preparata with cardiotoxicity were compatible with Rhizoma Pinelliae,and that Trichosanthes kirilowii Maxim,Fritillaria,Ampelopsis Radix and Bletilla striata without non-cardiotoxicity produced and increased cardiotoxicity systematically.

OBJECTIVE To investigate the effect of ketoconazole on the pharmacokinetic (PK) behaviors of midazolam and its metabolite through intranasal and intragastric(ig) routes in rats. METHODS Twenty-four rats were evenly divided into 4 groups. Two groups of rats were administrated singly with midazolam (1 mg?kg-1) through intranasal or ig route. The other two groups were concomitant with CYP3A inhibitor,ketoconazole(30 mg?kg-1),midazolam(1 mg?kg-1)through the same two routes. Blood samples were collected from different time points. Plasma concentration of midazolam and 1′-hydroxymidazolam was determined. Major pharmacokinetic parameters were calculated and statistical tests were performed by using t test. RESULTS Tmax was about 2 and 25 min for rats administered singly with midazolam via intranasal or ig routes,respectively and AUC was 296 and 179 μg?L-1?h, respectively. When concomitant with ketoconazole,AUC increased to 2.1 and 3.3 folds the original value for intranasal and ig routes,respectively. However,the Tmax value of midazolam via intranasally didn′t change after being coadministrated with ketoconazole,but Tmax increased to 1.14 h via ig. CONCLUSION Compared with administration via ig,intranasal route administrated midazolam displays significant advantages of faster absorption and higher exposure,which are vital for the first aid. Concomitant with CYP3A inhibitor and midazolam via intranasal route,the absorption speed is not affected,but with the metabolism blocked,the systemic exposure is greatly elevated. While via ig,both absorption speed and metabolism are inhibited. The dose should be cut down or the dosing interval increased in clinic practice in this concomitant situation.