Mechanisms Of Drug-induced Toxicity Research Articles

Stilbene glucoside: recent advances in pharmacology, bioinformatics investigation, toxicity and future opportunities.

Background: 2,3,5,4'-Tetrahydroxystilbene-2-O-β-<small>D</small>-glucoside (TSG) from Polygonum multijiorum Thunb. (PMT), is a major bioactive component. This review is aimed to summarize the present development of TSG regarding pharmaceutics, pharmacology and toxicology, with a focus on the novel mechanism of drug-induced toxicity and provides insight for its potential developments and applications in the future on traditional Chinese medicine. Methods: Studies about TSG's activities and toxicity were searched and summarized. Targets and mechanisms were predicted and analyzed with network pharmacology methods. Affinities and binding modes of key targets with TSG were verified by AutoDock Vina software. Results: TSG plays an essential role among the chemical components of PMT because of multiple pharmacological activities, which suggests a potential application of TSG for a variety of diseases, like atherosclerosis, Alzheimer's disease, Parkinson's disease, cerebral I/R injury, diabetes, osteoporosis, colitis. However, mild liver toxicity of TSG is also pointed out. Conclusions: As a biologically active natural product in PMT, TSG has shown prospective pharmacological activities, particularly as an agent for cardiovascular protection and neuroprotection.

Genome-wide association study: a useful tool to identify common genetic variants associated with drug toxicity and efficacy in cancer pharmacogenomics.

In recent years, the utilization of genome-wide association study (GWAS) has proved to be a beneficial method to identify novel common genetic variations not only for disease susceptibility but also for drug efficacy and drug-induced toxicity, creating a field of pharmacogenomics studies. In addition, the findings from GWAS also generate new biologic hypotheses that could improve the understanding of pathophysiology for disease or the mechanism of drug-induced toxicity. This review highlights the implications of GWAS that have been published to date and discusses the successes as well as challenges of using GWAS in cancer pharmacogenomics. The aim of pharmacogenomics is to realize the vision of personalized medicine; it is hoped that through GWAS, novel common genetic variations could be identified to predict clinical outcome and/or toxicity in cancer therapies that subsequently could be implemented to improve the quality of lives of patients with cancer. Nevertheless, given the complexity of cancer therapies, underpowered studies, and large heterogeneity of study designs, collaborative efforts are needed to validate these findings and overcome the limitations of GWA studies before clinical implementation. See all articles in this ccr focus section, "Progress in pharmacodynamic endpoints."

Future of ToxicologyMechanisms of Toxicity and Drug Safety: Where Do We Go from Here?

Recent high-profile drug withdrawals increase the pressure on regulators and the pharmaceutical industry to improve preclinical safety testing. Understanding mechanisms of drug toxicity is an essential step toward improving drug safety testing by providing the basis for mechanism-based risk assessments. Nonetheless, despite several decades of research on mechanisms of drug-induced toxicity and the application of various new technologies to preclinical safety assessment, the overall impact on preclinical safety testing has been modest. Assessing the risk of exposing humans to new drug candidates still depends on preclinical testing in animals, which in many, but not all cases, predicts outcomes in humans accurately. The following offers a perspective on the challenges and opportunities facing efforts to improve preclinical safety testing and outlines gaps and needs that must be addressed. A case is built for focusing solutions on defined problems within the current safety testing paradigm rather than imposing wholesale change. Targets for application of new technologies, including in silico screening, biomarkers, surrogate assays and 'omic technologies, are outlined. Improving drug safety testing will depend on improving the application of mechanism-based risk assessment but will also require improving public and private collaborations in order to focus research regarding the mechanism of drug-induced toxicity on the most important problems.

Difficulties in assessing adverse drug reactions in clinical trials

1. The discovery of an adverse drug reaction (ADR) depends on: the relative frequencies of the drug-related and non-drug events; the mechanism of drug-induced toxicity; the number of patients exposed to the drug; and the methods used for detecting toxicity. Clinical trials are usually short-term studies conducted in a few hundred patients before marketing a drug. Therefore only the most common acute, dose-related ADRs are usually detected in the pre-marketing phase. 2. The detection and assessment of ADRs in clinical trials is still inadequate. Unstructured (open-ended questionnaires) and structured procedures (checklists) are the methods most commonly used. Since both methods have limitations, the discovery of ADRs in pre-marketing trials (phases I to III) should also rely on the complementary information provided by other methods: physiological and physical examinations, and pertinent laboratory tests. A more definite assessment of individual cases of ADRs should include the use of the adverse drug reaction probability scale (APS) or similar procedures. 3. Because the knowledge on the clinical toxicity of a drug will always be incomplete at the time of marketing, further investigation of the frequency and determinants of ADRs must be pursued in the post-marketing phase.