Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 14, Issue 1, 2016

Drugs are generally tested on a large population of people via phase studies and the average response is reported in a sort of evidence-based medicine. Screening of genetic variations is necessary in understanding the underlying mechanisms of individual drug responses and to find out more targeted and unique therapeutic strategies focusing on this individual variations. The “-omics” (genomics/proteomics/metabolomics) technology can enable researchers to further understand the causative mechanisms/ biomarkers. Furthermore, they might be used to assess optimized drug efficacy and safety. The most common indications for traditional use of medicinal plants included gastrointestinal, urinary tract and gynecology, cough and cold, wound healing, pain and inflammation, and mental stress and mood disorders. The traditional use of these herbal medicines primarily incorporates a personalized approach and emphasis on prevention rather than a single disease targeted therapy with conventional mono-component drugs since these medicines have more than one component with multiple targets within the body. Therefore, because of the emphasis on individualization and prevention, the use of omics technology for precise or personalized approaches for medicinal plants is even more promising than it is for conventional medicines.

Background: Practical challenges and translational issues have affected the widespread implementation of pharmacogenomics and personalized medicine. There are significant barriers to the translation of personalized medicine from research labs to practical application in a healthcare setting. Methods: The information in this review paper was collected via search engines and Pub- Med using the following search entries “pharmacogenomics”, “personalized medicine”, “translational issues”. Articles and papers published from 2010 onwards were included. Results: The gathered data presented in this paper illustrate the main challenges and translational issues in the field of pharmacogenomics and personalized medicine. Conclusion: Costs in the drug discovery process and the implementation of personalized medical approaches are the main barriers to the translation of pharmacogenomics from laboratory to clinic. The lack of a unified system as well as the requirement for expert analysis of data is additional barriers.

DNA polymorphisms have an important role in the genes encoding. A number of cytochrome P450 (CYP) enzymes are leading to drug metabolism variation in different subjects. CYP2C9 and CYP2C19 metabolize many clinically important drugs. Inter-individual variability in drug metabolism may change drug reactions and variability in drug efficiency. Cytochrome P450 (CYPs) polymorphisms may show an important effect on drug metabolism, toxicity and hepatotoxicity. The most common clinical effects are associated with CYP2C19 and CYP2C9 mutants. Differences in genetic polymorphism of these cytochromic enzymes in inter-individual still remain unknown. This review article summarizes the most important polymorphisms of 2C9 and 2C19 diversity which is important for metabolism of some drugs and treatment of several diseases. Determining the pharmacokinetic effects of CYP2C19 and CYP2C9 genotypes may help physicians choose the optimal dosage of some drugs for the treatment and prevention of their side effects. Since different ethnic groups from all over the world use medications, it seems necessary to investigate the pharmacokinetic effects of CYP2C19 and CYP2C9 genotypes in different populations, due to drug consumption with optimal dosage in different ethnic groups.

The employment of comet assay has gained wide importance in various areas that focus on human bio-monitoring, genetic toxicology, molecular epidemiology and ecogenotoxicity. Comet assay has become among the standard methods for evaluating genotoxicity by the determination of DNA damage caused by mutagens, and this assay has been extensively applied by the researchers for the past 20 years. This review discusses comet assay, as well as its application in various fields.

Background: With the use of next generation sequencing technologies, translational research is becoming a catalyst for the implementation of personalized medicine (PM). To implement PM, we will also need to ensure that sensitive results are shared, used and returned to the participants in compliance with applicable ethical and legal frameworks. Furthermore, the increasingly blurred distinction between research and clinical practice in this context will require improving governance processes to better protect the rights and interests of research participants. In response to this challenge, innovative solutions are emerging in the literature, including that of a “trusted third party” or “gatekeeper”. Objective: Our research seeks to explore the multiple roles that such a gatekeeper could undertake in the context of PM and to implement some of these roles in a customized gatekeeper framework. Method: The research consists of a comparative analysis of the governance frameworks of selected large-scale PM projects. A gatekeeper framework, namely the DataTrust, is presented to provide a prototype for other research projects to use or build on. Results: Possible oversight functions, roles and responsibilities of a gatekeeper are identified leading to the development of the DataTrust. Such functions, roles and responsibilities may include, but are not limited to: protecting the integrity of the consent process; safeguarding data confidentiality; reviewing access requests from members of the scientific community; and ensuring overall ethics compliance and oversight for the return of results. Conclusion: We propose that the integration of a gatekeeper, with specific functions tailored to each project, could enhance compliance with applicable ethical and legal standards and protect the rights and interests of research participants.

Background: It is known that the distribution of polymorphism frequencies can vary greatly between different ethnic groups, resulting in variable percentages of poor, intermediate or extensive metabolizers in a given population. Objective: This study was carried out to estimate the genotype frequencies of common variants in the CYP2D6, CYP3A5 and DPYD genes in the Yakut population from North-Eastern Siberia. To compare the allelic distribution found with the frequencies reported for other ethnic groups. Method: Genotyping was carried out by real-time polymerase-chain reaction in a total of 100 healthy unrelated Yakut subjects (CYP2D6 c.100C>T, CYP3A5 g.6986G>A, DPYD c.1905+1G>A, DPYD c.1679T>G, DPYD c.2846T>A). Results: The allele frequencies for CYP3A5*3 and DPYD*13 in Yakuts were 0.08 and 0.01, respectively. No DPYD*2A and DPYD c.2846A alleles were detected. Conclusion: Our data on the distribution of frequencies of genotypes and alleles of polymorphisms of CYP2D6, CYP3A5 and DPYD genes in the Yakut population as a whole are more characteristic of the European populations.

Background: The drug response varies from person to person. The possibility for the drugs to move to a large number of bio molecular targets and lack of personalization are the major reasons for this. The multi targeting of drugs and resulted drug resistance and side effects can be minimized by designing and developing personalized drugs. Retro metabolic design strategy helps in generating promising molecules with less toxicity and side effects. Methods: In the development of personalized drugs, PARP inhibitors have been identified as powerful anticancer drug molecules controlling BRCA1 mutations for breast cancer. However, the effect of most of these PARP inhibitors has been increased while using a combination of PARP inhibitors and drugs preventing the alkylation possibility of DNA like chlorambucil. The Retro metabolic Drug Design (RMDD) template has been taken from metabolite of chlorambucil. In the present work, the possibility of making analogs of metabolites of chlorambucil as soft drugs in PARP1 inhibitor for controlling BRCA1 mutations has been excavated. As an added advantage, the molecules seem to have a direct interaction with mutated BRCA1 protein molecules also. Results: The designed molecules seem to be more personalized and their drug likeness is on a par with FDA approved drug for breast cancer subject to further in vivo and clinical evaluation. The approach has been identified as a promising technique for designing personalized anti-cancer drugs. Conclusion: The people with the genetic signatures, rs28897696 are more prone to breast cancer resulted by the BRCA1 mutation. For the PARP inhibition analysis, Human ARTD1 (PARP1) catalytic domain in complex with inhibitor Rucaparib (4RV6) has been considered. The inhibitors of PARP1 and BRCA1 have been designed in the retrometabolic manner from metabolites of chlorambucil and active/ inactive metabolites present in human body. The evolved molecules, 8-(5-acetyl-2-hydroxyphenoxy)-4-amino-3-hydroxy-5-methyloctanoic acid, 4-amino-3-hydroxy-9-(4-hydroxy-3-methoxyphenyl)-5,5-dimethyl-9-oxononanoic acid and 8-(5-acetyl-2-hydroxyphenoxy)-4-amino-3-hydroxy-5,5-dimethyloctanoic acid are found to be promising anti-breast cancer drugs with comparatively low side effects and more personalization subject to further in vivo and clinical evaluations.