Effect of pharmacodynamical interaction between nutlin-3a and aspirin in the activation of p53.

BACKGROUND AND OBJECTIVE: p53, an anti-tumour protein, is significantly inactivated in most tumours. A small molecule of nutlin-3a is used to activate its function by repressing (Mouse double minute 2 homolog) Mdm2 protein which inhibits its activity. In cancer patients, a high risk of drug-drug interactions (DDIs) is observed owing to their multi-dosing prescriptions, which may lead them to harmful effects. In the presented work, we have aimed to investigate the effect of pharmacodynamical interaction between two anti-cancer drugs, nutlin-3a and aspirin in the activation of p53 protein. METHODS: We have adapted control system techniques and designed a Proportional-Integral-Derivative (PID) controller. This controller is used to activate p53 protein. A drug interaction parameter is used to incorporate the effect of both drugs. Extensive simulation is performed using two different doses of aspirin, i.e. a low and a high dose of aspirin. RESULTS: The result shows no harmful effects of pharmacodynamical interaction when a low dose is administered along with nutlin-3a. When a high dose of aspirin is administered it acts as input disturbance and leads to undesirable over-expression of p53 protein. This can further harm other growth cells, thus inducing harmful effects. A comparative analysis is also tabulated with different dosing regimens which shows that a combination of nutlin-3a and a low dose of aspirin provides better results than a high dose of aspirin. CONCLUSION: Overall, the work provides an insight to the activation of p53 protein in cancer patients under the presence of pharmacodynamical interaction and might contribute to the effective management of cancer patients.

Pyrazinamide-resistant mycobacterium tuberculosis isolates from Khyber Pakhtunkhwa and rpsA mutations.

Pyrazinamide (PZA) is a key first-line antibiotic used for the short-course treatment of drug-sensitive and multidrug-resistant (MDR) isolates of tuberculosis. PZA exhibits potent action against semi-dormant bacilli in acidic environments. However, mutations that occur in target genes may cause technical difficulties in the diagnosis of PZA resistance during drug susceptibility testing. The objective of the current study is to identify mutations in pncAWT rpsA and rpsAWT panD genes among PZA-resistant isolates of Mycobacterium tuberculosis (MTB) circulating in the Pashtun dominant region, Khyber Pakhtunkhwa, Pakistan. We selected 18 PZA-resistant pncAWT strains from the Provincial Tuberculosis Reference Laboratory (PTRL) Khyber Pakhtunkhwa to investigate mutations in the coding region of rpsA and panD genes. The experiments were repeated for drug susceptibility testing using MGIT 960 automated system. In addition, eighteen PZA-resistant rpsA genes along with 5 susceptible strains and one H37Rv strain were sequenced. All 18 isolates were PZA-resistant. The majority of these isolates exhibited multidrug resistance (MDR) (13/18). We identified 14 non-synonymous and one synonymous mutation in the coding region of rpsA in 11 strains. All mutations were scattered throughout the gene and not reported previously. Further, we did not identify any mutation in 7 rpsAWT panD genes. Mutations in rpsA but not in panD occur in PZA-resistant pncAWT MTB isolates circulating in Khyber Pakhtunkhwa, Pakistan.

Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots.

Mathematical Modeling of E6-p53 interactions in Cervical Cancer

Background: Cervical cancer is the third most common cancer in women throughout the world. The human papillomavirus (HPV) E6 viral protein plays an essential role in proteasomal degradation of the cancer suppressant protein p53. As a result, p53 negative regulation and apoptosis relevant activities are abrogated, facilitating development of cervical cancer. Methods: A mathematical model of E6-p53 interactions was developed using mathematical laws. In-silico simulations were carried out on CellDesigner and as a test case the small molecule drug RITA was considered for its ability to rescue the functions of tumor suppressor p53 by inhibiting E6 mediated proteasomal degradation. Results: Using a computational model we scrutinized how p53 responds to RITA, and chemical reactions of this small molecule drug were incorporated to perceive the full effects. The evolved strategy allowed the p53 response and rescue of its tumor suppressor function to be delineated, RITA being found to block p53 interactions with E6 associated proteins. Conclusion: We could develop a model of E6-p53 interactions with incorporation of actions of the small molecule drug RITA. Suppression of E6 associated proteins by RITA induces accumulation of tumor suppressant p53. Using CellDesigner to encode the model ensured that it can be easily modified and extended as more data become available. This strategy should play an effective role in the development of therapies against cancer.

On p53 revival using system oriented drug dosage design.

We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The claimed dosage strategy achieves the p53 response in the first case. However, for the induction of oscillations, it is shown through bifurcation analysis that to achieve oscillating behavior of p53 inhibition of Mdm2 is not enough, rather antirepression of the p53-Mdm2 complex is also needed which leads to the need of a new drug design paradigm.