Question 1) What allowed for an increase in the number of new drug classes developed?
Nowadays many new classes of drugs are being developed. The most important Reason is the side effects produced by older drugs and the patient becomes Resistant to older drugs due to its regular intake. New drug classes developed With - minimum side effects
- Frequent dosing is very less
- minimum risk of drug resistance.
Question 2) what causes a new drug to fail approval for human use?
Reasons that fails a drug for human use are as follows
- poor knowledge about right target
- poor knowledge regarding molecular biology.
- Designing difficulties of proper clinical protocols.
- Difficulty to understands toxicological effects, pharmaceutical properties, ADME etc.
Question 3) Why is it preferable for a drug candidate to “fail early and fail often” than for compounds to enter testing in human subjects and then fail in late Phase II or Phase III clinical trials?
It is very costly to develop a new drug. Pharmaceutical companies spend lots of money Behind developing any new drug and it is also a time consuming process. It takes around 14 years to come into market. Thats why it is very important for a drug Candidate to fail at the preclinical stages rather than it tested in human subject so we can Save money as well as time.
Example: Because of toxic effect towards liver,fenfluramine has been withdrawn from the market.
Question 7) In relation to toxicity and drug metabolism, explain the significance of cytochrome P450 Monooxygenases.
cytochrome p450 is very important in phase I monooxygenase reaction. it combines with the drug and under goes the following reaction
thus it plays an important role in the drug metabolism in the liver.
In relation to toxicity: drug metabolism inhibit may be because of competition for the same Cyp450 isoenzyme.
Precipitant drug: object drug effect ciprofloxacin theophylline inhibition of metabolism leads to toxicity of theophylline.
Question 8) - A number of drugs, including some antineoplastics, damage cells and induce apoptosis by provoking ROS (reactive oxygen species) formation: explain what is meant by ROS and give an example of a drug that is toxic through this mechanism.
ROS are the free redicals and very small molecules containing oxygen ions and peroxide May be organic or inorganic. Presence of unpaired valance electrons shell makes ROS Highly reactive.
Harmful effect of ROS:
- DNA damage
- Amino acid oxidation
EXAMPLE OF DRUG PRODUCING ROS:
- Antiviral drug (zidovudine,lamivudine.acyclovir)
Question 9) Gentronix is a company which develops in vitro toxicity tests for drugs. One of these, based on a “GFP reporter gene” and the yeast RAD54 gene, detects genotoxicity. Explain this system. (Gentronix have a web-site, and a relevant paper is: J. van Gompel et al., (2005). An assessment of the utility of the yeast GreenScreen in pharmaceutical screening. Mutagenesis 20: 449-454.
Answer 9) Reporter system in the yeast cell combines
Inducible promoter of RAD 54 gene
Extremely stable green fluorescent protein(GSP)
Induction of RAD54 promotes due to DNA damage
Results in increasing fluorescent cells.
Above process is called Green screening assay.
Question 5) Give an example of how proteomics has been used to identify a biomarker of toxicity.
SELDI TOF ( Surface Enhance Laser Desorption Ionization Time Of Flight) is the method , Which is use for the cancer specific biomarker identification and proteomic pattern in the Tissue and body fluid. By this method we can measure the level of serum prostate specific membrane antigen which is very high in the prostate cancer patient. Than in those with benign cancer disease.
Question 6) Give an example of how metabolomics has been used to identify a biomarker of toxicity.
Example: metabonomics method were used on a compound which is known for causing Hepatotoxicity in many species. This method is used in preclinical study.the drug is given To a patient most of the drugs are excreted from the urine. alteration in urinary level Shows that dosed group is liberated from the control group with deviation of tricarboxylic Acid cycle intermediates with the appearance of medium chain carboxylic acid.if we doing in Vitro experiments with this compound it causes defective metabolish of fatty acids.
Question 4) Give an example of how genomics has been used to identify a biomarker of toxicity.
Biomarker is very important tool for the detection of cancer. Several methods can be used for the identification of biomarker of toxicity like
- Multi dimentional identification technology
Poynton discovered specific biomarkers of exposure inducing two probable metalothin Ion and serritin M RNA.
- Bowen, R. (2003) Free redicals and reactive oxygen, http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/redicals.html , Date accessed 20/11/2009.
- Dr.walsh, K. and Dr. walmsley, R. (2004) Genotoxicity assessment of drug
Candidates using yeast cells, http://www.gentronix.co.uk/portals/0/literature/articles/Drug Plus International.pdf , Date accessed 20/11/2009.
- Racechel , B. (2006) clinical paediatric emergency, 17:186-193.
- Renger , N. and Erik , N. (2005) the lancent infectious desease , 5:115-119.
- Robertson , R. (2004) NIH summit workshop on predictive drug toxicology, http://nihroadmap.nih.gov/molecularlibraries/WorkshopSummary-PredictiveToxicology-0604.pdf , Date accessed 21/11/2009.
- Tripathi , k. (2005) drug interaction , New Delhi, jaypee Brothers medical Publishers (p) ltd. , 1st edition .
- Wetmore , A. and Merrick , B. (2004) toticol pathol , 32:619.
- Wulfkuhle , J. and Petricoin , E. (2003) proteomic applications for the early detection of cancer , http://home.ccr.cancer.gov/ncifdaproteomics/pdf/nrc_early_detection.pdf Date accessed 21/11/2009.