Flashcards in PRG - New Drug Targets 1 Deck (17):
Choice of therapeutic targets --> depends on condition/ disease you're looking at.
Need to consider:
1. What disease are you targeting
2. Prevention, cure or alleviation of symptoms
3. Duration of disease
What is a disease?
An abnormal condition of a part, organ or system of an organism resulting from various causes such as infection, inflammation, environmental factors or genetic defect and characterised by an identifiable group of signs, symptoms or both.
A condition or tendency, as of society, regarded as abnormal or harmful.
Define disease mongering.
Widening the diagnostic boundaries of disease.
1. Normal human experiences are abnormal and in need of treatment
2. Exaggerate treatment benefits
3. Dubious clinical endpoint
4. Defining cause = ambiguous deficiency
(It is a term used for the practice of widening the diagnostic boundaries of illness, and promote public awareness, in order to expand the markets for those who sell and deliver treatments.
State the inverse benefit law.
Drug benefit: drug risk ratio is inversely proportional to marketing effort
Explain the inverse benefit law.
The inverse benefit law states that the ratio of benefits to harm amongst patients taking new drugs tends to vary inversely with how extensively a drug is marketed.
A drug effective for a serious disorder is less and less effective as it is promoted for milder cases and for other conditions for which the drug was not approved. As effectiveness becomes more diluted, the risks of harmful side effects profile rate, this the benefit: risk ratio worsens as a drug is marketed more widely. The law highlights the need for comparative effectiveness research and other reforms to improve evidence-based prescribing.
Outline the state of affairs.
The inverse benefit law is manifested through 6 basic marketing strategies.
1. Reducing diagnostic thresholds
2. Exaggerating safety
3. Exaggerating efficacy
4. Surrogate endpoints
5. Creating new diseases
6. Encouraging unapproved uses
What are the reasons for failure of compounds in development? And give their relative %
Poor biopharmaceutical properties - 39%
Lack of efficacy - 29%
Toxicity issues - 21%
Marketing - 6%
The principle aim of therapeutic intervention is to...
Alleviate the condition of the individual patient - either by approaching the symptoms or the underlying cause of those symptoms.
Pharmacoeconomics quantifies disease-related impact and therapeutic benefit in economic terms (the value of one drug over another)
Pharmacoepidemiology assesses the impact of the disease and therapy for the population as a whole (it is the study of the uses and effects of drugs in well defined populations)
Define orphan receptor.
A receptor for which the endogenous ligand is unknown.
What are some things that molecular biology, in vitro studies and computer technology cannot do?
- Integrated response (from molecule to man)
- Determine the therapeutic index
- Determine the pharmacokinetics
- Reveal the unexpected --> secondary actions, selectivity
- Assess safety + toxicology
- Assess the importance of multiple mediators
- Set clinical dose range
Difference between traditional and modern drug discovery.
Traditional drug discovery resulted in the pharmaceutical industry investing in decades and millions of pounds developing 'novel chemical entities' for which no disease state exists i.e. no therapeutic indication. Many marketed drugs were discovered by serendipity.
Modern drug discovery now often begins with screening massive compound libraries (old compounds), 'in silico', or using a high-throughput screen (cell-based/ ligand binding)
Why choose receptors as therapeutic targets? What about genetic material of cells?
New genes can be introduced, typically via a modified virus (vector), to replace missing or dysfunction genes, either inherited or acquired.
The genes are not replicated and passed on when the cell replicates, hence the treatment is TEMPORARY.
1. Can introduce new gene into CHROMOSOME using retroviral vectors. This treatment is designed to alter gene expression permanently. Some early success but problems with vectors, duration of action and adverse effects.
2. ANTISENSE DNA can be used to block mRNA and therefore expression of specific proteins. The effects are only present when the antisense DNA is present.
Explain analysis of pathophysiology.
First you need to understand the pathway leading form the primary disturbance to the appearance of the disease. Identify the biochemical steps amenable to therapeutic intervention and select key molecules as targets e.g. HTN and renin angiotensin system.
Explain analysis of MOA of existing drugs.
First you need to understand the MOA of clinically effective drugs. Identify the key molecular targets and design novel analogues e.g. Depression and monoamine transporters.