Drug Development Process Lecture II

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    • Natural Products: the earliest medicines
    • – Plants, plant parts, plant extracts, herbs (the first drugs)
    • • Foxglove (Digitalis purpurea) → digitalis
    • • Pacific yew (Taxus baccata) → taxol
    • • Asian poppy (Papaver somniferum) → opium → morphine
    • • Quinine tree (Cinchoma pubescens) → quinine
    • • Nightshade (Atropa belladonna) → atropine
    • • Common willow tree (Salix alba) bark & leaf → salicylic acid → acetyl salicylicacid → aspirin
    • Natural Elements
    • – Sulfur
    • – Platinum
    • Biologicals
    • – Vaccines (not drugs in the true sense)
    • – Immune sera / Immune globulins
    • – Antitoxins & antivenins
    • – Natural or recombinant DNA derived (~125 currently marketed; >400 indevelopment)
    • • Interferons
    • • Monoclonal antibodies: Herceptin®
    • • Hormones / Enzymes
    • – Insulin (Humulin®) Pulmozyme®
    • – hGh (Nutropin®) Activase® (TPA)
    • – Many in development
    • Fermentations / Secondary Metabolites
    • – Penicillin
    • – Streptomycin
    • – Gentamicin
    • – Other antibiotics / antibacterials
    • Chemical Synthetics/Chemotherapeutics
    • – Chemically synthesized inorganic / organic molecules
    • – Modified chemical entities
    • – New chemical entities (NCEs)
    • – NCE derived from SAR optimization
    • – Many currently used drugs (e.g., antiretrovirals)
    • Safe (minimal side effects / toxicity)
    • – No drug is absolutely safe
    • • Efficacious (“the drug works”)
    • Therapeutic Window
    •     Efficacy---- Toxicity
    • Selectivity / Specificity
    • – E.g., cancer chemotherapies
    • Desirable Pharmacokinetic (ADME) Properties
    • – Absorption / Distribution / Metabolism / Excretion
    • – Route
    • – Plasma level
    • – Dosages per day
    • – “Hit and Run” Concept
    • Pharmacoeconomics
    • – Cost of drug in balance with target disease
    •       - E.g., common cold vs. genital herpes           vs. malignant melanoma
    • Drug “Manufacturable”
    • – Scale up manufacturing feasible
  3. MOA
    Mechanism of Action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there.

    Drugs that do not bind to receptors produce their corresponding therapeutic effect by simply interacting with chemical or physical properties in the body. Common examples of drugs that utilize this method are antacids and laxatives.

    For example, the mechanism of action of aspirin involves irreversible inhibition of the enzyme cyclooxygenase, therefore suppressing the production of prostaglandins and thromboxanes, thereby reducing pain and inflammation.

    However, some drug mechanisms of action are still unknown. For example, phenytoin is used to treat symptoms of epileptic seizures, but the mechanism by which this is achieved is still unknown, despite the fact that the drug has been in use for many years
  4. Cytotoxicity
    Cytotoxicity is the quality of being toxic to cells.

    Treating cells with the cytotoxic compound can result in a variety of cell fates. The cells may undergo necrosis, in which they lose membrane integrity and die rapidly as a result of cell lysis. The cells can stop actively growing and dividing (a decrease in cell viability), or the cells can activate a genetic program of controlled cell death (apoptosis).Cells undergoing necrosis typically exhibit rapid swelling, lose membrane integrity, shut down metabolism and release their contents into the environment.

    Cytotoxicity assays are widely used by the pharmaceutical industry to screen for cytotoxicity in compound libraries. Researchers can either look for cytotoxic compounds, if they are interested in developing a therapeutic that targets rapidly dividing cancer cells, for instance; or they can screen "hits" from initial high-throughput drug screens for unwanted cytotoxic effects before investing in their development as a pharmaceutical.

    Assessing cell membrane integrity is one of the most common ways to measure cell viability and cytotoxic effects. Compounds that have cytotoxic effects often compromise cell membrane integrity.
  5. GLP
    Good Laboratory Practice (GLP)standards
  6. PDUFA
    Prescription Drug User Fee Act (PDUFA I, II, III, & IV): Sponsors pay drug application fee ($1,958,800 for 2013).

    Objective: to speed up review/approval process of NDA
  7. public clinical trial registry
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Drug Development Process Lecture II
Drug Development Process
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