Summary Class notes - Drug development

Course
- Drug development
- Meerdere
- 2016 - 2017
- Rijksuniversiteit Groningen (Rijksuniversiteit Groningen, Groningen)
- Medical Pharmaceutical Sciences
335 Flashcards & Notes
1 Students
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Summary - Class notes - Drug development

  • 1473026400 Introduction of the course

  • What is the definition of a drug?
    A drug can be defined as any chemical substance that can be used in the medical diagnosis, cure, treatment or prevention of the disease. 

    A drug is a compound with a pharmacological activity:
    - It influences processes in the body
    - A receptor is most of the time involved
    - adverse effects are often related to the main effect
  • What is the drug development triangle?
    It has 3 points: Disease, drug and human. 
    1: The disease pathology  goes from Disease to Human.
    2:  The repair/ defense mechanisms go from Human to Disease
    3: The mechanism of drug action goes from Disease to Drug
    4: The drug resistance / inactivation goes from Drug to Disease 
    5: The pharmacokinetics go from Human to Drug  
    6: The Toxicity go from Drug to Human
  • What kind of knowledge requires the Drug development?
    - Normal behavior of the human body
    - Basic mechanisms leading to the disease
    - Molecular players involved in disease progression
    - Chemistry/ construction of drugs

    chemistry, mathematics, physics, cell biology, molecular biology, pathology
  • What are the phases in the drug development?
    Firstly, there are two main phases; the preclinical and the clinical phase. 
    - The preclinical phase can be divided into the drug discovery phase and the preclinical development phase.
    -  The clinical phase can be diveded into  phase 1, 2 and 3.
    - After those phases a phase 4 exist that is focused on the post marketing surveillance.
  • What is the length of all phases?
    Preclinical = 2-4 years
    regulatory review= 2-6 months
    Clinical: 3-4 years
    Regulatory review 1-3 years
    In total it can take 10-13 years
  • Which instances are involved in the first stage of the drug development? (drug discovery)
    - Pathology, pathophysiology, pharmacochemistry, High throughput screening, molecular modeling, pharmacodynamics.
  • Which instances are involved in the second stage of the drug development? (Preclinical development)
    Drug targeting, Pharmaceutical phase, Pharmacokinetics (ADME). In vitro  versus  in vivo toxicology.
  • The clinical phase consist of ..
    phase 1: clinical trials with healthy volunteers (or in patients in case of severe adverse side effects). But also long term toxicology studies in animals and formulation research
    phase 2:  small scale trials in patients to assess the efficacy and the dosage. But also long term toxicology studies in animals and formulation research. 
    phase 3: Large-scale controlled clinical trials but also long-term toxicology studies in animals and formulation research.  
    phase 4: post marketing surveillance. (officially, it does not belong to the clinical phase)
  • What was Vioxx?
    It was released in 1999 as a very selective COX-2 inhibitor. COX enzymes block the production of prostaglandines. That means that the angiogenesis, apoptosis, platelet function, vascular reactivity, the invasiveness and the inflammation processes are also blocked. COX-1 has a protective function in the stomach but COX-2 is not present in the stomach. Therefore Vioxx (Rofecoxib) was developed because it had no effect on the stomach. Furthermore COX-2 inhibition also inhibits cancer. 
    Although the perspectives looked very good, a complete COX-2 inhibition seemed also to lead to a higher risk of heart and brain infarcts. So Vioxx started als a blockbuster and ended up as a disaster.
  • How goes the softenon story?
    Softenon/Thalidomide has sedative effects and in the 50ths and 60ths many pregnant women used the medicine as during the first three months of their pregnancy.  During these three months the limbs of the baby were formed and the drug very badly involved this process. As a result  there were many baby's with abnormal limbs.Although in humans the drug seemed to be toxic in rats it was not. So this story learned us that extrapolation from animal to human is not always possible.
  • So an understanding of the mechanisms of the action of the drug can lead to application of old drugs for new diseases.
  • In the beginning of the human population pains were solved with natural products. Religeous aspects were coupled to those natural products. Later people said that those aspects were unnecessary. One should take an other formulation. In the 20th century one received antibiotics for all kind of things. Now we think that is artificial so we should come back to the natural products.
  • Who was Paracelsus?
    He lived in the 15th century as a physician, alchemist, astrologer and general occultist. 

    He said that All things are poison and nothing is without poison, only the dose permits something not to be poisonous. 

    Nowadays we know that the exposure makes that something is not poisonous instead of the dose.
  • The foxglove Digitalis purpurea was one of the twenty herbs used in a folk remedy to treat dropsy ( as swelling of soft tissues) in the 17th century in England. Nowadays it is still used to treat heart failures. 
    Paracelsus found out that signs in herbs reveal their medicinal use. Before him it was all about trial and error.
  • Referend Edward Stone who lived in the 1760 found that the bark of the willow was effective in reducing fever. 
    Nowadays we know that this bark contains salicyl that can become metabolised to the active compound salicylic acid.
  • In 1897 Felix Hoffman (Chemist) synthesized the drug acetylsalicylic acid and he founded the company Bayer. It became a blockbuster.
  • Who came up with the receptor idea?
    Paul ehrlich. Agents do not act unless they are bound. 
    He got the Nobel prize for medicine in 1908.  
    The first synthetic medicine was sythesized in 1910 and it was called salvarsan and it contained arsenic!
  • Who was Domagk?
    He worked at Bayer and (originally this was a dye company) and discovered the sulfonamides like sulfanilamide.
  • Who discoverend the penicillin?
    Alexander Flemming in 1929. Penicillins are beta lactam antibiotics that act as suicide substrates for peptidoglycan transpeptidases involved in crosslinking the bacteria wall. 

    Later in 1939 Florey, Chain in Oxford worked on it and demonstrated its in vivo efficacy.

    After this many persons worked on it to scale the production process. From the 1940 it was available.
    Renal clearance was used to get more penicillin.
  • How went the extraction of insulin?
    In 1921 Banting, Bestand Collip worked on the fetal calf pancreas and came with isletin what we now know as insulin. 
    In December of that year Macleod invited Collip and within a month it was ready to become clinical tested. 
    In january 1922 a 14 year old boy was suffering from diabetes and was the first one tested with insulin. However he developed a severe allergic reaction and further treatment was cancelled.
    Over the next 12 days Collip worked day and night on it and on the 23th of that month a second dose was given that completely eliminated the sigh of diabetes.
  • extraction of insulin (2)
    In the spring of 1922 Best managed to scale the insulin production in such a way that it could be extracted on demand. 
    The drug firm Eli Lilly helped and made a breakthrough and were able to produce large quantities of highly purified insulin. Insulin was offered for sale shortly thereafter.
  • How went the production of insuline?
    In the 1950's, the amino acid structure of insulin was established. 
    In 1977 the first genetically engineered human insulin was produced in a laboratory
    In 1982 the first genetic (human) produced insulin was sold under the brand name Humulin.
  • During the years many little companies fused with others to become bigger companies. For example the company Pfizer.
  • The FDA was founded in the early 1900. It approves all drugs in the US.
    The EMA is a comparable instance in Europa and the CBG in the Netherlands.
  • What is the Sulfanilamide tragedy?
    Around 1937, sulfanilamide was only available in pill form and therefore not that suitable for children. Therefore it was put into a potion and contained Diethyle glycol (DEG). This made the drug become lethal. More than 100 people died. Since that also the adjuvants are tested.
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What is the profile for a ideal covalent inhibitor?
- fast irreversible binding to target
- target should have a long t1/2 in vivo.
 -rapid clearance to minimize off-target interactions (both covalent and non-covalent)
- reduce non-mechanism-based toxicity
What are benefits of covalent inhibitors?
- there is a prolonged duration of a drug action on the target.
- Target inhibition persists after the drug has been cleared.
- less frequent dosing and lower drug doses.
What is a problem with penicillin?
Resistence due to an upregulation of beta-lactamases that can deactivate beta lactam antibiotics.
What are side effects of aspirin?
- stomach ulcers
- stomach bleeding
- worsening asthma
It is due to an irreversible inactivation of COX
What are examples of irreversible covalent drugs?
- Finasteride
- Neratinib
What are examples of reversible covalent drugs?
- Bortezomib
- Dimethyl fumarate
- Telprevir, Boceprevir
- Rivastigmine
What kind of classes of electrophiles in small molecules do we have?
- halides
- acrylamides
- subst. acrylamide
- vinyl sulfones
- beta lactame
- beta lactone
- epoxide
- nitrile
- disufite
What biological amino acids are nucleophiles?
cysteine (is the best)
lysine
Serine
Threonine
Tyrosine
What is the chemistry of covalent bonding?
It is a bond between an electrophile and a nucleophile.
What are some historical examples of approved covalent drugs?
- aspirin
- Penicilin
- cephalosporin C
- Fosfomycin
- Lansoprazole
- omeprazole
- clopidogrel