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Pharmacology > Serendipity in the age of rational drug design: a case study > Flashcards

Serendipity in the age of rational drug design: a case study Flashcards

1
Q

Pharmacology/Toxicology is ….?
-> Definition

A
  • the discipline dealing with the interactions of drugs and humans
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2
Q

Walter Schweckendiek

A

Assuming a defect in the citrate cycle as the cause of his own psoriasis Walter Schweckendiek, a German chemist, treated himself with large doses of succinic acid. When this first attempt was ineffective, he turned to the next metabolite in the cycle, fumaric acid, and experienced a ‘cure’ from his disease as he reported in 1959. To improve the gastrointestinal tolerance of fumaric acid he later used esters of fumaric acid. Although Schweckendiek published his own case report in a well-known German medical journal, his discovery first remained largely unrecognized by the academic medical community and spread mainly among alternative practioners.

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3
Q

Marketing of Dimethylfumarate
-> Hans-Peter Strebel

A

Hans-Peter Strebel was pharmacist in Muri (AG), a small Swiss village. He learnt about a drug prescribed by a non-medical practitioner and analyzed its ingredients, one being dimethyl fumarate. Based on this, in 1983 he founded the company Fumapharm that marketed dimethyl fumarate as Fumaderm.
Fumaderm received market authorisation for Germany in 1994.

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4
Q

Multicenter double blind study: Inclusion and exclusion criteria

A
  • Inclusion criteria:
    – 100 patients of both sexes, age 18 – 70 years
    – Diagnosis of psoriasis for > 2 years only insufficiently responsive to external therapy
    – > 10% of body surface was involved
    – Topical antipsoriatic drugs had to be withdrawn at least 2 weeks before the study (with the exception of oitments and bath oils)
  • Exclusion criteria:
    – No pregnant women (contraception was required)
    – Disorders of kidney, liver, heart, gastrointestinal tract, blood
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5
Q

Study design: Randomized controlled trial (RCT)

A
  • Randomisation: Allocation to treatment arm is by chance
  • Placebo controlled: all patients are treated but not each drug contains the active compound
  • Double blind: neither patients nor study team know to which group patients have been allocated
  • Multicenter: Bochum, Dortmund, Krefeld, Bonn, Dresden, Zürich
  • Prespecified treatment, evaluation, and statistical analysis: Psoriasis Area and Severity Index as primary outcome parameter,
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6
Q

Phytotherapy -> caffeine

A

Discovery of caffeine:
- Caffeine
- Theophylline

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7
Q

Phytotherapy -> Atropy belladonna

A

Big eyes through Atropa belladonna -> atropine

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8
Q

Phytotherapy -> poisining with curare

A
  • Strychnos toxifera
  • Alexander von Humboldt
  • Tubocurarin
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9
Q

Nobel prize 2015 for discovery of anti-malaria drug artemisinin

A
  • Tu YouYou, Chinese pharmacologist
  • Artemisia annua
  • Artemisinin
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10
Q

Plant metabolites led to the discovery of drugs

A

Plant -> Extract -> Modern drug -> Disorder/Purpose

Papaver somniferum -> Opium -> Morphin -> Pain
Strychnos toxifera -> Curare -> Vecuronium -> Muscle relaxation
Cannabis sativa -> Haschisch, Marihuana -> Dronabinol (delta9-Tetrahydrocannabinol) -> Nausea
Coffee arabica -> Coffee -> Thephyllin -> Asthma bronchiale
Artemisia annua -> -> Artemisinin -> Malaria
Atropa belladona -> -> Atropin -> Bradycardia
Digitalis purpurea (Foxglove) -> -> Digitoxin -> Heart failure
Laburnum anagyroides -> -> Varenicline -> Nicotine dependency
Colchicum autumnale -> -> Vincristin -> Lymphoma
Taxus brevifolia -> Taxol -> Paclitaxel -> Mamma carcinoma and other cancers

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11
Q

Secondary metabolites in plants

A

Evolutionary significance:
- Transmitter or hormone
- Defense

Poppy

  • Morphin
  • Kodein
  • Thebain
  • Noscapin
  • Papaverin
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12
Q

Phytotherapy -> definition

A

In physiotherapy non-purified plant extracts instead of purified compounds are used

Non-purified plant extracts
- are difficult to standardize
- are associated with side effects due to other ingredients in the extract

Plant extracts are not first choice for pharmacotherapy.

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13
Q

Purification of the active ingredient

A

1806 Friedrich Sertürner isolated morphin as the main alkaloid of Papaver somniferum

Morphin is used as analgesic drug for tumor-associated pain and other severe pain syndroms

Administration: p. o., i. m., s. c., i. v.

Side effects: Obstipation, suppression of respiration, nausea, tolerance

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14
Q

Toxicology of dimethyl fumarate
-> Phocomelia induced by thalidomide

A
  • 2,800 children affected in Germany in the 1960s
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15
Q

Preclinical testing for teratogenic effects

A
  • Embryotoxicity studies
    – Compound is repeatedly administered during pregnancy; from day 6 till day 15 (in mice and rats); investigation in two species (e.g., mice and rabbits)
    – The highest dose used should be mildly toxic in the mother
    – Caesarean sectio to prevent mothers from eating malformed litter
    – Investigation of litter for malformations
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16
Q

Preclinical testing of dimethyl fumarate I

A
  • Femalepregnantrats (25 rats per dose group) were treated with doses of 0, 25, 100, 250 mg/kg body weight
  • Femalepregnant rabbits (20 rabbits per dose group) were treated with doses of 0, 25, 75 and 150 mg/kg body weight
  • Drug was administered by gavage.
  • Treatment during the period of organogenesis.
  • Maternal animals were observed for clinical signs.
  • Laparahysterectomy
  • Fetuses were investigated for malformations
17
Q

Preclinical testing of dimethyl fumarate II
-> Rat tests

A
  • Rat study to assess postnatal development of offspring
  • Rat study to assess fertility of male and female animals
  • Rat study for juvenile toxicology study: rats were treated from day P28 till day P93 and were assessed for behavior, fertility and morphological changes
18
Q

Preclinical testing of dimethyl fumarate III

A
  • Carcinogenicity studies in mice and rats
  • Toxicology studies in mice, rats, dogs and monkeys
19
Q

Phases of drug development
-> Phase I

A
  • first in human
  • 10 - 100 participants
  • usually healthy volunteers, occasionally patients with advanced or rare diseases
  • open label
  • safety and tolerability
  • months - 1 year
  • 10 million €
  • success rate 50 %
20
Q

Phases of drug development
-> Phase II

A
  • first in patient
  • 50 - 500 patients
  • patient-subjects receiving experimental drug
  • randomized and (placebo-) controlled, may be blinded
  • efficacy and dose ranging
  • 1 - 2 years
  • 20 million €
  • Success rate 30 %
21
Q

Phases of drug development
-> Phase III

A
  • Multi-site trial
  • a few hundreds to a few thousand patients
  • patient-subject receiving experimental drug
  • randomized and (placebo-) controlled or uncontrolled, may be blinded
  • confirm efficacy in larger population
  • 3 - 5 years
  • 50 - 100 million €
  • success rate 25 - 50 %
22
Q

Phases of drug development
-> Phase III

A
  • Post-marketing surveillance
  • many thousands of participants
  • patient in treatment with approved drug
  • open label
  • adverse events, compliance, drug-drug interactions
  • no fixed duration
23
Q

Risks of first-in-man studies
-> TGN1412

A
  • Anti-CD28 monoclonal antibody
  • CD28 is an accessory protein of the immunological synapse
  • 2006 in a phase I-study subjects received low doses of TGN1412 (0.1 mg/kg, 1/500 of the dose that had no adverse effects in animals)
  • Six subjects developed a capillary leak syndrome with multi-organ failure because of a cytokine storm
24
Q

Progressive multifocal leukoencephalopathy

A
  • About 250 cases have been observed with natalizumb
  • Mortality: 20%
  • Risks increase with preceding immunosuppression, duration of drug treatment, and JC virus infection
  • So far only a few cases with dimethyl fumarate
25
Q

Experimentelle autoimmune Enzephalomyelitis zeigt die Bedeutung der peripheren Immunstimulation

A
  • 1:1 MOG peptide 2mg/mL and Complete Freund’s adjuvant
    -> Emulsion preparation
    -> Subcutaneous injection: 2x100 µL emulsion on the front side near axillary lymph nodes and 200 ng percussion toxin (i.p.)
    -> dpi 0: Immunization with MOG
    -> 1st PTX injection
    -> dpi2: 2nd PTX injection
    -> dpi16: FACS analysis
    -> dpi28: Histology
26
Q

Dimethyl fumarate

A
  • is effective in EAE
  • is converted into mono methyl fumarate
  • Nrf2 mediates the effects of dimethyl fumarate
  • Diemethyl fumarate is neuroprotective
  • Monomethylfumarat (MMF) - an agonist of the HCA2 receptor
  • neutrophile Granulozyten sind Zielzelle
27
Q

HCA2 receptor

A

Corpora not Abgunst nice fixata

How many targets mediate drug effects?
- Genes: 29.679 (ENSEMBL data bank)
- Drug targets: 667 human, 189 microbial
- Drugs: 1.578
- Medicinal products: >21.000 are approved by the FDA

  • mediates the effect of nicotinic acid on adipocytes
  • in EAE DMF protects by activating HCA2
  • DMF reduces inflammation in EAE
  • Flushing is mediated by HCA2 activation
28
Q

Which targets are druggable?

A

Polypharmacology: on average one drug has two targets; usually kinase inhibitors have many targets

29
Q

Consequences from preclinical pharmacology
-> DRF and DMF

A
  • Diroximel fumarate is converted into monmethyl fumarate in the gut

Better gastrointestinal tolerability?

30
Q

Summary -> Fumarate

A
  • Dimethylfumarateisaprodrug;theactive metabolite is monomethyl fumarate
  • Mode of action:
    – Covalent binding to Keap1 → Activation of NRF2
    – MMF is an agonist of HCA2-receptors on neutrophil granulocytes and macrophages → reduced immune cell infiltration
  • Monomethyl fumarate has a short half-life of 1.5 h
  • Side effects: Gastrointestinal disorder,flush, lymphopenia, PML
31
Q

Nomenclature of drugs

A
  • Chemical name: 4‘-Hydroxyacetanilide
  • International nonproprietary name (INN, generic name): paracetamol = acetaminophen
  • Tradename: Benuron® tablets, Captin® and 40 others
32
Q

Pharmacology Funding

A
  • DFG
  • BMBF
  • European Union
  • Investigator initiated trials funded by the pharmaceutical industry

Pharmacology (22 decks)

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