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cellular parasitology > Vl 2 - drug discovery > Flashcards

Vl 2 - drug discovery Flashcards

1
Q

African sleeping sickness: pathogen ,vector, symptoms

A
  • trypanosoma brucei
  • Vector: Tsetseflies
  • Initial symptoms: fever, headaches, joint pains, and itching, swollen lymph nodes
  • disruption of sleep-cycle, confusion, tremor, paralysis
    ⇒ fatal within months
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2
Q

River Blindness: Pathogen, vector, symptoms

A
  • Onchocerca volvulus
  • Vector: blackflies
  • Motile male
  • female worms produce 100s of microfilariae/ day
  • Chronic papules, depigmentation, skinatropy, glaucoma, blindness
  • O. volvulus depends on symbiotic Wolbachia
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3
Q

Suramin

A
  • Highly toxic against cells

- Mode of action unknown (NADH, P2 receptors)(epigenetic influence against antigen variation?)

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4
Q

Leishmaniasis: pathogen, vector, symptoms

A
  • leishmania spp.
  • vector: sandfly
  • invades macrophages
  • fever, weight loss, fatigue, anemia, and substantial swelling of the liver and spleen
  • Fatal if untreated
  • Chronic
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5
Q

Pentavalent Antimonials

A
  • pentavalent antimony compound urea stibamine and sodium stibogluconate
  • Active and still recommended against visceral Leishmaniasis
  • Intramuscular injection
  • Strong side-effects: pot. fatal cardial arrythmia, increased mortality in HIV patients
  • Threatened by resistance in India
  • Mode of action unclear: via toxic trivalent Sb or complexation with ribose-derivatives
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6
Q

Babesiosis: pathogen, vector, symptoms

A
  • Babesia spp.
  • vector: ticks
  • infects red blood cells ⇒ haemolysis, fever, weight loss
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7
Q

Pentamidine

A
  • against african sleeping sickness, leishmaniasis, babesiosis
  • mild side-effects
  • Threatened by resistance
  • Needs to be injected/inhaled, does not cross blood brain barrier
  • Mode of action unclear, involves crosslinking adenines and inhibition of topoisomerases
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8
Q

Pyrimethamine

A
  • against Malaria (but extensive resistance)
  • Active against Toxoplasma gondii
  • Clear mode of action, anti-folate, DHFR-TS
  • Use in research as a selection marker
  • Serious side effects
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9
Q

Ivermectin

A
  • active against: head lice, scabies, river blindness, strongyloidiasis, trichuriasis, and lymphatic filariasis
  • mode of action clear: binds glutamate-gated chloride channel
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10
Q

why are parasitic diseases often neglected?

A
  • drug component development often too expensive to be worth it for companies
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11
Q

2 diseases (and their pathogens) which can be treated with suramin

A
  • sleeping sickness: t.brucei (vector: tsetse fly)

- river blindness: Onchocerca volvulus (vector:black fly)

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12
Q

what does the pathogenicy of o. volvulus depend on?

A
  • symbiotic wolbachia bacteria
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13
Q

how can sleeping sickness and river blindness be treated?

A

Suramin

  • highly toxic, mechanism unknown (inhibits epigenetic machinery?), NADH and P2-receptors involved
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14
Q

how can Leishmania be treated? mechanism?

A

sodium stibogluconate

  • vs visceral leishmaniosis, strong side effects (potenial heart arrythmia)
  • mode of action unknown: via toxic trivalent Sb or complexation with ribose-derivatives.
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15
Q

how are leishmaniosis, trypanosomiasis and babesiosis treated?

A
  • Pentamidin: mild side effects, mode of action unknown
  • involves cross linking adenines and inhibition of topoisomerases.
  • resistances in babesiosis
  • in trypanosoma only effective if not in neurological tissues (e.g. central nervous system)
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16
Q

what kind of malaria is caused by p. falciparum? how was it first treated? mechanism?

A

Malaria tropica

  • Quinine: basis of Chloroquine. Isolated from cinchona bark. vs Babesia and Plasmodium
  • mechanism: presumably disrupts hemoglobin metabolism by interfering with heme detoxification by hemozoin crystals.
  • Chloroquine: 1st blockbuster drug vs Plasmodium -> massive side effects (damage of vision, muscles, low rbc levels) -> extensive resistances developed
17
Q

which cells are attacked by toxoplasma? how many humans are affected worldwide?

A
  • all cells with a nucleus in warm blooded animals

~1/3 of humanity permanently infected

18
Q

how is toxoplasma treated? what was the drug used for previously?

A

Pyrimethamin
- exact mode of action unknown: antifolat, dihydrofolatreduktase enzyme inhibition, strong side effects

  • previously used vs malaria, but extensive resistances developed
19
Q

2 anti parasite drugs with known mechanisms

A

Pyrimethamin and Ivermectin

  • Pyrimethamin: exact mode of action unknown: antifolat, dihydrofolatreduktase enzyme inhibition. strong side effects
  • Ivermectin: vs river blindness and lymphatic filiariose
  • binds glutamate-gated chloride channel
20
Q

process of drug development? costs for a new drug?

A

Stage 1: Drug discovery (~ 10000 components tested).

Stage 2: pre-clinic development (250 components).

Stage 3: clinic development (5 components):

Phase 0: effect in the body

Phase I: safety in humans

Phase II: efficacy of disease treatment (what barriers can the drug pass?)

Phase III: large scale safety and efficacy?

Phase IV: long term safety

regulatory approval

whole process costs ~0,7-2,7 billion US-dollars per drug

21
Q

typical approaches to drug development? exsample

A
  • Target-based approach:
    Essential genes ⇒ Structure-guided inhibitor design ⇒
    in vitro SAR optimization ⇒ Cell-based tests ⇒ Animal and clinical studies ⇒ approval
    BUT: Very high drop-out rates, Expensive
  • Phenotypic screen-based approach:
    Screen for parasiticial hits ⇒ hit-to-lead optimization ⇒
    Further animal and clinical studies ⇒ approval
    BUT: inefficient optimisation and high toxicity
22
Q

what drug us suited to treat which disease/eradicate which parasite?

A
  • Suramin: river blindness and african sleeping sickness
  • Ivermectin: river blindness and
    lymphatic filariosis
  • pentavalent antimonials ⇒ today Sodium stibogluconate: leishmaniosis
  • Pentamidin: leishmaniosis, sleeping sickness and babesiosis
  • Quinine: malaria, babesiosis
  • Pyrimethamin: toxoplasmosis, (previously Malaria)

cellular parasitology (10 decks)

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