Parasitology test 1 lecture 3 Flashcards


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1

malaria chemotherapy

...

2

gates malaria funding

from online: development of a malaria vaccine, new drugs, and innovative mosquito control methods to help defeat malaria

they donate money for this

3

IPTi for malaria control

  • intervention preventive treatment for infants (IPTi)
  • gates foundation recommends + funds it
  • giving normal children in malaria endemic areas Fansidar
    • at 2, 3, and 9 months when they receive their normal vaccines
    • bad bc possible for SJS to devel
      • steven johnson syndrome
    • fansidar also bad bc drug resistance
    • clearly needed new drugs

4

malaria control through diet

  • Vitamin E level decreased
    • vitamin E stabilize many membranes
    • decreased vitamin E so membrane cannot protect parasites
  • polyunsaturated fatty acids
    • fish oil / omega-3 fatty acids: replaced fats in diet
    • = free radical forms = lipid peroxidation damages parasite membranes = death of parasites
    • = these are good for treating malaria

5

experiment: treated malarial infected mice w/ omega-3 fatty acids

good results

6

tried with other fatty acids (coconut oil, palm oil, etc.) but these are not good for you

all mice died

  • bad oils
  • parasite grew + killed the host

7

RANE LAB

  • started at U of michigan in 1960 to test antimalarial drugs sponsored by the ARMY
  • > 300k compounds have been checked for antimalarial activity in mice
  • 2 diff test systems
    • blood schizonticidal test
    • liver schizonticidal test
      • tested many drugs against this stage

8

blood schizonticidal test

  • Thompson test
  • how tests of many drugs are done
  • mice injected day 0
  • bled + collected parasites
  • treat w/ drugs on days 3, 4, 5
  • day 6 make blood film
  • follow mice for 30 days, then 60 days
  • did blood films on mice 2x per week
  • Blood films on day 6 and biweekly then for 31 days
  • mice w/ drugs that did NOT work, died day 9/10

9

measure activity in Thompson Test

measured suppression of parasites basically

  • found level SD90 on day 6
  • considered cures - mice day 31 negative blood film
  • problem: mice not actually cured, even tho day 31 doesnt show parasites
    • millions of cells unchecked
    • same problem with humans
  • increased survival compared with controls and other mice by mean survival time
  • comparison of parasitemias at weekly intervals after controls die on days 8-12

10

liver schizonticidal test

  • sporozoite induced test
  • give drugs 1x a day for 3 days (-1, 0, +1)
  • inject IV on sporozoites day 0 4 hrs after giving drug
  • blood films days 6, 11, 14
  • measure activity
  • cured - negative films days 6, 11, 14
  • dont see well in liver bc rings (small)
    • solution: do PCR (difficult in rural areas)
  • day 60 NEG mice
    • took blood + did PCR + injected blood into native mouse + injected spleen into native mouse
    • then did blood films w/ all of these
      • if any positive, the original mouse was not cured

11

measure activity in liver schzonticidal test

  • if blood films after sporozoite inoculation = positive
    • compound = inactive
  • mice without parasites on all 3 films = compound killed either sporozoite or exoerythrocytic stage

12

blood stage drugs

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  • not true prophylactics since no liver stage activity
  • some are antibiotics that are used for antimalarial
  • quinone also treats cramps and in tonic water
    • give tonic water bitter flavor
      • would need 64 liters to get enough quinine to treat malarial infection
    • from ecuador (not peru)
  • quinacrine
    • used as birth control for women in india (inserted into uterus)
    • atabrine - quinacrine turns humans skin yellow
  • chloroquine - A-4-amino-quinoline
    • resistance starting to spread in the world
    • expecially in countries that combated malaria by adding it to table salt
      • drug resistance induced bc give low levels of it that's not enough to do much to parasite -> they change
  • mefloquine
    • lariam (drug)
    • resistant areas = (see slides)
  • antifol drugs
  • fanisar
    • combination of 2 drugs (sulfadoxine + pyrimethamine)
    • causes stevens johnson syndrome
      • online: disorder of the skin and mucous membranes. It's usually a reaction to medication that starts with flu-like symptoms, followed by a painful rash that spreads and blisters. Then the top layer of affected skin dies, sheds and begins to heal after several days.
      • can be oral as well
  • doxycycline
  • azithromycin

13

costs and stages they treat

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14

side effects of antimalarials

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15

resistance due to mutations

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16

drug combinations

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17

malarone

...

18

proguanil

  • prodrug - must be metabolized to activate component
  • if not broken down by liver - wont work
  • cycloguanil - the active metabolite

19

atovaquone

...

20

qinghaosu

  • artmisinin - QHS
  • a plant
  • gov set up big contracts for growing
  • complicated to synthesize this chemical
  • can make it now
  • thick paste
  • work as sopositories (for rectum for ppl too sick to take orally)
  • active component - dihydroartemisinin

21

ACT drugs

ACT - artemisinin combination therapy

combination of artemisinin like drugs + another antimalarial

artemisinin type drugs act as free radicals as their mechanism of action

dihydroartemisinin - active metabolite of all the artemisinin like drugs

notes

  • this = best therapy
  • difficult to induce resistance in
  • now finding some resistance in certain areas

22

true prophylactic drugs - 8-aminoquinolines

  • all active against liver stages (primary exoerythrocytic stage and hypnozoite)
  • pamaquine 1st synthetic drug for any disease but very toxic
    • only 1 on market for last 60 years
    • only for ppl without G6PD deficiency
  • primaquine - used today but toxic to G6PD deficient people
  • tafenoquine - new drug waiting FDA approval

23

primaquine

  • active only against liver stages + gametocytes
    • more for ppl w/ vivax
  • can cause hemolytic anemia in ppl with deficiency in G6PD
  • short half life (must be given daily 14 days)
    • only in body for 4-6 hrs
  • give only after returning
  • give only after returning from malarial area

24

tafenoquine

  • active vs all stages
  • can cause hemolytic anemia (less than primaquine)
  • long lasting
  • other toxicity (not approved for humans yet)

25

pamaquine

  • 1st synthetic drug
  • toxic 8-aminoquinoline
  • not until WWII that found structure of chloroquine (thought to be toxic) -> allies in Germany sent to states -> started making it to test it

26

PABA

  • Paraaminobenzoic acid = PABA
  • parasites need this to grow
  • PABA is not in milk so if a mother nurses her child + gives no other food = child will NOT develop malaria