Exam 1: Lecture 1 (Anti-malaria) Flashcards
Malaria Generic Info
~ 400K deaths per year, mostly kids (used to be closer to 1 mil)
about half the world is at risk for malaria
Mostly prevalent in Africa
Symptoms of Malaria
Fever, flu-like, shaking chills, headache
N,V,Diarrhea
Anemia and Jaundice possible
Start 8-25 days after infection
Who found Artemisine?
Youyou Tu from traditional herbal medicine
Stages of Malaria Lifecycle
- Transmission to humans
- Human Liver stage
- Human Blood stage
- Mosquito stage
Human Liver Stage (Malaria)
- Once in liver, parasite transforms to be able to infect blood cells
- Preventative drugs act at the liver stage, few exist
- Once in liver, parasite transforms to be able to infect blood cells.
Human Blood Stage (Malaria)
- Causes the symptoms & sickness associated with malaria.
- Drugs at this stage have to act fast
- Parasite has no sex, cant reproduce
Dormant Stage
Under drug pressure, parasite goes dormant and symptoms can
When can malaria reproduce?
- End of Human blood stage, turn into Gametocytes
2. get picked up by mosquitos which will spread to other humans
Global impact of malaria
Number at risk: 3.3 bit
Clinical cases/yr: 219 mil
Deaths/yr: >500k
Deaths: 85% children under 5
Why do you want to limit dosing regimen in malaria?
Make sure pts take all the doses and don’t “save” doses after a few days for the next occurrence since it can be expensive (relatively for African countries)
Max = 3 pills
Usually costs < $1
Ideal Antimalarials would block….
Liver, blood and transmission stage and Radical Cure
Target Candidate profiles (Split into a few pills)
TCP1 = fast clearance of parasiteaemia (blood stage)
TCP2 = Long-acting post treatment prophylaxis (Liver form)
TCP3b = Transmission blocking
TCP3a = Radical Cure
Target Candidate profile (1 Pill)
TCP4
Long acting, casual liver or slow onset asexual
Different MOA to SERCaP
TCP1 Key attributes
Rapid Clearance
Immediate/rapid action
Dose < 1g, decrease in parasitemia = 6-9 log units
TCP2 Key attributes
Long duration
Partner drug protecting against resistance and delivering cure
Dose < 1g
Time > MPC = 8 days (4 life cycle)
TCP3a Key attributes
Relapse prevention
Dose < 1g
TCP3b Key attributes
Blocking oocyst formation similar to ABS MIC
TCP4 Key attributes
Casual liver stage or slow onset blood stage
Dose <1 g
Time > prophylactic conc = 7 days
Which strains aren’t resistant to Chloroquine
D6
Which strains aren’t resistant to Mefloquine
W2
RCS
PH1
Which strains aren’t resistant to Pyrimethamine
D6
PH1
Which strains aren’t resistant to Atovaquone
W2 D6 RCS PH1 TM90-C2A TM91C235
Which strains aren’t resistant to Artemisinin
Chart shows that none are, but now there are certain strains that no drugs work
Which stages of Malaria Cycle does Atovaquone work>
Human liver stage = Schizont
Human Blood stage = Schizont, Gametocytes
Mosquito stage = Micro-gametocyte or Ookinete
Which drug is given with Atovaquone?
in Combo with Proguanil
What does Atovaquone target?
Targets Cytochrome bc1
This complex is important in ATP production
Binds to the Qo site
Artemisinin general info
derived from plant, used as tea extract in china
- shortens treatment
- reduces occurrences of resistance
- dec viral load within 1/2hr
Artemisinin Mechanism of Action
- Parasites digest hemoglobin releasing heme
- Endoperoxide bridge is cleaves by iron, releasing artemisine radicals
- Artemisine radicals covalently bond to parasitic proteins, causing parasite death
What gives Artemisinin selectivity for parasite?
Parasite will accumulate iron, giving Artemisinin selectivity for parasite
where has resistance to Artemisinin appeared?
2003, began appearing in Cambodia
Spread throughout Cambodia, into Vietnam, Myanmar and Thailand
Delayed Parasite Clearance - Artemisinin
how to deal with patients who had emergence of resistance to Artemisinin….increase the dose and it works
Artemisinin combo therapies
- Don’t use alone
- Artemisinin acts fast allowing for quick parasite clearance
- 2nd treatment in pair will have different mode of action and longer half-life
- total of 5 combo therapies currently recommended
Coartem (Novartis Combo)
Artemether
Lumefantrine
Eurartesim (Sigma-Tau)
Dihydroartemisinin
Piperquine
ASAQ (DNDi and Sanofi)
Artesunate
Amodiquine
Pyramax (Shin Poong
Artesunate
Pyronaridine
What causes resistance of Atovaquone?
Mutation at amino acid position 268, causing change in binding site and drug won’t be as effective
Artemisinin and Mefloquine combo
Artemisinin = reduces parasite fast but doesn’t last long
Mefloquine = lasts way longer, artemisinin reduces parasites enough for mefloquine to finish the job
