Exam 1: Lecture 1 (Anti-malaria)

Question 1

Malaria Generic Info

Answer 1

~ 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

Question 2

Symptoms of Malaria

Answer 2

Fever, flu-like, shaking chills, headache
N,V,Diarrhea
Anemia and Jaundice possible

Start 8-25 days after infection

Question 3

Who found Artemisine?

Answer 3

Youyou Tu from traditional herbal medicine

Question 4

Stages of Malaria Lifecycle

Answer 4

1. Transmission to humans
2. Human Liver stage
3. Human Blood stage
4. Mosquito stage

Question 5

Human Liver Stage (Malaria)

Answer 5

1. Once in liver, parasite transforms to be able to infect blood cells
2. Preventative drugs act at the liver stage, few exist
3. Once in liver, parasite transforms to be able to infect blood cells.

Question 6

Human Blood Stage (Malaria)

Answer 6

1. Causes the symptoms & sickness associated with malaria.
2. Drugs at this stage have to act fast
3. Parasite has no sex, cant reproduce

Question 7

Dormant Stage

Answer 7

Under drug pressure, parasite goes dormant and symptoms can

Question 8

When can malaria reproduce?

Answer 8

1. End of Human blood stage, turn into Gametocytes

2. get picked up by mosquitos which will spread to other humans

Question 9

Global impact of malaria

Answer 9

Number at risk: 3.3 bit
Clinical cases/yr: 219 mil
Deaths/yr: >500k
Deaths: 85% children under 5

Question 10

Why do you want to limit dosing regimen in malaria?

Answer 10

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

Question 11

Ideal Antimalarials would block….

Answer 11

Liver, blood and transmission stage and Radical Cure

Question 12

Target Candidate profiles (Split into a few pills)

Answer 12

TCP1 = fast clearance of parasiteaemia (blood stage)

TCP2 = Long-acting post treatment prophylaxis (Liver form)

TCP3b = Transmission blocking

TCP3a = Radical Cure

Question 13

Target Candidate profile (1 Pill)

Answer 13

TCP4

Long acting, casual liver or slow onset asexual

Different MOA to SERCaP

Question 14

TCP1 Key attributes

Answer 14

Rapid Clearance

Immediate/rapid action

Dose < 1g, decrease in parasitemia = 6-9 log units

Question 15

TCP2 Key attributes

Answer 15

Long duration

Partner drug protecting against resistance and delivering cure

Dose < 1g
Time > MPC = 8 days (4 life cycle)

Question 16

TCP3a Key attributes

Answer 16

Relapse prevention

Dose < 1g

Question 17

TCP3b Key attributes

Answer 17

Blocking oocyst formation similar to ABS MIC

Question 18

TCP4 Key attributes

Answer 18

Casual liver stage or slow onset blood stage

Dose <1 g
Time > prophylactic conc = 7 days

Question 19

Which strains aren’t resistant to Chloroquine

Answer 19

D6

Question 20

Which strains aren’t resistant to Mefloquine

Answer 20

W2
RCS
PH1

Question 21

Which strains aren’t resistant to Pyrimethamine

Answer 21

D6

PH1

Question 22

Which strains aren’t resistant to Atovaquone

Answer 22

W2
D6
RCS
PH1
TM90-C2A
TM91C235

Question 23

Which strains aren’t resistant to Artemisinin

Answer 23

Chart shows that none are, but now there are certain strains that no drugs work

Question 24

Which stages of Malaria Cycle does Atovaquone work>

Answer 24

Human liver stage = Schizont

Human Blood stage = Schizont, Gametocytes

Mosquito stage = Micro-gametocyte or Ookinete

Question 25

Which drug is given with Atovaquone?

Answer 25

in Combo with Proguanil

Question 26

What does Atovaquone target?

Answer 26

Targets Cytochrome bc1

This complex is important in ATP production

Binds to the Qo site

Question 27

Artemisinin general info

Answer 27

derived from plant, used as tea extract in china

• • shortens treatment
• • reduces occurrences of resistance
• • dec viral load within 1/2hr

Question 28

Artemisinin Mechanism of Action

Answer 28

1. Parasites digest hemoglobin releasing heme
2. Endoperoxide bridge is cleaves by iron, releasing artemisine radicals
3. Artemisine radicals covalently bond to parasitic proteins, causing parasite death

Question 29

What gives Artemisinin selectivity for parasite?

Answer 29

Parasite will accumulate iron, giving Artemisinin selectivity for parasite

Question 30

where has resistance to Artemisinin appeared?

Answer 30

2003, began appearing in Cambodia

Spread throughout Cambodia, into Vietnam, Myanmar and Thailand

Question 31

Delayed Parasite Clearance - Artemisinin

Answer 31

how to deal with patients who had emergence of resistance to Artemisinin….increase the dose and it works

Question 32

Artemisinin combo therapies

Answer 32

1. Don’t use alone
2. Artemisinin acts fast allowing for quick parasite clearance
3. 2nd treatment in pair will have different mode of action and longer half-life
4. total of 5 combo therapies currently recommended

Question 33

Coartem (Novartis Combo)

Answer 33

Artemether

Lumefantrine

Question 34

Eurartesim (Sigma-Tau)

Answer 34

Dihydroartemisinin

Piperquine

Question 35

ASAQ (DNDi and Sanofi)

Answer 35

Artesunate

Amodiquine

Question 36

Pyramax (Shin Poong

Answer 36

Artesunate

Pyronaridine

Question 37

What causes resistance of Atovaquone?

Answer 37

Mutation at amino acid position 268, causing change in binding site and drug won’t be as effective

Question 38

Artemisinin and Mefloquine combo

Answer 38

Artemisinin = reduces parasite fast but doesn’t last long

Mefloquine = lasts way longer, artemisinin reduces parasites enough for mefloquine to finish the job