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Parasites and infectious disease > WEEK 2 DRUGS > Flashcards

WEEK 2 DRUGS Flashcards

1
Q

what are three important things to consider when thinking about treatment for HAT

A

stage
blood brain barrier
sub species

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2
Q

what are 4 drugs used?

A

Suramin
Pentamidine
Melarosprol
Eflornithine

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3
Q

4 points about suramin structure

A

symmetrical
derivative of urea
napthylamine
polysulfonated - negative charge at blood pH

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4
Q

when was suramin introduced?

A

1922

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5
Q

what is suramin the drug of choice for?

A

early stage east african

t.b.rhodesiense

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6
Q

why is suramin not used against t.b.gambiense

A

because it is used against river blindness in west africa

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7
Q

how is suramin delivered?

A

weekly 1g intravenous injections over 5-6 weeks

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8
Q

how expensive is suramin?

A

it is relatively cheap - $10/g

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9
Q

what is the distribution of suramin like in the body?

A

99% protein bound due to the charge

because of this charge it passes poorly through the blood/brain barrier

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10
Q

How is suramin eliminated?

A

it is not metabolised by the body, the liver cannot get rid of it, the only way it can be excreted is via sweat because of this the half life is long 35 - 60 days

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11
Q

what are the side effects of suramin?

A

protein in the urine

but this clears up after treatment stop and this side effect is mild compared to other drugs for HAT

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12
Q

Why is the mode of action unclear for suramin?

A

because all the suggestions so far have been performed in vitro and as such may not be indicative of in vivo.

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13
Q

has resistance in the field been detected in suramin?

A

no

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14
Q

what are all the suggested mode of action of suramin? (4)

due to the negative charge

A

suramin inhibits enzymes encountered in the endocytic pathway

suramin inhibits glycolytic enzymes

suramin inhibits polyamine synthesis

suramin inhibits synthesis of a molecule found in the GPI ANCHOR

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15
Q

explain pentamidine structure (3)

A

aromatic
diamidine
positively charged

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16
Q

when was pentamidine introduced?

A

1937

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17
Q

pentamidine is the drug of choice for which trypanosome?

A

early stage west african trypanosomiases (T.b.gambiense)

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18
Q

what else is pentamidine used for?

A

antimony resistant leishmania and pneumonia

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19
Q

how is pentamidine given to the patient?

A

7-10 daily intramuscular injections

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20
Q

how much does pentamidine cost?

A

20$ a course

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21
Q

what is pentamidine like when inside the body?

A

70% is protein bound due to charge and it passes poorly through blood/brain barrier

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22
Q

how is pentamidine eliminated from the body?

A

this drug is not metabolised by the body but 15% is cleared in the urine in 24hours
its half life is short 9 - 13 hours

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23
Q

what are the side effects of pentamidine?

A 
allergic reactions
stomach upset
loss of apetite
nausea
vomitting
cough
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24
Q

How is pentamidine uptake into the parasite? which transporter?

A

P2
AQP
LAPT

25
Q

what happens to pentamidine once inside the cell?

A

we dont know for sure but there are 2 possible mechanisms:

  1. binds to mitochondrial DNA prevents synthesis
  2. mitochondrial membrane potential collapses
26
Q

What is the only drug used against the CNS stage of HAT?

A

Melarsoprol

27
Q

describe the structure of melarsoprol

A

trivalent with arsenic

highly toxic - 5-10% patients die from drug alone

28
Q

what are the side effects of malarsoprol?

A 
convulsions
fever
loss of consciousness
bloody stools
vomitting
29
Q

when was melarsoprol introduced?

A

1949

30
Q

how is melarsoprol administered?

A

a very painful intravenous injection

31
Q

why does melarsoprol have to be mixed with an antifreeze like substancec?

A

because it is hydrophobic and needs to be suspended

32
Q

what are the 2 schemes for adminstering melarsoprol?

A

scheme 1- one per day for 4 days, then a rest period of 7-10 days, and repeat 3 or 4 times

scheme 2 - daily injections for 10 days

33
Q

how much does each scheme for melarsoprol cost?

A

both $50

34
Q

what is the distribution of melarsoprol like in the body?

A

in plasma and can cross blood brain barrier but in the cerebral fluid it is 50 fold lower than in the blood

35
Q

what is the half life of melarsoprol

A

rapidly excreted in urine. half life 35 hours, converted to melarsen oxide

36
Q

which transporters in the parasite take up melarsoprol?

A

P2 and AQP2

37
Q

what is the other alternative drug against the CNS stage of HAT?

A

Eflornithine

38
Q

describe a little about eflornithine (4)

A

originally developed as cancer drug, very few side effects, miracle drug, analogue of ornithine

39
Q

when was eflornithine introduced?

A

1981

40
Q

what is eflornithine used against?

A

late stage west african t.b.g.

not t.b.r

41
Q

how is eflornithine administered?

A

4 daily intravenous infusions for 7-14 days

42
Q

how much is a course of eflornithine?

A

500$ and as such can only be administered by NGOs as people in africa cannot afford it

43
Q

how is eflornithine distributed?

A

in plasma can cross blood brain barrier is up to 50% in spinal fluid

44
Q

how is eflornithine eliminated from the body?

A

it is not metabolised but it is rapidly excreted in the urine, 80% in 24 hours and its half life is 3.5 hours, but this is why it works so well

45
Q

which transporter is used in the uptake of eflornithine?

A

AAT6

46
Q

why did eflornithine stop being produced?

A

because of the cost in 1995

47
Q

What are the 5 reasons current drug treatments are problematic?

A 
toxic
limited efficacy
resistance
medical supervision
expensive
48
Q

which drugs are toxic?

A

melarsoprol (5-10% die)
pentamidine
suramin

49
Q

which drugs have limited efficacy? (4)

A

suramin only works against east HAT

pentamidinde only works against west HAT

pentamidine and suramin only effective on non-cerebral stages of sleeping sickness

eflornithine is not effective againts t.b.r

50
Q

which drugs have there been resistance to?

A

melarsoprol

51
Q

which drugs require medical supervision?

A

all of them

52
Q

which drugs are most expensive?

A

eflornithine

53
Q

How is suramin uptaken in to the parasite?

A

this is relative recent work using a novel genome loss of function asset.
ALSFORD ET AL 2012
The initial uptake was backed up by specific cell work (KOUMANDOU et al 2013)
On the cell surface is the invariant surface glycoprotein 75 (ISG75) this acts as a magnet for the suramin. The suramin is attracted or sticks to ISG75. As a result of this fluid mosaic model of the membrane these charged molecules end up into the flagella pocket.

When the receptors are within the flagella pocket the IGS75 go through unbiquitination and this ubiquitin acts as an attractant for a molecule and this acts as a scaffold for another molecule which when formed ends up with a clathrin coated vesicle.

54
Q

How is melarsoprol uptaken into the cell?

A

the melarsen oxide sticks with trypanothione to form a metal thiol conjugate and this can stick and inhibit key enzymes (trypanothione reductase) for the parasites. the major thiol found within the parasite is trypanothione. Down stream processes will be reduced considerably, this includes DNA synthesis. So the cell is going to suffer.

55
Q

how do we know that the P2 transporter is vital for melarsoprol?

A

We know about the P2 transporter because of resistance to these drugs. If you grow parasites in the lab on increasing concentrations of melarsoprol you can select out cell lines and they have a reduced capacity for uptake of melarsoprol and the gene which appears to be mutated is the P2 transporter gene. This gene has been identified and cloned. But remember this is in vitro. In the cell lines generated when you pull out the P2 you can find 6 point mutations within this gene and these are sufficient to stop P2 interacting with melarosprol

56
Q

What gene knockout work has been done?

A

The P2 gene has been deleted to create a more mutant line. This was done in vitro and in animals.

57
Q

what other resistance work apart from P2 has been done?

A

Half resistant cases are attributable to P2 but other cases that are not related. In the lab you can knock out AQP2 gene and this renders the cell resistant to melarsoprol and pentamidine.

P2 has been proven to play a role in resistance to uptake whereas AQP2 is a relatively new resistance and uptake role.

Resistance in the lab using drug selective lines has informed us for what we should be looking out for in the field. If you lose a component of either one of those 2 transporters you get resistance.

58
Q

How does eflornithine affect the parasite?

A

once within the cytoplasm of the parasite, we know what is going on, this is the one case where we know. Binds to ODC which is an enzyme involved in polyamine synthesis. Problem is both the parasite and us have ODC. The mammalian enzyme is turned over and replaced at a very rapid life, the half life of the enzyme is 20mins. Every 20mins you are getting rid of the inhibited enzyme and being replaced with fresh enzymes.
Works in the parasite because this replenishing takes longer in the oarasite, it takes 18 hours to replenish enzyme.

The drug itself does not kill the parasite it stops it dividing and our immune system then comes in and wipes the parasite out. So it does rely on the patient having a healthy immune system.

Parasites and infectious disease (15 decks)

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