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Parasitology and entomology > Chemotherapy of leishmania and the trypanosomes > Flashcards

Chemotherapy of leishmania and the trypanosomes Flashcards

1
Q

What are the disadvantages of the current drugs for leish?

A
  • Ineffective
  • Toxic
  • Adverse side effects
  • Long treatment duration
  • Hard administration (e.g. parenteral)
  • Expensive
  • Resistance
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2
Q

What are the problems with the current diagnostics? (leishmania)

A
  • Poor at seeing infection
  • Invasive
  • Complex
  • Poor biomarkers
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3
Q

Describe the success of vaccinations against leishmania.

A

Trialled in Brazil. Variable levels of protection. Not widely used as dependent on the stage of infection.

Vaccinations for dogs are thought to be somewhat effective.

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4
Q

What are the goals we would like to achieve with future drugs?

A
  • Basic short oral drug course
  • Drugs that are effective against Cl and PKDL
  • A treatment for VL with HIV coinfection
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5
Q

What are two properties of the location of the leish parasite that makes drug less effective

A

The parasite is obligate intracellular inside the parasitophorous vacuole. Membranes present barriers to the drug. We need drugs that can cross membranes in a way that is challenging to the parasite but not to the host.

pH of vacuole presents a challenge- the drug must be able to operate at this pH or not be changed by the acidity.

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6
Q

How many species of leish are there that infect humans? How does this cause problems for drugs?

A
  1. Each species has different susceptibilities to each drug. E.g. a drug that has sensitive parsites in S america may not work as well on parasites in the Middle east (parasites differ in susceptibility).
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7
Q

How does immune status provide a challenge for drugs?

A

Pentavalent antimonials need a healthy CD4 T cell count to be effective (because the drug activates macrophages that have a T cell effect).

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8
Q

Why do the complex manifestations produce challenges for drug activity?

A

-Located in different places and so different sites require different pharmacokinetics.

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9
Q

What are the 4 current drugs in use (location dependent)? Which is the first-line treatment (and which areas are excluded from this)

A
  • Pentavalent antimonials (SBV/SB5)
  • Amphotericin B
  • Miltefosine
  • Pentamidine

Pentavalent antimonials are the first-line treatments for VL in most locations except Bihar state (Bangladesh).

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10
Q

Where is miltefosine mainly used (location) and what is the benefit of this particular drug?

A

Latin America and India.

Is an oral formulation (the only oral drug).

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11
Q

Where is pentamidine used and why is it used?

A

Restricted to use in South America for CL treatment. It is used if they cannot get a hold of anything else.

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12
Q

What is the first line of treatment used in East Africa?

A

Combination of pentavalent antimonial SB5 and paramomycin.

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13
Q

Ambisome is the currently used lipid formulation of amphotericin B. What is the problem with other lipid formulations?

A

Other formulations are highly toxic.

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14
Q

What is the basis of clinical trials at the moment?

A

Most clinical trials are trying combinations of current drugs to see if these have better outcomes.

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15
Q

Describe the disadvantages of pentavalent antimonials. Give an example of the drug.

A
  • Intravenous/muscular administration (requires hospitalisation)
  • Hepatotoxicity
  • Cardiac arrhythmia
  • Not suitable during pregnancy
  • At least 10 doses over 28 days
  • Must be careful with HIV coinfection as requires high CD4 T cell count.

-Glucantime

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16
Q

What are the two proposed modes of action of pentavalent antimonials?

A
  • Reduction of SB5 to SB3 (in host cell, amastigote or both?) is the active ingredient
  • SB5 directly inhibits purine transporters which interfere with DNA cleavage.

Both routes induce apoptosis and the actual mechanism is likely to be a mixture of both.

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17
Q

Where is pentavalent antimonial resistance located? Why did resistance arise?

A

Focally in Bihar and surrounding Nepal and Bangladesh. resistance has NOT been seen elsewhere in S America or East Africa.

Resistance arose due to lack of compliance (sub optimal dose, not full course of treatment).

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18
Q

How is paramomycin administered? Wherabouts is it used? Where is it more/less effective? How can we get a higher cure rate from paramomycin?

A
  1. IV/IM
  2. Used more in India, not adopted in Asia
  3. Combined with antimonials for a higher cure rate
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19
Q

How does the context of drug administration affect the cure rate?

A

Efficacy varies depending on location due to differences in parasites and human populations.

20
Q

Which study suggests that context of the drug affecting outcome is because the human population?

A

In vitro drug tests show no differences when investigating differing dosing regimens needed for India and E Africa. NO difference in vitro suggests the difference is due to the human populations.

21
Q

What is the usual outcome/ what does not usually occur with co administration? What is the benefit of coadministration?

A

We usually do NOT see synergy/ additive activity. However, often we reduce the time taken for the treatment course and perhaps fewer treatments being needed).

One benefit is that it reduces the risk of emerging resistance.

22
Q

Describe the method of drug administration used for complex cases of leishmania (such as TB, HIV, pregnancy and PKDL).

A

Use cyclical administration of drugs. However, with each cycle, the drug gets less effective.

23
Q

What type of drug is amphotericin B? What was its previous use?

A

A polyene antibiotic. Previously an antifungal.

24
Q

What is the mode of action of amphotericin B? What is the risk of this mechanism?

A

Targets ergosterol of promastigotes and amastigotes to create pores in the membrane. Can also bind to cholesterol (host cells) but binds to ergosterol with a higher affinity, therefore there is a risk of toxicity.

25
Q

What is the fungizone formulation of amphotericin B and why was this sub ideal to administer?

A

Amphotericin B complexed to a deoxycholate salt to make it water-soluble. Very toxic so had to infuse very slowly in litres of saline so required hospital admission.

26
Q

What is a more ideal ampB formulation when compared to fungizone but despite this what are its limitations?

A

Ambisome. Liposomal package reduces toxicity and delivers it to the site of infection.

Still requires IV administration, is very expensive and a single dose (usually effective) is NOT effective in East Africa.

27
Q

What line is miltefosine? What type of drug is it?

A

Second-line drug (in some areas).

Alkyl phospholipid.

28
Q

What are the disadvantages of miltefosine?

A
  • Teratogenic
  • Gastric discomfort
  • Long course (28 days)
  • Not good on its own against East African VL
  • Reports of treatment failure in India and Nepal (may be due to poor compliance due to gastrointestinal discomfort or may be real treatment failure, don’t know).
29
Q

What is the mechanism of action of miltefosine?

A

Disrupts lipid membranes
Affects transport
Cell death via apoptosis.

30
Q

Why must we carefully monitor coinfection of VL and malaria?

A

Although there is no data on drug interactions yet, malaria reduces the spleen and liver function so drugs may be dangerous.

31
Q

How is CL usually treated?

A

Intralesional (IM) injections of SB5. Amphotericin as a second line treatment.

Sometimes lesions are superheated to trigger macrophage activation and promote healing (Vanessa says “wtf, should be illegal”).

32
Q

Describe immunomodulation during treatment of leishmania.

A

Immunomodulators such as imiquimod added to treatments of SB5 to attempt to improve cure rates.

33
Q

Which drugs are used for the acute and chronic stages (I and II) of r and gHAT?

A

Gambian: pentamidine for stage I and melarsoprol for stage II.

Rhodesian: suramine for stage I and melarsoprol for stage II.

34
Q

Which drugs are used for stage I (haemolymphatic stage)?

HAT

A

Pentamidine (use salt to ease administration), diamidine is preferred for gambian form via parenteral administration. Has unpleasant side effects.
Suramine for rhodesian HAT, intravenous injection, also unpleasant side effects.

35
Q

What is the first choice treatment against phase II rhodisiense and second choice for gambiense?

A

Melarsoprol. Is arsenical. Has severe sie effects e.g. fatal encephalopathy in 10% of cases.

36
Q

WHich drug is used when melarsoprol has failed? What are the issues with this drug? (HAT)

A

Eflournithine. Parenteral. Requires a HUGE amount of drug and frequently (every 6 hours).

37
Q

What is used as a last resort? (HAT)

A

Nifurtimox. Ineffective on its own so combined with other drugs e.g.eflournithine.

38
Q

Which is the new drug for HAT?

A

Fexinidazole. However, is mutagenic so there are safety issues.

39
Q

What was the original purpose of oxaboroles and how are they active against stage II HAT?

A

Antifungals. Accumulate in the spinal fluid.

40
Q

Why is nifurtimox combined with eflornithine as opposed to eflornithine monotherapy?

A

Treatment outcome is no worse when combined (i.e. did not improve) BUT reduces length of treatment, thus reducing toxicity. Is, therefore, a recommended first-line treatment.

41
Q

What type of drug is fexinidazole? How is it administered?

A

A nitroimidazole. Oral!

42
Q

What are the two current drugs for chagas? At which stages are they effective/ used?

A

Nifurtimox and benznidazole.
N: acute stage
BZ: early chronic stage.
Both long courses of treatment.

43
Q

Which aspect of metabolism is exploited for drug targets in chagas?

A

Mevalonic acid pathway producing ergosterol as it is unique to fungi and T cruzi.

44
Q

Which drug is being repurposed and is in cinical trials for chagas?

A

Fexinidazole. LOW doses showed no side effects (high doses did).

45
Q

Which aspect of metabolism is exploited for drug targets in chagas?

A

Mevalonic acid pathway producing ergosterol as it is unique to fungi and T cruzi.

46
Q

Which drug is being repurposed and is in cinical trials for chagas?

A

Fexinidazole. LOW doses showed no side effects (high doses did).

Parasitology and entomology (26 decks)

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