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93 Cards in this Set
- Front
- Back
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What are the 4 goals of chemotherapy for parasitoses?
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1) Prevention/prophylaxis
2) Cure 3) Reduction in pathology 4) Prevention of transmission |
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What is an exmaple of the primary indication for antiparasite chemotherapy?
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Malaria control starts with mosquito control
->Larvacide, adulticide, reduce exposure (bed nets, treated with permethrin) |
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What are the goals of chemotherapy for malaria?
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1) Prevention/prophylaxis: 8-aminoquinolines
2) Cure: 4-aminoquinolines, quinolinemethanols, artermisinins, DHFR inhibitors, others 3) Reduction in pathology: not relevant now 4) Prevention of transmission: Primaquine, 4-aminoquinolines, artermisinins (resistance management) |
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What do quinolines do?
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Attack the liver (outside the bug)
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Why would people bother to try and reduce pathology?
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Don't stop ppl from getting malaria, but stop them from getting very sick
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How would you prevent transmission of malaria?
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Gametocidal way
->Kill gametocytes ->Designed for good of the community (doesn't help infected person) |
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Where did quinine come from?
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Cincona tree
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Which drugs came from quinine?
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Quinolinemethanols (mefloquine)
4-aminoquinolines (chloroquine) 8-aminoquinoline (Primimaquine) |
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What was the 1st wonder drug?
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Penicillin
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What was the 2nd wonder drug?
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Chloroquine: cheap, safe, very good at controlling malaria
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Describe the use of primaquine (8-aminoquinoline)
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More potent vs hepatic stage than blood stage parasites
Used to prevent symptomatic infection with P. falciparum for radical cure of species with persistent liver stages |
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Describe the mechanism of action of primaquine
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Probably involves metabolism to a quinone, which acts as a mitochondrial poison
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How is primaquine given?
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15 mg primaquine base daily 2-3 weeks for radical cure (G6PD normal patients)
30 mg daily for prophylaxis |
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What is the toxicity to primaquine?
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G6PD deficient patients may show hemolysis due to oxidant stress (quinone mediated)
-->G6PD people usually protected vs malaria (something missing from redox cycle) , but if they take primquine, can have side=effects |
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At what dose is primaquine gametocytocidal?
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30-45 mg single dose
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What malaria would primaquine be best against?
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P. vivax because it has a very long liver stage (and primaquine best against hepatic stage, not blood stage)
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What is the most important antimalarial target?
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hemozoin
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How does artemisinin work?
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Triheane can react with Fe to make Reactive O2 species
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Where do quinolinemethanols and 4-aminoquinolines target Hz?
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In the food vacuole
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Do these 2 antimalarials have the same mechanism of action?
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No, because haven't seen resistance across both classes
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Which currently shows more resistance: CQ or amodiaquine?
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CQ has more resistance to it
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How is CQ used ion Africa?
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In combination with artersunate
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When is quinine used?
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I.V for severe cases of P. falciparum malaria resistant to other drugs
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Why is mefloquine used less often?
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Has relativelt high incidence of CNS side effects and resistance to it has already appeared
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Where is there CQ resistance?
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Almost everywhere
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Why is the situatioin of antimalarial drrug resistance getting desperate?
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Drug pressure selects existing alleles, so resistance develops locally and spreads globally
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Where is artermisini from?
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Shrub: Artermisia annua
-->Chinese army found this when looking for a new antimalarial cuz of CQ resistance |
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What have the 2 main advancements in malaria research been?
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Bed nets
Discovery of drugs |
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What is artemisinin very useful for?
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cerebral malaria
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What is the problem with limitations on artemisinin production?
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Shortages in clinical supplies and over havsting of A annua
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What is the solution to this problem?
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CLone synthetic pathway into yeast for fermentation
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What are the synthetic analogues used?
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Ozonolides
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What are clinical characteristics of artemisinin based antimalarials?
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Very rapid onset of parasite killing
Low toxicity Short T1/2 is ass't with recrudescence -->clears very quickly .: might slow down resistance Given in combo with other drugs (amodiaquine, lumefantrine or antibiotic) yo ensure efficacy and forestall resistance (new worries from the fiels) |
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Whatis DHFR important for?
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Enz for purine synthesis
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What is pyrimethamine given in combination with?
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p-aminobenzoic acid synthesis inhibitor (sulphadoxine) as a synergistic preparation
Fansidar is safe and effective |
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Is there resistance yet tp Fansidar?
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Yes
Due to multiple mutations in DHFR |
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How is Proguanil used?
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Prophylaxis and cure
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What is proguanil used with?
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In combo with Atovaquone
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What is cycloguanil active against?
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Some Fandisar resistant strains
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Where is there Fandisar resistance?
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Mostly in the smae places as CQ resistance, but less prevalent
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What are 2 other antimalarial drugs?
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Halofantrine
Coartem (lumefantrine + artemether) |
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What is the problem with halofrantrine?
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Has CV toxicity (arrhythmis)
Bioavailability increased with food Cure only No longer marketed |
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What is the new 1st choice antimalarial?
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Coartem
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What is Atovaquone?
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Analogue of an old series used in vet med
A nephthoquinone (mimic of ubiquinone (coenz Q)) |
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What does ubiquinone do?
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Participates in e- transport in plasmodial mito
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Where does atovaquone block?
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At cytochrome b/c as a result of mimicking ubiq.
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What is atovaquone used in combo with?
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Proguanil (malarone) which is used as a prophylaxis
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Why is atovaquone not used as a cure for blood stage infections?
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Worried about resistance
Also Malarone is expensive |
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Does ubiquinone select for resistance if used as prophylaxis?
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No because initial parasite load is low, so odds are, not many parasite strains that have a mutation to make them ubiqujinone resistant
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Which antibiotics are also used as antimalarials?
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Doxycycline
Clindamycin |
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Why can antibiotics be used?
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Antibiotics inhibit ptn synthesis on 70s ribosomes
Affect ptn synthesis in malaria parasite apicoplast They can be used alone for a cure (5-7 days) or in combo (ex with quinine) or as an alternative to prophylaxis for falciparum malaria (daily dosing) |
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Whats the problem with using antibiotics as an antimalarial?
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Can change normal bact flora
Can start developing bact resistance |
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What are the goals of chemotherapy for leishmaniases?
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1) Prevention/prophylaxis: not relevant
**2)Cure: Pentostam; amphotericin B, new drugs (miltefosine, paromycin, imiquimod) 3) Reduction in pathology 4) Prevention of transmission |
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Why is there less drug discovery activity and poorer chemotherapy for leishmaniases?
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Less cases, less Westerners exposed to VL
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What's the problem with VL therapy?
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Need prolonged therapy in hospital because drugs need to be given I.M or I.V
Need daily dosease for 10-20 days Significant toxicity |
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What are the 2 main drugs used in leishmaniases?
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Stibophen
Pentostam |
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Which drug is used in SA?
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Meglumine antimonate (similar concerns as the other drugs)
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Why are new drugs being researched for Leish?
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Increasing concerns about resistance, economic hardship of therapy and toxicity
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What is the target for chemotherapy?
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Intracellular amastigote
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What is the mechanism of action?
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Non specific, based on antimony toxicity
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How does amphotericin B work on leish?
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Highly toxic antigfungal drug
Efficacy vs VL New preparations made in liposomes: great reduction in toxicity Must be given I>V Effective but expensive Requires in-patient treatment High efficacy in 10-21 day regimen Single dose regimen under evaluation now |
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Why would the drug be preoared in liposomes?
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Cover amphotericin B in fat so that it gets absorbed
90% more curative |
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What role does Imiquimod play in Leish?
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Immunomodulator
Works by stimulating the immune system to destroy the parasite Activates macs Increases meglumine efficacy Stimulated interferon production Given as a topical cream |
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What type of leish is Imiquimod good against?
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Cutaneous leish
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Describe miltefosine with regards to leish
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Originally anticancer drug
Orally administered Fairly safe 2 doses/day X 28days Registered in several countries Resistance is a concern Efficacy good so far |
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What does Paromomycin do?
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Ancient aminoglycoside antibiotic
Rescued by Old World Health for dev'p for VL Active vs other protozoa approved in India Daily injections for 3 weeks May be best in combos |
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What is the only cure for schistosomiasis? (all species)
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Praziquantel
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Describe Praziquantel helminth chemotherapy
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Safe ad effective (but not good vs immature worms)
Repeated treatment needed in endemic areas Compliance not100% Casuses N&V No immediate change in health in MDA programs Mostly target school kids in highly affected areas. No elimination in sight yet |
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What's the problem with only having one drug?
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Resistance a concern
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What is the mechanism of action of praziaquantel?
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Opens a calcium channel in worm mbs
Paralysis and destruction of tegument may release Ag that stimulate immunre response |
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What are the goals of chemotherapy for onchocerciasis/LF?
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1) Prevention/prophylaxis: not relevant
2) Cure: not yet 3) Reduction in pathology: Ivermectin/DEC 4) Prevention of transmission: Ivermectin/DEC |
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What is onchocerciasis?
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Host response to microfilaria
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How can this be treated to prevent tranmission?
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Need to treat ppl until the parasite dies
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What are the drugs for filariasis?
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Ivermectin
Diethylcarbamazine (DEC) Doxycyclin |
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Describe Ivermectin
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Introduced in 1980s by Merck
Mainstay of oncho/LF control Opens glutamate-gated chloride channels in worm mbs |
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How is ivermectin given?
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SIngle dose 150 ug/kg once per year
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What is onchocerciasis?
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Host response to microfilaria
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How can this be treated to prevent tranmission?
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Need to treat ppl until the parasite dies
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What are the drugs for filariasis?
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Ivermectin
Diethylcarbamazine (DEC) Doxycyclin |
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Describe Ivermectin
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Introduced in 1980s by Merck
Mainstay of oncho/LF control Opens glutamate-gated chloride channels in worm mbs |
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How is ivermectin given?
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SIngle dose 150 ug/kg once per year
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How does Ivermectin work?
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Long term suppression of reproduction
Microfilaria disappear from skin/blood for 6-12 months Eliminates transmission and pathology Relatively safe |
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Does Ivermectin kill all the parasites?
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No, doesn't kill the adults
Adults can live >15 years |
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What is threatening eradicaiton in Africa of Leish?
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Black flies (400 km range)
$$$$ fatigue IVM resistance Severe adverse reactions in loa loa co-infection is a major issue |
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When was DEC introduced?
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in the 1950s
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What does DEC do?
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Causes persistent sterility in LF and removal of microfilaria from blood
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When is ivermectin not useful?
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If filaria gets to the brain. Ivermectin cannot get to the brain (this is why can't kill adult worm)
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What happens if ivermectin is used and the person is also infected with Loa loa?
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Get major problems
Not sure why, because loa loa by itself doesn't really cause much pathology |
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Is DEC useful in onchocerciasis?
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No because of Mazzotti rxn
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Can antibiotics be used against filariarsis?
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Yes, because filaria parasite need the support provided by bacteria like Wolbachia, which are endogenous symbionts of most filarial species
Antibiotics kill these bacteria 4-6 weeks of daily docycline or rifampicine cause permanent sterilization and even death in adult filariae ->Problem: compliance |
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What are some drugs used for GI nematode chemotherapy?
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Albendazole\Mebendazole
Levamisole Pyrantel ->Gut worms harder to diagnose Use benzamidazoles to interact with tubulin, paralyze the worms |
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What are the limits of therapy in MDA campaigns?
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Single dose regimen of albendazole or mebendazole
->Cost, delivery prevent multiple doses (animals get 3 daily doses) Regimen excelennt vs Ascaris, good vs hookworms, poor vs whipworms |
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Whats the difference between Hookworms and ascaris and whipworms?
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Hookworms survive and last in adults (unlike the others, which are most problematic for children)
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