Neglected diseases Flashcards
What is a communicable disease?
Infectious disease
Where are communicable diseases common?
Populations living in poverty without adequate sanitation and in contact with infectious vectors, domestic animals and livestock
What is a neglected disease?
Diverse group of communicable diseases in tropical and subtropical conditions
Often overlooked by industry and those instrumental in drug access (Government, media)
Some are even found in the US where there are high levels of poverty (these diseases are spreading)
What 3 conditions used to be neglected diseases?
HIV/AIDs
Malaria
TB
There are now medicines for these
Why are neglected diseases overlooked by drug developers?
- Cannot recover the cost for developing and producing treatments for these diseases
- In underdeveloped nations- industries mainly focus on these diseases affected by the western world where they can get their money e.g. cancer, cardiovascular disease
- Generally do not cause dramatic outbreaks worldwide that would kill large numbers of people
- Limited funding for basic research
What 3 main regions of the world do these neglected diseases come from and what is the problem?
India, South America and Africa
They all have large populations but the government is investing very little money into the healthcare system
How are parasites transmitted?
Vectors
Contaminated water and soil
Why do we need to treat neglected diseases?
- Drug resistant organisms
- Few newly approved therapies and only a handful of novel drugs
- International travel and immigration means that these diseases are no longer geographically restricted
- Diseases e.g. Ebola spread around the world very quickly
- Significant mortality- social and economic consequences
What are the disadvantages of current treatments?
- Decades old
- Resistance
- Serious side effects
- Poor patient compliance
- Limited efficacy
What is malaria caused by?
Protozoan parasite genus Plasmodium (eukaryote)
Malaria is caused by Plasmodium, a eukaryote. What are its features and makes it characteristic?
- Has two hosts in its life cycle. Insect host (sexual) and vertebrate host
- 14 chromosomes in the nucleus
- Genetic material in the mitochondria
- Genetic material in the apicoplast, a double-membrane organelle making it very characteristic
How is malaria transmitted?
Infected female Anopheles mosquito
What can an initial infection of malaria lead to?
Anaemia, cerebral malaria and eath
Why is it not possible to spread malaria in the northern hemisphere?
Mosquitoes do not exist here
Malaria can be transmitted through a blood contaminated needle. True or false?
True
What are the 4 species of malaria that affect humans and which one is the most fatal one?
- Plasmodium falciparum (malignant, most dangerous, tertian)
- Plasmodium vivax (benign, tertian)
- Plasmodium malariae (quartan)
- Plasmodium ovale (tertian)
What does tertian and quartan mean?
Tertian- fever occurs every 48 hours
Quartan - fever occurs every 2 hours
What is the life cycle of malaria?
- Infected female Anopheles mosquito parasite and injects sporozoite
- Sporozoites travel to liver and take up residence in hepatocytes
- Sporozoites multiply asexually and become merozoites. Liver cells then burst releasing it into the blood (7-10 days)
- In the blood, merozoites invade erythrocytes and multiply until the cell bursts
- The cycle then repeats itself. Merozoites invade RBCs, multiplies and bursts. Each time, it causes fever and chilld
- After several asexual cycles, the merezoites can invade RBCs and instead of replicating, developing into sexual gametocytes
- Mosquitoes bite infected humans. It digests gametocytes which allow development into mature sex cells (gametes)
- Gamete - zygote - oocyte.
- When oocyte ruptures, it releases sporozoites which move to salivary glands of mosquito
What drug is effective against the exoerythrocytic and gametocytic form in malaria?
Primaquine
What drugs are effective against the erythrocytic form in malaria?
- Artemisinin
- Chloroquine
- Quinine
- Mefloquine
- Pyrimethamine
Quinine:
What groups are fundamental for action?
What type of malaria is it particularly good for?
What is the relevance of its stereochemistry?
- Benzene ring and tertiary amine fundamental for action
- From bark of cinchona tree
- Good for chloroquine-resistant strains of Plasmodium falciparum
Both diastereomers are active against malaria:
i) Quinine - must abundant
3R:4S:8S:9R
ii) Quinidine
3R:4S:8R:9S
Its epimers are inactive
All quinoline- based antimalarials have which 2 funtional groups?
Tertiary amine
Benzene ring
Quininacrine is good for what conditions?
Malaria and tapeworm infections
Chloroquine:
What is its structure?
What are its side effects
- Chiral centre and used as a racemic mixture
- Chlorine in the compound increases activity
- Most effective and safe medicine to treat malaria
- Limited side effects- muscle problems, appetite loss, diarrhoea
What 5 drugs are under the class quinoline-based compounds?
- Quinine
- Quinacrine
- Chloroquine
- Mefloquine
- Pamaquine
What is mefloquine used for and how is it taken?
What is the problem with mefloquine?
What is the structure?
Treatment for mild to moderate malaria- once a week dosing
Prophylaxis- once a week 1 or 2 weeks before potential exposure and continue for 4 weeks after
Sold as a racemate
Problems:
- Resistance common in Asia
- Side effects are more serious - depression, hallucinations, anxiety, seizures and ringing in the ears
What is amodiaquine used for?
Does it have a long half-life?
What is it usually given with and why?
What are the side effects associated with it?
- Uncomplicated Plasmodium falciparum (works against chloroquine-resistant PF)
- It has a long half-life
- Given with artesunate in ACT to reduce risk of resistance
Rare but serious side effetcs- liver problems or low blood cell levels
What is the MOA of chloroquine and other quinolone-based compounds?
- Haemaglobin is transported into the food vacuoles of the plasmodium where digestion of the haemaglobin supplies the organism with a source of amino acids
- Free heme is not metabolised as it is toxic to Plasmodium cells and instead, Plasmodium polymerises free heme to form hemozoin (non-toxic)
- Quinolines bind hemes together via a pi-pi interaction preventing polymerisation into hemozoin
- This allows poisoning of plasmodium
Works at erythrocyte stage
What is ACT and why is it used?
Artemisinin- based combination therapies to prevent resistance in malaria treatment
Name a drug under the artemisinin class?
Artesunate
From sweetworm wood (Chinese herbal medicine)
What is the MOA of artemisinins?
- Works at erythrocyte stage
- Contains Oxygen-oxygen peroxide bond which is very reactive and allows the compound to have anti-malarial activity - free radical production
- Iron 2 reacts with peroxide - oxidation into iron 3
- The compound then either breaks down into:
i) Non toxic metabolite + toxic iron radical
or
ii) Alkylating radical which covalently binds to the heme (Heme-artemisinin adduct) stopping polymerisation into the non-toxic form hemozoin
What are the two ACT combinations?
- Artesunate and amodiaquine
Acute uncomplicated Plasmodium falciparum
Side effects- nausea, loss of appetite, abdo pain
- Artesunate and mefloquine
1st line treatment in Thailans
Uncomplicated falciparum
Side effects of mefloquine (depression, hallucinations, seizures) seem to be reduced when in this combination
What is the MOA of proguanil in malaria?
- Dihydrofolate reductase inhibitor (DHFR)
- Prodrug that metabolises into cycloguanil
- Stops production of tetrahydrofolate, which is a cofactor in synthesis of amino and nucleic acids
- Therefore stops cycle of malaria
Although humans have DHFR, it is selective to malaria
What are the 3 conditions under kinetoplastid disease?
- Leishmania
- Sleeping sickness
- Chaga’s disease
What are kinetoplastids? What is a distinguishing feature of them?
- Protozoa
- Eukaryotic and possess normal eukaryotic organelles
- Kinetoplasts - organelle with a large massed DNA
What vector causes Leishmania?
- Female sandfly of the genus Phlebotomus
Who does Leishmania effect?
Humans, dogs, foxes
What are the 2 types of Leishmaniasis?
- Cutaneous
- Self-healing or chronic lesions on the skin or mucous membranes
- Skin sores usually start at site of the bite
- Not life-threatening
- Not usually treated with drugs unless re-occurring - Visceral
- 2-8 months after initial bite
- Parasite damages immune system
- Fatal without treatment
What is the life cycle of Leishmaniasis?
- Infected sandfly bites and injects promastigotes into skin of host
- Macrophages phagocyte promastigotes that differentiate into amastigotes and multiply in cells of various tissues
- Macrophages burst releasing more amastigotes that are re-phagocytosed
- Uninfected sandfly bites and ingests amastigotes
- Amastigotes differentiate into promastigote stage and divides in the midgut of the fly
- Promastigotes migrate to proboscis (sucking mouthpart) and are now able to transmit the disease
What are the 3 drugs used to treat visceral leishmaniasis and which one can also treat cutaneous?
- Sodium stibogluconate antimonium (Sb) complex
- Amphotericin B
- Pentamidine works against both
What is sodium stibugluconate antimonium (Sb) complex used for?
How does it work?
What are some side effects?
- Visceral leishmaniasis
- Inhibition of DNA replication via inhibiting topoisomerase enzymes and cell signalling via inhibiting tyrosine photsphatases
- Nausea, loss of appetite, muscle pain
What is amphotericin B used for?
How does it work?
- Visceral leishmaniasis if nothing else wors
- Forms pores in cell membrane that cause rapid leakage of potassium, sodium, chloride and hydrogen ions - cell death
What is Pentamidine used for in leishmaniasis?
How is it given and why?
What are some side effects?
What is its MOA?
What is its pharmacophore?
Visceral and cutaneous leishmaniasis
Via IV, IM or inhalation. It has a lack of oral bioavailability and poor BBB penetration
Side effects - low blood sugar, nausea, low BP
Hydrogen bonds to DNA of parasite at N3 of adenosine via amidine moiety
This stops DNA replication and causes death of parasite
Pharmcophore- dibasic
How have they tried to make a new drug from pentamidine and why?
Dibasic pharmacophore with a different linker to try and improve oral bioavailability and enhance cell permeability
What causes Human African trypanosomiasis?
Trypanosoma brucei
Sleeping sickness
What is the vector for sleeping sickness?
Tstetse fly
What are the two forms of sleeping sickness?
- TBG - 95% cases
West and central Africa
Chronic infection
Latent and symptomless for months and years. Symptoms may only emerge in advanced disease states where CNS is affected
2. TBR Eastern and Southern Africa Acute infection Symptoms weeks-months after infection Develops rapidly and invades CNS
What are the 2 stages of symptoms for sleeping sickness and what are the treatment options?
- Haemolymphatic
- Parasites multiply in subcutaneous tissues, blood and lymph
- Boughts of fever, headaches, joint pains and itching
- Treatment options- pentamidine, suramin - Neurological
- Parasite crosses BBB and infects the CNS
- Behaviour change, confusion, sensory disturbances
- Lethal without treatment
- Melarsoprol, eflornithine
Why can you not use pentamidine in the neurological stage of sleeping sickness?
Cannot cross BBB
What is the lifecycle for sleeping sickness?
- Tstetse fly bites human and injects metacyclic trypomastigotes
- Metacyclic trypomastigotes transform into bloodstream tyrpomastigotes which are carried to other sites
- Trypomastigotes multiply by binary fission in various body fluids (blood, lymph, spine)
- Trypomastigotes in blood
- Tstetse fly bites human and bloodstream trypomastigotes are ingested
- Bloodstream trypomastigotes transform into procyclic trypomastigotes in midgut of fly. Then these divide by binary fission
- Procyclic trypomastigotes leave the midgut and transform into epimastigotes
- Epimastigotes multiply in salivary glands and transform into metacyclic trypomastigote
What is the diagnostic stage for sleeping sickness?
Trypomastigotes in blood
How does eflornithine work in Neurological stage of sleeping sickness?
- Originally developed as an anti-cancer drug
- Inhibitor of ODC (ornithine decarboxylase)
- ODC catalyses decarboxylation of L-ornithine into putrescine, a step in polyamine synthesis
- Mimics L-ornithine which is commonly used in many living organisms and prevents decarboxylase via covalently bonding to ODC