Tackling Viral Epidemics and Neglected Diseases - Neglected Tropical Diseases

What are neglected tropical diseases? (1)

A diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries and affect more than one billion people, costing developing economies billions of dollars every year.

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What are neglected tropical diseases? (2)

They mainly affect populations living in poverty, without adequate sanitation and in close contact with infectious vectors and domestic animals and livestock.

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What are neglected tropical diseases? (3)

1/6 of world population has one of these diseases. Affects people in poorer countries, inadequate sanitation, lack of investment from companies to find drugs to treat diseases. Difficult to monitor these diseases. Lack of drugs to treat neglected diseases

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Why do we call these diseases neglected? (1)

Often overlooked by drug developers/pharmaceutical companies. Cannot recover dose of developing and producing treatments for these diseases. Affects people who live in underdeveloped nations.

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Why do we call these diseases neglected? (2)

Doesn't cause dramatic outbreaks that kill large numbers of people

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Why do we call these diseases neglected? (3)

Other organisations/people instrumental in drug access (government officials, public health programmes, news media)

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Where do neglected tropics diseases occur in the world?

The diseases are most heavily concentrated in low-income nations in Africa and Latin America, Asia and the Middle East. Some of these diseases also are occasionally found in areas of the United States with high rates of poverty.

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Which countries invest more in healthcare?

Europe and USA, Japan

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Which countries invest less in healthcare?

India, Africa – no investment in healthcare systems to treat diseases and no interest in finding treatment

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Many neglected tropics diseases are caused by which type of micro-organisms?

Parasites which are spread by insects or contact with contaminated water or soil

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Give examples of neglected tropical diseases

Leishmaniasis (Africa, Asia, Europe, Americas). African trypanosomiasis/sleeping sickness (Central and East Africa). American trypanosomiasis /Chagas disease (Latin America). Malaria. Helminth infections (parasitic worms, worldwide). Leprosy

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Why is treating a neglected disease a priority? (1)

Travel: growth in international travel and immigration, NTDs are no longer geographically restricted as people in the western world may present with infections. Only a few dozen newly approved therapies and only a handful of truly novel drugs.

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Why is treating a neglected disease a priority? (2)

Re-infection and emergency of drug-resistant organisms

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Why are there no better therapies?

Affect mostly poor people in poor regions of the world. Limited funding for basic research. (Current therapies: old, limited efficacy, resistance, S/E, poor patient compliance)

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Describe features of malaria (1)

Disease caused by the protozoan parasite of genus Plasmodium. Plasmodium is a genus of parasitic alveolates. The parasite always has two hosts in its life cycle: a Dipteran insect host and a vertebrate host. Sexual reproduction always occurs in the insect

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How is the Plasmodium species transmitted to humans?

By the infected female Anopheles mosquito (vector)

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What are the four species of Plasmodium that affect humans?

Plasmodium falciparum (malignant tertian malaria). Plasmodium vivax (benign tertian malaria). Plasmodium malariae (quartan malaria). Plasmodium ovale (tertian malaria).

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What is tertian malaria and quartan malaria?

Tertian malaria: a malarial fever with paroxysms that typically recur every 48 hours or every other day. Quartan malaria: a malarial fever with paroxysms that typically recur every 72 hours or every fourth day. Plasmodium destroy rbcs

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Outline the life cycle for Plasmodium falciparum (1)

The P. falciparum life cycle in humans begins with the bite of an infected female mosquito. Parasites reach the liver and grow and multiply by asexual division within liver cells in 5 to 7 days. As merozoites, leave liver, invade rbcs, multiple for 1-3 da

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Outline the life cycle for Plasmodium falciparum (2)

Infected RBCs disrupt approximately every 48 hours releasing merozoites. Some merozoites develop into male and female sexual forms, called gametocytes, and can be acquired by mosquito

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Outline the life cycle for Plasmodium falciparum (3)

Protozoa have life cycle stages evolved to allow them to survive the wide variety of environments they are exposed to during their complex life cycle.

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Outline the life cycle for Plasmodium falciparum (4)

Each stage in the life cycle of protozoa is typified by a cellular variety with a distinct morphology and biochemistry.

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What are the drug targets for anti-malaria drugs?

Target plasmodium during hepatic stage, erythrocyte stage or prevent reinfection of mosquitoes (gametocytes stage)

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Describe features of quinine

Natural compound, used to treat chloroquinine-resistant strains of Plasmodium falciparium. Quinine ring, side ring with tertiary amine group – keep structure of antimalarial drugs, can exist as stereoisomer (quinidine), epimers are inactive

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Describe features of quininacrine

Synthetic product, synthetic derivative of 9-aminoacridine, 3 aromatic cycle, also used to treat tapeworm infection, enantiomers have same activity, similar structure to quinine

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Give examples of the modifications of quinine and quinacrine

Have bicyclic ring/quinine ring. Hydroxy group used for the development of mefloquine. MeO group used to develop pamaquine. Chloroquine – formed from quinacrine. All structures have tertiary amine within quinine ring – needed to antimalarial activity

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Describe features of chloroquine (1)

Most effective and safe medicine to treat malaria. Limited side effects: muscle problems, loss of
appetite, diarrhoea, and skin rash. Can be used as racemic mixture, both enantiomers have same activity, but issue of emergence of plasmodium resistance.

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Describe features of chloroquine (2)

Chlorine increases activity

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Describe features of mefloquine (1)

Taken once a week to treat and prevent malaria. Prevention: one or two weeks before potential exposure and continued for four weeks after potential exposure. Used to treat mild or moderate malaria only.

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Describe features of mefloquine (2)

Potential serious side effects: depression, hallucinations, and anxiety, seizures, and ringing in the ears. Resistance to mefloquine is now common in Asia. Sold as a racemate

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Describe features of amodiaquine (1)

It is recommended to be given with artesunate to reduce the risk of resistance. Rare but serious side effects: liver problems or low blood cell levels. It is widely available in Africa.

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Describe features of amodiaquine (2)

It is often used in combination with artensunate as a by mouth artemisinin-based combination therapy (ACT) for uncomplicated P. falciparum malaria. Amodiaquine has also been found to work against chloroquine-resistant P. falciparum strains of malaria.

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Outline the mechanism for chloroquine and quinoline-based compounds (1)

Hemoglobin is transported into the food vacuoles of the plasmodium, where digestion of the hemoglobin supplies the organism with a source of amino acids. Free heme is not metabolised. Free heme is toxic to the plasmodium cells.

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Outline the mechanism for chloroquine and quinoline-based compounds (2)

Plasmodium polymerise free heme to form hemozoin (non-toxic).

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Outline the mechanism for chloroquine and quinoline-based compounds (3)

Quinolines bind heme preventing polymerization into hemozoin via pi-pi interactions.

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Describe features of artemisinin (1)

Artemisinin and its derivatives can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence.

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Describe features of artemisinin (2)

Analogues produced, different stereocenters, all have the presence of O-O bonds, peroxide group (reactive bond, has antimalarial effect). Artemesinin has a very different mode of action than conventional anti- malarials.

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Describe features of artemisinin (3)

Used in combination with another non-artemesinin based therapy to prevent drug-resistance. Artemisinin produces a very rapid reduction in the parasite biomass with an associated reduction in clinical. No known resistant, few S/E

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Describe features of artesunate and amodiaquine

Recommended for acute uncomplicated Plasmodium falciparum malaria. Side effects include loss of appetite, nausea, abdominal pain, sleepiness, trouble sleeping, and cough

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Describe features of artesunate and mefloquine

Efficacious first-line treatment regimen in areas of Thailand for many years. It's recommended by the WHO for uncomplicated falciparum malaria. Adverse effects of mefloquine seem to be reduced when the drug is combined with artesunate

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What is the mechanism of action of artemisinin?

Blocks polymerization of heme in a different way, O-O (peroxide group) reacts with iron in hemoglobin, peroxide group breaks, Fe II to Fe III, formation of radical, very reactive species, forms covalent bond with heme, prevents polymerization of heme

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What is the mechanism of action of proguanil? (1)

Prodrug, converted into cycloguanil, inhibits DHFR enzyme, prevents replication of plasmodium, proguanil/atovaquone. DHFR – enzyme, converted dihydrofolate into tetrahydrofolate (involved in synthesis of amino acids, nucleic acids, RNA and DNA for plasmod

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What is the mechanism of action of proguanil? (2)

Tetrahydrofolate (or tetrahydrofolic acid) is a cofactor in many reactions, especially in the synthesis (or anabolism) of amino acids and nucleic acids.

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What are kinetoplastids?

Kinetoplastids or trypanosomatids are protozoan parasites responsible of the human diseases Leishmaniasis, African trypanosomiasis and American trypanosomiasis. They have eukaryotic/kinetoplastic features (organelle with large massed DNA)

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Give three examples of kinetoplastid (eukaryotic) diseases

Leishmania, Sleeping sickness and Chagas disease

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Describe features of Leishmaniasis

Leishmaniasis is a disease caused by a number of protozoa in the genus Leishmania. Transmitted via the vector, sandfly. Common in South Europe, affects humans and dogs (mammals)

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What is cutaneous leishmaniasis?

Cutaneous leishmaniasis (CL): spectrum of presentations, typically involves self-‐healing or chronic lesions on the skin and mucus membranes
skin sores usually start at the site of the sandfly bite not life‐threatening.

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What is visceral leishmaniasis?

Occurs 2 ‐ 8 months after the initial bite parasite damages the immune system fatal without treatment

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Outline the lifecycle for Leishmaniasis (1)

Protozoa may be harbored in diseased mammals (i.e. dogs) and transmitted from the infected mammal to man by bites from female sandflies of the genus Phlehotomus.

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Outline the lifecycle for Leishmaniasis (2)

Protozoa can exist in different morphological/ biochemical forms, sand fly bites human, protozoa enters body, affects macrophages, multiplication, differentiates into amastigotes, infect other tissues and macrophages, sand fly bites again, protozoa goes b

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Which drugs are used against visceral leishmaniasis?

Sodium stibogluconate Antimonium (Sb) - complex and Amphotericin B.

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Describe features of Sodium stibogluconate Antimonium (Sb) - complex

Inhibition of DNA replication (inhibition of topoisomerase enzymes), inhibition of tyrosine phosphatases (cell signalling). S/E: loss of appetite, nausea, muscle pains, headache, fatigue (IM - painful)

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Describe features of amphotericin B

An antifungal medication used for also for leishmaniasis. Used in otherwise- untreatable visceral leishmaniasis. Amphotericin B forms pores in cell membranes (or cell wall in fungi) that cause rapid leakage of monovalent ions (K+, Na+, H+ and Cl−), cell d

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Describe features of pentamidine

Used for both VL and CL. Pentamidine can be given by injection into a vein or muscle or by inhalation. S/E: low blood sugar, pain at the site of injection, nausea, vomiting, low blood pressure, kidney problems. Lack of oral bioavailability, poor BBB penet

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Describe features of improving existing drugs

Newer diamidine analogues. Increase lipophilicity of pentamidine so it has pass through BBB, still in clinical trials. Enhanced cell permeability. Improved p.o. availability in animal models. Design strategy: retain dibasic pharmacophore, replace linker

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What is the mechanism of action of pentamidine?

Pentamidine bind the DNA at the N3 of the adenosine through its amidine moiety via H-bond. Intercalating agent. Block replication resulting in death of parasite

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Describe features of Human African trypanosomiasis (Sleeping sickness)

Causative agent: Trypanosoma brucei (kinetoplastid protozoon). The protozoa is transmitted by the tsetse fly

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What are the two forms of Trypanosoma brucei? (1)

Trypanosoma brucei gambiense: in west/central Africa, accounts for >95% of reported cases of sleeping sickness, chronic infection, latent, symptomless (months-years), symptoms may emerge in advanced disease stage (CNS)

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What are the two forms of Trypanosoma brucei? (2)

Trypanosoma brucei rhodesiense: found in eastern and southern Africa, represents <5% of reported cases, causes an acute infection, first signs and symptoms are observed
months-weeks after infection, disease develops rapidly and invades the CNS.

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What is the first stage of the African Sleeping Sickness symptoms?

Haemolymphatic phase. Parasite multiplies in subcutaneous tissues, blood and lymph. Symptoms include bouts of fever, headaches, joint pains and itching. Treatment options: pentamidine, suramin

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What is the second stage of the African Sleeping Sickness symptoms?

Neurological. Parasite crosses BBB & infects CNS. Symptoms more obvious: changes of behaviour, confusion, sensory disturbance, poor coordination. Disturbance of the sleep cycle. Lethal without treatment. Treatment options: melarsoprol, eflornithine

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Outline the lifecycle of African trypanosomiasis

Infect tsetse fly, in human body, multiplication, infect organs, back in fly, sexual reproduction, infect other humans (diagram)

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Describe features of eflornithine (1)

Eflornithine is used in the treatment of the Sleeping Sickness. Originally developed as anti-‐cancer drug. Inhibitor of ornithine decarboxylase (ODC). ODC catalyzes the decarboxylation of ornithine into putrescine. Committed step in polyamine synthesis

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Describe features of eflornithine (2)

Amino acid (similar to lysine), fluoro-metho group, inhibitor of ornithine decarboxylase (enzyme in protozoa, responsible of decarboxylation of ornithine for polyamine synthesis). Pyridoxal phosphate – cofactor interacts with amine group

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Describe features of Chagas disease

Causative agent: Trypanosoma cruzi (kinetoplastid protozoon). Vector: “kissing bugs” (large, blood-sucking insects)

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What are the acute symptoms of Chagas disease?

Lethal for 5% of affected children. Fever, malaise, facial oedema, generalised lymphadenopathy, hepatosplenomegaly. Often resolves spontaneously in 4‐6 weeks

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What are the chronic symptoms of Chagas disease?

Asymptomatic “indeterminate” disease. Patients can transmit parasite to others while showing no signs of the disease, can last 10 years to life. Develops in 10% to 30% of infected patients and involves heart/GI tract (cause of infectious cardiomyopathy)

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Outline the infection cycle of Chagas disease (1)

Triatomine bug takes a blood meal. Metacyclic trypomastigotes penetrate cells, transform into amastigotes. Multiplication in cells of infected tissues. Amastigotes transform into trypomastigotes, burst into bloodstream.

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Outline the infection cycle of Chagas disease (2)

Triatomine bug takes blood meal. Epimastigotes in midgut multiply. Metacyclic trypomastigotes in hindgut. Cycle repeats

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Describe features of benznidazole (1)

Nitroaryl compounds. Benznidazole – aromatic ring, imidazole ring, link to nitro-group, fundamental for activity. Used to treat Chagas Disease. Highly effective in early disease, this decreases in those with long-term infection

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Describe features of benznidazole (2)

It should not be used in people with severe liver and/or kidney disease. Pregnant women should not use benznidazole because it can cross the placenta and cause teratogenicity

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What is the mechanism of action of benznidazole?

Metabolism of nitro group to form nitroso group (imidazole compound – reactive species), inhibition of trypanothione (found in protozoa, scavenger of radials, protects protozoa), micro-organisation accepts oxidative stress, able to kill protozoa

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What is the major function of trypanothione?

A major function of trypanothione is in the defence against oxidative stress. Essential for trypanosoma cruzi to survive

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Describe features of helminth infections

Helminthiasis, or worm infestation, is one of the most prevalent in the world. Worms are parasitic in humans. Ability to evade host immune defenses for reasons that are not fully understood.

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What are the two categories of helminths?

Platyhelminths (flatworms), include classes of cestode and trematode. Aschelminths or nematodes (roundworms)

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Why is there limited investment in drug discovery to target helminthiases?

Due to lack of lethality. Helminthiasis can run asymptomatic or cause anemia or damage to liver, eyes and blood vessels. Most helminthiases are localised in the intestinal tract, can pass to other organs (heart, liver, lungs, muscles) – hard to remove/not

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Describe features of diethylcarbamazine

Aryl group. MOA still unclear. Filaricidal action – kill nematodes. Inhibition of microtubule polymerization. Interference with arachidonic acid metabolism

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Describe features of benzimidazoles

Mebendazole, alvendazole, thiabendazole, flubendazole. MOA - prevent microtubule polymerisation, to prevent mitosis

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What is the mechanism of action of ivermectin

Acts at level of NS of worms, bind to GABA receptor, Cl channel of worms, Cl ion influx enhanced, hyperpolarisation occurs, leads to paralysis of NS of worm, paralysis of the worm

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Describe features of leprosy

Leprosy, also known as Hansen's disease (HD), is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis

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Describe features of mycobacteria (1)

Genus of acid-fast bacilli belonging to the Mycobacteriaceae, include organisms responsible for TB and leprosy. Mycobacteria are not readily stained by Gram method due to high surface lipid content (mycolic acids)

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Describe features of mycobacteria (2)

Mycolates containing cyclopropane rings, difficult to penetrate mycobacterium. Cell envelope is the main responsible for mycobacterium pathogenicity. Lipophilic drug – poor oral availability

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What are the symptoms of leprosy?

Granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract. Primary external sign: skin lesions (light or dark patches). If untreated leprosy can progress and cause permanent damage
to the skin, nerves, limbs, and eyes.

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How is leprosy transmitted?

Transmission of leprosy occurs during close contact with those who are infected (no vector)

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How is leprosy diagnosed?

Skin lesion consistent with leprosy and with definite sensory loss. Positive skin smears

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Describe features of dapsone

Commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. Common side effects include nausea and loss of appetite. Severe side effects may include: a decrease in blood cells, red blood cell breakdown

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What is the mechanism of action of dapsone?

Dapsone is an antimetabolite, inhibits bacterial synthesis of dihydrofolic acid, competition with para-aminobenzoate for active site of dihydropteroate synthase

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Tackling Viral Epidemics and Neglected Diseases - Neglected Tropical Diseases

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