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    Antiparasitic drugs

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    Male fern (Dryopterisfilix-mas(L.) Schott)

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    Anthelminthic Drugs

    Vermicide- kill

    Vermifuge- expell Unlike protozoa, helminths are large and have complex

    cellular structures

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    Developing countries

    Most of the protozoal infections are due to

    unhygienic conditions. Harm host by

    depriving him of food,

    blood loss, injury to organs,

    toxin,

    obstruction of intestine or lymphatics Rarely fatal

    Resistance no big issue

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    Anthelminthic drugs

    Three major groups of helminths (worms)areNematodes

    Trematodes

    Cestodes

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    Nematodes :

    Round worm ---Ascariasis

    Hook worm --- Ancylostoma duodenale, Nectar Americans

    Pin worm --- Enterobiasis

    Thread worm--- Strongyloides Whipworm --- Trichuris trichuria

    Nematodes :

    Trichinosis Trichinella spiralis

    Filariasis Wucheria bancrofti

    Onchocerciasis (River blindness) -Onchocerca volvulus

    TREMATODES ( FLUKES ) :

    Chinese liver flukeClonorchis sinesis

    Lung fluke---- Paragonimus westermani

    Schistosomiasis

    Schistosoma spCestodes Tape worm

    Beef tape wormTaenia saginata

    Pork tape wormTaenia solium

    Fish tape wormDiphyllobothrium latum

    Dog tape wormEchinococcus granulosis

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    Modes of Transmission Four main mechanisms for parasitic transfer:

    Ingestion of eggs from the

    fecal material of an infected

    individual Ascaris lumbricoides

    The larva of the parasite can burrow into

    the skin of a person Schistosomes

    The larva of the parasite can

    move from person to personthrough an insect vector

    Trypanosomes

    Plasmodia

    Sexual transmission

    Trichomonas vaginalis

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    Mode of worm infestation

    A. In the hosts gut:

    Round worms (nematodes)

    Tapeworms (cestodes)B. In the tissues of hosts:

    Schistosomiasis (flukes: bilharzias): S.

    mansoni, etc. Tissue round worms: filiareae, dranculus

    medinensis (guinea worm)

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    Anthelminthic drugs

    Drugs for helminths

    Nematodes :Albendazole, Mebendazole,Pyrantel pamoate, Diethylcarbamazine,Ivermectin

    Trematodes :Praziquantel,metrifonate,bithionol, emetine, dehydroemetine

    Cestodes :Niclosamide, Praziquantel,Albendazole

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    Anti-helminthic drugs

    Benzimidazole :

    Thiabendazole, Albendazole & Mebendazole

    Effective against wide spectrum ofnematodes

    It acts by binding and interfering the

    assembly of microtubules It also decreases the glucose uptake

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    Inhibits the polymerization of tubulin into microtubulesThis inhibition prevents cellular division and the absorption of

    glucose in its intestines

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    Thiobendazole

    First benzimidazole

    Effective for all species of nematodes infesting the g.i.t.-

    roundworm, hookworm, Enterobius, Trichuris,

    Strongyloides and Trichinella spiralis.

    It also inhibits development of the eggs of worms and

    kills larvae.

    Thiabendazole affords symptomatic relief in cutaneous

    larva migrans and skeletal muscle symptoms produced

    by migration of Trichinella spiralis larvae to muscles.

    HasAntiinflammatory, analgesic and antipyretic actions.

    These may contribute to its effect in cutaneous larva

    migrans and other inflammatory conditions produced by

    larvae or worms in tissues.

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    well absorbed from g.i.t., systemic adverse effects are

    frequent and often interfere with normal activity

    Nausea, vomiting, loss of appetite, headache, giddiness

    are most common. It can impair alertness-driving andoperation of machinery should be prohibited.

    Itching, abdominal pain, diarrhoea and a variety of other

    symptoms are also produced.

    Dose - 25 rng/kg/day in two divided doses taken aftermeals. Tablets must be chewed;

    Uses

    Because of frequent side effects and poor patient

    acceptability, thiabendazole is used only when otherbetter tolerated drugs are ineffective.

    Strongyloidosis

    Cutaneous larva migrans

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    Mebendazole congener of thiabendazole

    it retained the broad-spectrum anthelmintic activity but notthe toxicity of its predecessor.

    It has produced nearly 100% cure rate/ reduction in egg

    count in roundworm, hookworm (both species), Enterobius

    and Trichuris infestations, but is much less active on Strongyloides.

    Upto 75% cure has been reported in tapeworms, but H.

    nana is relatively insensitive.

    It expelsTrichinella spiralis from intestines, but efficacy inkilling larvae that have migrated to muscles is uncertain.

    Prolonged treatment has been shown to cause regression

    of hydatid cysts in the liver. Treatment after resection of

    the cyst may prevent its regrowth

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    Mechanism of action

    It acts probably by blocking glucose uptake in theparasite and depletion of its glycogen stores.

    The site of action of mebendazole appears to be

    the microtubular protein beta-tubulin' of theparasite.

    It binds to beta-tubulin of susceptible worms with

    high affinity and inhibits its polymerization.

    Intracellular microtubules in the cells of the wormare gradually lost.

    The immobilizing and lethal action of mebendazole

    on worms is rather slow: takes 2-3 days to develop.

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    p/k- Absorption of mebendazole from

    intestines is minimal; 75-90% of an oral dose

    is passed in the faeces. The fraction absorbedis excreted mainly as inactive metabolites in

    urine/faeces.

    s/e- Diarrhoea, nausea and abdominal pain.

    Incidents of expulsion of Ascaris from mouth

    or nose have occurred, probably due to

    starvation of the parasite and their slow death.

    High doses --Allergic reactions, loss of hairand granulocytopenia

    Pregnancy- C/I

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    Uses of mebendazole

    The dose and duration of treatment is the same for

    children above 2 years as for adults; 1/2 dose for

    1-2 yr age.

    Roundworm, Hookworm, Whipworm

    100 mg twice a day for 3 consecutive days. No fasting,purging or any other preparation of the patients is needed.

    Enterobius100 mg single dose.

    Strict hygienic measures and simultaneous treatment of all

    children in the family or class Trichinella spiralis: 200 mg BD for 4 days; less effective

    than albendazole.

    Hydatid disease: 200-400 mg BD or TDS for 3-4 weeks;

    less effective than albendazole.

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    Albendazole congener of mebendazole: retains the broad-spectrum

    activity and excellent tolerability of its predecessor, and hasthe advantage of single dose administration

    One dose treatment has produced cure rates in ascariasis,

    hookworm (both species) and enterobiasis which are

    comparable to 3 day treatment with mebendazole.

    Results in trichuriasishave been inferior to mebendazole.

    In strongyloidosis, more effective than mebendazole: a 3

    day course has achieved nearly 50% cure, and a second

    course repeated after 3 weeks cured practically all patients.

    Three day treatment has been found necessary for

    tapewormsincluding H. nana.

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    Results in hydatiddisease and hookwormhave been

    superior to mebendazole.

    Albendazole has weak microfilaricidalaction, kills cysticerci,

    hydatid larvae, ova of ascaris/hookworm and is alsoeffective in cutaneous larva migrans.

    The mechanism of action is similar to that of mebendazole.

    Absorption of albendazole after oral administration is

    moderate, but inconsistent. It is enhanced when the drug istaken with fatty meal (may help in treating

    neurocysticercosis and hydatid disease).

    Active metabolite

    albendazole exert antihelmintic activity in tissues as well. Albendazole is well tolerated; only gastrointestinal side

    effects have been noted. Few patients have felt dizziness.

    Prolonged use, as in hydatid or in cysticercosis, has caused

    headache, fever, alopecia, jaundice and neutropenia

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    No preparation or postdrug fasting/

    purging is required.

    For intestinal worms it should be given on

    empty stomach,

    while for cysticercosis, hydatid and

    cutaneous larva migrans it should be given

    with a fatty meal.

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    Ascaris, hookworm, Enterobius and Trichuris: single

    dose of 400 mg (for adults and children above 2 yrs, 200

    mg for 1-2 yr age).

    Tapeworms and strongyloidosis: 400 mg daily for 3

    consecutive days.

    Trichinosis: Three day treatment expels the adult worm

    from intestine, but has limited effect on larvae that have

    migrated to muscles.

    Neurocysticercosis: Albendazole is the anthelmintic

    of choice for the treatment of neurocysticercosis. Usually

    8-15 days course of 400 mg BD (15 mg/kg/ day) is

    employed. Cysticercosisof other tissues (muscles,

    subcutaneous area) also responds, but no drug should

    be given for ocular cysticercosis-blindness can occur

    due to the reaction.

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    Cutaneous larva migrans: Albendazole 400 mg

    daily for 3 days is the drug of choice; kills larvae

    and relieves symptoms. Hydatid disease: 400 mg BD for 4 weeks, repeat

    after 2 weeks (if required), up to 3 courses. It is

    the preferred treatment given before and after

    surgery as well as to inoperable cases.

    Filariasis: Added to diethylcarbamazine (DEC) or

    ivermectin, albendazole has adjuvant value

    C/I pregnancy

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    Benzimidazole :

    Albendazole and Mebendazole are poorlyabsorbed from GIT whereas thiabendazoleis well absorbed.

    Albendazole and Mebendazole are well

    tolerated , thiabendazole causeshallucinations

    Mebendazole and Albendazole are used

    to treat intestinal nematode infections Thiabendazole is preferred drug of choice

    in cutaneous larva migrans.

    Contraindicated in pregnancy

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    Pyrantel Pamoate :

    It acts as a depolarizing neuromuscular agent

    persistent activation of nicotinic receptors -resulting in

    persistent depolarizatio-- slowly developing contracture

    and spastic paralysis. Worms are then expelled.

    An anticholinesterase action.

    Because piperazine causes hyperpolarization and flaccid

    paralysis, it antagonizes the action of pyrantel.

    Cholinergic receptors in mammalian skeletal muscle

    have very low affinity for pyrantel.

    Only 10-15% of an oral dose of pyrantel pamoate is

    absorbed: this is partly metabolized and excreted in

    urine

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    Used to treat round worm, hook worm and pin

    worm. Efficacy comparable to mebendazole.

    Lower cure rates (about 60%) have beenobtained in case of Necator infestation. It is less

    active against Strongyloides and inactive against

    Trichuris and other worms.

    g.i. symptoms,headache and dizziness isreported. It is tasteless, nonirritant; abnormal

    migration of worms is not provoked.

    Its safety in pregnant women and in childrenbelow 2 years has not been established.

    For Ascaris, Ancylostoma and Enterobius: a

    single dose of 10 mg/kg

    No fasting, purging or other preparation needed.

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    Piperazine

    highly active drug against Ascaris and Enterobius

    now considered a second choice drug

    Piperazine causes hyperpolarization of Ascaris muscle by a

    GABA agonistic action -- opening Cl- channels that causes

    relaxation and depresses responsiveness to contractile

    action of ACh. Flaccid paralysis

    worms are expelled alive

    often a purgative (senna) is given with it, but is not

    necessary. No fasting or patient preparation is required.

    Piperazine does not excite Ascaris to abnormal migration.

    It does not affect neuromuscular transmission in man.

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    safe and well tolerated.

    Nausea, vomiting, abdominal discomfort and urticaria.

    Dizziness and excitement occur at high doses;

    toxic doses produce convulsions; death is due to respiratory failure.

    It is contraindicated in renal insufficiency and in

    epileptics, but is safe in the pregnant.

    4 gm OD for 2 days. Intestinal obstruction due to roundworm.

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    Levamisole, Tetramisole

    use is restricted to ascariasis andancylostomiasis, because action on other worms

    is poor.

    The ganglia in worms are stimulated causing

    tonic paralysis and expulsion of live worms.Interference with carbohydrate metabolism

    (inhibition of fumarate reductase) may also be

    contributing.

    Single dose of 50, 100, 150 mg according to

    weight.

    Immunomodulator

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    Diethylcarbamazine :

    It acts by immobilizing the microfilaria andrender them susceptible to host defense

    Well absorbed orally

    Used mainly in the drug of choice forFilariasis and Visceral larva migrans

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    Diethylcarbamazine : Piperazine derivative.

    Diethylcarbamazine has a highly selective effect on

    microfilariae (Mf).

    A dose of 2 mg/kg TDS clears Mf of W. bancrofti and B.

    malayi from peripheral blood in 7 days.

    However, Mf present in nodules and transudates

    (hydrocoele) are not killed.

    Mechanism of action- alteration of Mf membranes so that

    they are readily phagocytosed by tissue fixed monocytes,

    but not by circulating phagocytes.

    Muscular activity of the Mf and adult worms is also

    affected causing hyperpolarization due to the piperazine

    moiety,

    active against Mf of Loa loa and onchocerca volvulus

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    Filariasis: 2 mg/kg TDS produces rapid smptomatic

    relief.

    However, the adult worm survives in the lymphatics and

    gives rise to intermittent microfilaraemia and symptoms.

    Elephantiasis due to chronic lymphatic obstruction is not

    affected by DEC, because fibrosis of lymphatics is

    irreversible.

    Yearly treatment with a combination of DEC and

    albendazole on mass scale has brought downtransmission of filariasis by reducing microfilaraemia.

    Tropical eosinophilia: 2 mg/kg TDS for 2-3 weeks

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    Mazzoti reaction

    Onchocerciasis t/t with DEC

    Fever, urticaria, swollen tender LN,tachycardia, hypotension, arthralgia,

    oedema.

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    Anti-helminthic drugs

    Ivermectin :

    obtained from Streptomyces avermitilis

    Ivermectin is the drug of choice for single dose

    treatment of onchocerciasis and strongyloidosis,and is comparable to DEC for bancroftian and

    brugian filaria. It is also highly effective in

    cutaneous larva migrans and ascariasis,

    while efficacy against Enterobius and Trichuris is

    moderate.

    Certain insects, notably scabies and head lice

    are killed by ivermectin.

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    It acts through a special type of glutamate gated

    Cl- channel found only in invertebrates.

    Such channels are not involved in the motor

    control of flukes and tapeworms which are

    unaffected by ivermectin. Potentiation of GABAergic transmission in the

    worm has also been observed.

    The lack of GABA-related actions in man could

    be due to its low affinity for mammalian GABA

    receptors and its exclusion from the brain,

    probably by P-glycoprotein mediated efflux at

    the blood brain-barrier.

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    Anti-helminthic drugs

    Ivermectin :

    Well absorbed orally, metabolized in liver and

    excreted in feces.

    Contraindicated in pregnancy

    does not cross mammalian blood / brain barrier

    Drug can act as a GABA agonist causing

    increased muscular contaction e.g Levamisol Used for Onchocerca volvulus, strongyloides

    and cutaneous larva migrans.

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    Ivermectin has replaced DEC for

    onchocerciasis and has been used in the

    'river blindness' control programme of

    WHO in Africa and Latin America.

    Ivermectin is the only drug effective orally

    in scabies and pediculosis. Single 0.2

    mg/kg dose cures most patients.

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    Anti-helminthic drugs

    Praziquantel :

    It acts by increasing the permeability of

    tegument to calciumparalysis of the

    parasite.

    Well absorbed orally

    Good tissue distributionCNS.

    Metabolites are excreted in bile and urine

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    Anti-helminthic drugs

    Praziquantel :

    Active against trematodes like

    Chinese liver flukeClonorchis sinesisLung fluke ---- Paragonimus westermani

    SchistosomiasisSchistosoma sp

    Also active against Cestodes

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    Anti-helminthic drugs

    Praziquantel :

    Not advised for ocular cysticercosis

    because of destruction of the organism in

    the eye may damage eye.

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    Anti-helminthic drugs

    Bithionol used for the treatment of

    fasciola hepaticasheep liver fluke.

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    Anti-helminthic drugs

    Niclosamide

    Acts by inhibition of parasite mitochondrialphosphorylation of ADP to ATP.

    The drug is lethal for Cestodes scolex andsegments but not for ova.

    Laxative is used to purge all the dead

    segments of the intestineova liberationand absorption can lead to cysticercosis.

    It is used for most Cestodes infections.

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    Niclosamideblocks glucose uptakeby intestinal tapeworms. It may

    cause some mild gastrointestinal symptoms.

    Piperazinemay cause hypersensitivity reactions, neurologicalsymptoms (including worm wobble) and may precipitate epilepsy.

    Praziquantelparalyses both adult worms and larvae. It is extensively

    metabolised. Praziquantel may cause nausea, headache, dizziness

    and drowsiness; it cures with a single dose (or divided doses in oneday).

    Mebendazoleblocks glucose uptakeby nematodes. Mild GI

    distarbunces may be caused, and it should not be used in preg-

    nancy or in children under the age of 2.

    Albendazoleis similar to mebendazole.

    Levamisoleparalyses the musculatureof sensitive nematodes which,

    unable to maintain their anchorage, are expelled by normal peristalsis.

    It is may cause abdominal pain, nausea, vomiting, headache anddizziness.

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    Thiabendazole inhibits cellular enzymes of susceptiblehelminths. Gastrointestinal, neurological and hypersensitivity

    reactions, liver damage and crystalluria may be induced.

    Pyranteldepolarises neuromuscular junctionsof susceptible nematodes which are expelled in the faeces. It

    cures with a single dose. It may induce GI disturbance,

    headache, dizziness, drowsiness and insomnia.Diethylcarbamazinekills both microfilariae and adult worms.

    Fever, headache, anorexia, malaise, urticaria, vomiting and

    asthmatic attacks following the first dose are due to products of

    destruction of the parasite, and reactions are minimised by

    slow increase in dosage over the first 3 days.

    Ivermectinmay cause immediate reactions due to the death

    of the microfilaria. It can be effective in a single dose, but is

    best repeated at 612-month intervals.

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    Anthelminths

    Drugs that are active against roundworms and flatworms Benzimidazoles

    Macrocyclic lactones

    Symptoms of a round or flatworm infection: Loss of appetite, distended abdomen, painful abdomen,

    coughing, fever, vomiting, diarrhoea, listlessness and generallyfeeling unwell

    Can lead to malnutrition and anemia, with a small chance ofmore severe problems due to wandering worms

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    Niclosamide

    Active against T. saginata, D. latum,

    H. nana(6 days), D. caninum, T. solium

    (risk of autoinfection due to disintegration;

    prefer praziquantel).

    Molluscicide used in snail control

    programs (Bayluscide WP 70).

    Pearson R.D. 2005. Chapter 41, In Mandell G.L. etal.

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    Praziquantel

    Works by:

    Disrupting the membrane of the schistosome that coats the

    parasite with host molecules

    Causing the rapid influx of calcium ions into the parasite,

    resulting in muscular tetany Paralysis of adult worms, ...

    Over 80% is absorbed after an oral dose.

    Adverse effects are mild but common (in over 30% of

    patients): dizziness, lethargy, headache, nausea,abdominal pain, ...

    Active against almost all trematodes (including all

    schistosomes, but not Fasciola hepatica) and cestodes.

    I ti I

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    Ivermectin I Related to avermectin, also produced by

    Streptomyces avermitilis. By interfering with the target animal's nervous

    system. These drugs kill by interfering with the target animal's nervous

    system

    Drugs bind to glutamate-gated Cl ion channels in the musculature of theworm

    This binding causes an unregulated ion flux through the cellsmembranes

    Paralysis of the parasite

    Active on most common intestinal worms(except tapeworms), most mites, and some lice.

    Used for Strongyloidesstercoralis,onchocerciasis, body lice, and scabies.

    Common for animal use (e.g. heartworm

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    Ivermectin II

    Category IV, or very low toxicity. Occasional Mazzoti-type (anaphylactoid) reactions seen

    in onchocerciasis.

    Available for human use in the US, Canada, France, TheNetherlands ...

    Mectizan Donation Program (MDP) by Merck & Co., Inc.,in collaboration with the WHO,

    Elimination of lymphatic filariasis (LF) in areas that are

    co-endemic for onchocerciasis and lymphatic filariasis.Mectizan is co-administered with albendazole, which isdonated by GlaxoSmithKline, in these settings.

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    schistosomiasis

    Drugs that are active against schistosomiasis Currently, praziquantel is the most common drug used for the

    treatment of all species of schistosomes

    The drug artemisinin, an antimalarial, is also effective againstschistosomes

    Symptoms of schistosomiasis: May develop a rash or itchy skin, fever, chills, cough, and

    muscle aches during the early phases of infection

    Most people have no symptoms at this early phase of infection

    The eggs of the parasite can damage the liver, intestines, lungs,and bladder

    Schistosomes are very difficult to kill because theydisguise themselves within the host by coating theirouter membrane with the hosts own molecules

    The immune system will not respond to an infection, because itwill not recognize the invading schistosomes as a threat

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    Worms (helminths) Drug of choice

    Tapeworms (cestodes) Niclosamide or Praziquantel orAlbendazole

    Roundworms (nematodes)Enterobius vermicularis(pinworm)

    Ascaris lumbricoides

    Trichuris trichiura(whipworm)

    Trichinella spiralis (trichinellosis)

    Strongyloides stercoralis

    Necator americanus(hookworm)

    Ancylostoma duodenale

    Onchocerca volvulus(Onchocercosis)

    Wuchereria bancrofti (Elephantiasis)

    Mebendazole or Pyrantel

    Mebendazole or Pyrantel

    Mebendazole or Albendazole

    Mebendazoleand Thiabendazole

    Thiabendazole

    Mebendazole or Pyrantel

    Mebendazole, Pyrantel or

    Albendazole

    Ivermectin

    Diethylcarbamazine

    Flukes (trematodes)