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TREATMENT AND CONTROL METHODS IN PARASITOLOGYPart 1: Antiparasitic

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INTRODUCTION

There is a wide variety of parasites and an equally wide range of substances and practices used in their treatment and control.

Focus on general concepts and also introduce some of the most recent advances in parasitology for treating and preventing parasitic infections.

Part 1: Treatment Part 2: Control Part 3: Recent advances

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IMPORTANCE OF UNDERSTANDING PARASITE LIFE CYCLES FOR EFFECTIVE TREATMENT AND CONTROL

To understand parasite life cycles it is complicated

Without knowledge of a parasite’s life cycle, one cannot begin to understand how it is transmitted and how it cause disease.

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For example in UK, rainfall and temperature are the key factors determining the transmission efficiency of Fasciola hepatica – principally through their effect upon the snail intermediate host.

This factor has enabled the development of a liver fluke forecasting scheme.

Which is operated by National Animal Disease Information Service (NADIS).

So farmers can use this to determine when their flock is most at risk of infection and therefore should be treated with anthelmintics or if possible moved to less risky pasture.

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HOW A PARASITE’S LIFE CYCLE CAN INFLUENCE ITS TREATMENT AND CONTROL?

Direct life cycle Life cycle involves one or more species of vector Life cycle involves one or more intermediate hosts Parasite has a variety of definitive hosts Parasite has life cycle stages that are exposed to

the environment Sequence and timing of life cycle stages within a

host Location within host

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DIRECT LIFE CYCLE

Importance in treatment/ control - Provision of sanitation and basic hygiene

practices can prevent many gastrointestinal parasitic diseases

Application of life cycle knowledge - Washing fruit and vegetables in clean water can

remove protozoan cysts and helminth eggs

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LIFE CYCLE INVOLVES ONE OR MORE SPECIES OF VECTOR

Importance in treatment/ control - Disease transmission can be controlled by

targeting the vectors

Application of life cycle knowledge - Bed-nets can prevent mosquitoes transmitting

malaria

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LIFE CYCLE INVOLVES ONE OR MORE INTERMEDIATE HOSTS

Importance in treatment/ control - Disease transmission can be controlled by

targeting the intermediate hosts

Application of life cycle knowledge - Drainage to remove the habitat of snail

intermediate hosts of Fasciola hepatica

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PARASITE HAS A VARIETY OF DEFINITIVE HOSTS

Importance in treatment/ control - Reservoir hosts are a potential source of

infection

Application of life cycle knowledge - Schistosoma japonicum has numerous reservoir

hosts which can contaminate paddy field etc with eggs

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PARASITE HAS LIFE CYCLE STAGES THAT ARE EXPOSED TO THE ENVIRONMENT

Importance in treatment/ control - Environmental conditions can promote or limit

infection

Application of life cycle knowledge - Composting can kill the infective stages of many

gastrointestinal parasites

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SEQUENCE AND TIMING OF LIFE CYCLE STAGES WITHIN A HOST

Importance in treatment/ control - Optimal time for diagnosis

Application of life cycle knowledge - Mf of Wuchereria bancrofti exhibits

periodicity

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LOCATION WITHIN HOST

Importance in treatment/ control - Optimal time for diagnosis

Application of life cycle knowledge - Cattle should be treated for warble fly infections

before the larvae reach their resting site

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PART 1: TREATMENT

Antiparasitic

- Chemical/ Pharmaceutical drugs

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PROPERTIES OF AN IDEAL ANTIPARASITIC DRUG OR TREATMENT REGIME

Kills 100% of the parasites Broad spectrum Rapid action Provides long-lasting protection Simple to administer Requires only one or two treatments to achieve a

cure Safe (does not cause harmful side-effects) Does not have contra-indications Affordable to the individual/population Chemically stable with a long shelf life Does not cause harm to the environment

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KILLS 100% OF THE PARASITES

Obviously drugs need to be effective Need to kill all the parasites found in (or on) the

body of the host Should be less harmful to the host cells than to the

parasites. This selective toxicity is hard to achieve for

antiparasitic drugs. For example praziquantel if only effective against

adult schistosomes but not good killing the developing schistosomulae.

If the drug is not effective killing 100% parasites, it will increases the risk of resistance developing.

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BROAD SPECTRUM

Drugs that have a broad spectrum of action are beneficial since they can be used to treat a variety of parasites.

For example the avermectin drugs such as ivermectin and doramectin active against gastrointestinal nematodes as well as ectoparasites such as lice, fleas and ticks

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RAPID ACTION

Drugs that kill parasites rapidly reduce the chances of resistance developing

Since less time the parasite has to interact with the drug, the less chance there is of it evolving a physiological means of counteracting it.

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PROVIDES LONG-LASTING PROTECTION

Can reduce the cost of treatment

Can protect the hosts from the same disease infection.

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SIMPLE TO ADMINISTER

Drugs are seldom administered as compounds on their own.

Most of the drugs are ‘formulated’ with a cocktail of chemicals

The composition of which varies with the intended means of delivery e.g liquid, tablet or injection

Alters the effectiveness of the drug The formulation can influence drug’s stability,

toxicity to both host and target parasite, rate of absorption and excretion, bioavailability and pharmacokinetics.

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Ease of administration is important in order to ensure compliance and can be treated quickly with minimum of fuss.

Drugs can be taken without supervision tablets and liquid

Injection – intravenous or intra- peritoneal supervised by trained medical personnel

For domestic animals Dosing gun, ‘pour on/ spot on’ formulation on the body of animal, slow-release bolus (placed the drugs into rumen using special device.

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REQUIRES ONLY ONE OR TWO TREATMENTS TO ACHIEVE A CURE

The fewer the number of treatments required to remove the parasite, the better the chance of patient compliance

Especially if the treatment has to be delivered at a medical centre or veterinary surgery

If repetitive treatments are required, then there is a high possibility that when the patient starts to feel better or animal seems to be improving, the patient of owner will cease or forget to complete the treatment regime.

This will increase the possibility that the parasite will persist and increases the chances of any resistance developing.

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SAFE (DOES NOT CAUSE HARMFUL SIDE-EFFECTS)

There is always a risk that the drugs will harm the hosts.

The chance is reduced if the drug selectively acts upon a physiological process that does not occur in the host.

For example: Cryomazine and Diflubenzuron targeting the moulting process in arthropods

- Safe to use in mammal because no comparable metabolic pathway.

- Cryomazine interferes with the deposition of chitin in the cuticle

- Diflubenzuron inhibits chitin synthesis

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DOES NOT HAVE CONTRA-INDICATIONS

All chemicals are toxic if taken in sufficient concentration.

It is very rare for the drug to be so specific that only interacts with a single physiological process.

Patients normally will cease treatment if the drug induces unpleasant side effects such as nausea and vomiting.

The host’s health and generic constitution can influence the way it respond to drugs.

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For example: Ivermectin – is considered safe for use in most mammals.

In certain breeds of domestic dogs, very low concentration induce neurological symptoms –e.g hypersalivation, ataxia, blindness, respiratory distress, which can be fatal.

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AFFORDABLE TO THE INDIVIDUAL/POPULATION

Cost, a major consideration for any treatment regime – especially for poor people living in developing countries.

Even if the drug is ideal in every way, if it is too expensive then it becomes irrelevant to all but those who are rich.

Drugs that are still in patent are usually expensive the manufacturer needs to make sufficient profit to recoup the costs of development and fund the development of new drugs.

Once drug is out of patent it can be manufactured by any commercial concern and its cost usually declines.

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Example : albendazole and praziquantel - In the early 2000s, tablets of albendazole

US$0.20 per tablet and praziquantel US$3.00 per tablet.

- When out of patent, tablets of albendazole US$0.02 per tablets and praziquantel US$0.07 per tablets.

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CHEMICALLY STABLE WITH A LONG SHELF LIFE

The cost of drug is partly linked to its chemical stability.

If the drug is stable and has a long shelf life, and does not need to be stored in a fridge is usually going to be cheaper.

It can be bought in bulk and can be stored and transported at low cost.

It also will instantly available when needed.

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DOES NOT CAUSE HARM TO THE ENVIRONMENT

The environmental impact of the drug should be considered.

All the drugs that go into us and our animals are ultimately passed out of us in one way or another and they enter the environment.

Sometimes drug are metabolized completely

But very often breakdown products or unmetabolized drug are passed in urine or faeces or in the milk or present in the meat.

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Residues of drugs can persist in the environment under suitable conditions.

Therefore affect susceptible invertebrates both in soil and in surrounding water systems.

30Anticipated exposure routes of veterinary drugs in the environment

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ANTIPARASITIC Antiparasitics are a class of medications which are indicated

for the treatment of parasitic diseases such as nematodes, cestodes, trematodes, infectious protozoa and amoebas.

There are different medications suited to different types of parasites.

- Antinematodes are one group that can address infection with nematodes

- Anticestodes these target tapeworms - Antiprotozoal treat parasitic infections caused by protozoa

that enter the body - Antitrematodes treat parasitic infections caused by

trematodes

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ANTIPROTOZOAL

Kinetoplastid protozoa 'Anaerobic' protozoa Sporozoan protozoa

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KINETOPLASTID PROTOZOA

Human sleeping sickness are usually treated with suramin, though occasionally pentamidine is used.

Where trypanosomes are present in the CNS, are treated with melarsaprol or eflornithine (Trypanasoma brucei gambiense infections only)

Pentamidine intramuscular injection Eflornithine is active by the oral route.

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Suramin is also used to treat trypanosome in infections in equines and camels.

Quinapyramine works well in camels, pigs and cattle, but

Homidium bromide, isometamidium and diminazine aceturate are the principal drugs used to control such diseases in sheep and cattle

Chagas disease orally administered courses of nifurtimox or benznidazole are effective.

For leishmaniasis remains the antimonials sodium stibogluconate and meglumine antimonate administered by injection

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'ANAEROBIC' PROTOZOA Trichomoniasis, giardiasis and amoebiasis in both humans

and domestic animals can all be controlled by metronidazole.

This drug is orally active, very efficacious and relatively free of side effects.

The alternative in giardiasis is mepacrine

The alternatives in amoebiasis are diloxanide, which is only effective in non-invasive cases, and tinidazole, which is another potentially mutagenic 5-nitroimidazole.

Subsequently, satranidazole, yet another 5-nitroimidazole, was marketed in some territories for giardiasis and amoebiasis.

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SPOROZOAN PROTOZOA

Coccidiosis, especially in broiler chickens, is controlled by the continuous administration of drugs in the diet.

Currently, the ionophores such as lasalocid, salinomycin and especially monensin are the coccidiostats of choice.

Others, such as amprolium, clopidol, decoquinate and robenidine, are however still used.

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Malaria, which is the most common of the parasitic diseases of humans, can be treated by a wide range of drugs, all active by the oral route.

Until recently, the standard drugs were chloroquine for treatment, ptimaquine to prevent relapse (Plasmodium vivax malaria) and chloroquine or pyrimethamine + sulphadoxine (Fansidar) or pyrimethamine + dapsone (Maloprim) for prophylaxis.

Babesiosis in cattle can be controlled by diminazine aceturate, and theileriosis by parvaquone (East Coast Fever only), buparvaquone and possibly halofuginone.

Injectable formulations are available in all cases

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ANTINEMATODES

A large number of drugs are available to control the gastrointestinal nematode infestations of domestic animals.

Piperazine (small animals), haloxon (horses), dichlorvos (especially pigs), napbthalophos (sheep), the benzimidazoles, the benzimidazole carbamates and their prodrugs (e.g. thiabendazole, albendazole, oxfendazole, fenbendazole), morantel (cattle), pyrantel (horses and dogs), levamisole and ivermectin.

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A large number of drugs are also available for the treatment of human gastrointestinal infestations, including piperizine, thiabendazole, albendazole, mebendazole, levamisole, pyrantel and bephenium.

All are active via the oral route.

The most commonly used is mebendazole, which probably covers the broadest spectrum.

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Tissue-dwelling nematodes, the filariae diethylcarbamazine

Adult worms can be eliminated with suramin

Diethylcarhamazine was used also for onchocerciasis

Ivermectin also might be macrofilaricidal.

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ANTITREMATODES

Sheep and cattle infected with liver fluke are likely to contain all three developmental

stages: 1) early immature stages 2) immature stages 3) adults. Treatment of animals harbouring such mixed-

stage infections will be ineffective unless all three stages are eliminated.

Unfortunately most drug to treat trematodes infection is a stage specific.

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Most drugs are active against the adults, including rafoxanide, closantel, nitroxynil, nidoiolan, bromophos, bithinol sulphoxide, oxydozanide and albendazole.

Diamphenethide is very effective against early immature and immature stages, but is not against adults.

Triclabendazole, however, works well against all stages.

Fluke infections in humans are controlled by praziquantel

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The treatment of schistosomiasis in humans relies on three drugs, oxamniquine, metrifonate and praziquantel.

Oxamniquine works well against Schistosoma mansoni

Metrifonate against S. haematobium

Praziquantel against both species and also against S. japonicum.

All are active by the oral route and are generally well-tolerated

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ANTICESTODES

A number of chemotherapies are available to control these infections in both farm and companion animals, including dichlorophen (mainly companion animals), niclosamide, resorantel, bunamidine, mebendazole (sheep and cattle only), nitroscanate (companion animals only), pyrantel (horses only, at double dosage) and praziquantel (companion animals only).

Key drugs for human use are niclosamide, albendazole and praziquantel.

All three drugs can be administered via the oral route, work well against adult stages in the intestine and are generally well tolerated.

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Niclosamide works only against adult worms in the gut;

Albendazole and praziquantel can kill Taenia solium cysticerci

Mebendazole and especially albendazole are now being used with some success in cases of hydatid disease due to Echinococcus species

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AntinematodesAnticestodesAntitrematodes

Anthelmintics

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2 types - Broad spectrum - Narrow spectrum

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BROAD SPECTRUM

Class Anthelmintic Mode of action

Benzimidazoles (BZs) ThiabendazoleFenbendazoleAlbendazoleOxfendazole

Bind to a specific building block called beta tubulin and prevent its incorporation into certain cellular structures called microbutbules, which are essential for energy metabolism

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Class Anthelmintic Mode of action

Imidazothiaoles – tetrahydropyrimidines

LevamisoleMorantelPyrantel 

Mimic the activity of acetylcholine, a naturally occuring neurotransmitter that initiates muscular contraction

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Class Anthelmintic Mode of action

Macrocyclic lactones (ML) IvermectinEprinomectin Doramectin

Interfere with GABA-mediated neurotransmission, causing paralysis and death of the parasite.

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Class Anthelmintic Mode of action

 Amino-acetonitrile derivatives (ADDs)

Monepantel It paralyzes worms by attacking a previously undiscovered receptor HCO-MPTL-1, present only in nematodes

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Anthelmintics Parasite covered

Triclabendazole Fluke (including immature flukefrom 2 days of age)

Closantel Fluke (including immaturefluke over 5 weeks of age),Haemonchus contortus,Nasal bots

Nitroxynil Fluke (including immature fluke),Haemonchus contortus

Praziquantel Fluke and tapeworm

Diethylcarbamazine Filariasis worms

Narrow spectrum anthelmintics