After reading this article you will learn about:- 1. Anthelmintic Need 2. General Mode of Action of Anthelmintics 3. Properties of Ideal Anthelmintics 4. Classification.
Anthelmintic Need:
We know that parasitic infestation in animals makes them anaemic and weak. They can interfere with the growth of young ones. Parasitic infestation in lactating animals generally decreases milk yield. As a whole, the parasitic load in animals make them debilitated and bad looking. If an animal with worm load is seen, its skin and hair texture is not charming.
General Mode of Action of Anthelmintics:
i. Neuromuscular Blockers:
Some of the anthelmintics have action on the neuromuscular system. For example, piperazine acts in the similar fashion as the curare and causes paralysis of the worms, especially Ascaris. The paralysis of the worms is due to hyperpolarization of the muscle membranes.
ii. Cholinomimetics:
e.g. Levamisole, methyridine, morantel, pyrantel, bephenium, thenium etc. The above cited drugs affect neuromuscular system of worms acting like cholinomimetics. These agents possess functional groups similar to acetylcholine and bind to the receptors from which the acetylcholine binds. By doing so, it causes a continuous stimulatory effect. However, these are not inactivated by acetylcholine esterase.
iii. Inhibitors of Glucose Transport:
Some anthelmintic agents like dithiazanine which is given for canine whipworm, inhibits glucose uptake. Thus, by reducing glycogen content causes death of the worms.
iv. Disruptors of Glycogen Metabolism:
Schistosomicidal drug (niridazole) reduces phosphorylase phosphatase activity and increases the breakdown of glycogen reserve in worms. The death of worms is due to starvation.
v. Inhibitors of Glycolysis:
e.g. Arsenicals (thiacetarsamide), antimonials, (potassium antimony tartarate), stibophen etc. are organic trivalent heavy metals and bind with sulfhydryl (-SH) group. By binding with -SH they change the tertiary structure of proteins and the active site of enzymes.
vi. Inhibitors of Mitochondrial Reactions:
Benzimidazoles and thiophanate work in this way. For muscle contraction in works, high energy (ATP) is required which is provided after reduction of fumerate to succinate in mitochondria. The above drugs exert their action by inhibiting fumerate reductase which is required for conversion of fumerate to succinate.
vii. Un-Couplers Electron Transport:
Salicylanilides (clioxanide), niclosamide, oxyclozanide, rafoxanide, substituted phenols (bithionol, dinitrophenol, hexachlorophene, niclofolam, nitroxynil etc. are un-couplers of electron transport. These drugs interfere with electron transport associated with phosphorylation process which is an important biochemical process for generation of ATP. As ATP is an important source of chemical energy to parasites, the worms lack this energy and die.
Properties of Ideal Anthelmintics:
(i) Efficacy:
An ideal anthelmintic should have high level of anthelmintic activity. The efficacy is said to be good if it removes 95% of a gastro-intestinal nematodes from ruminant species. If it removes only 70% of the worm burden it is considered as a poor anthelmintic. It should have effect on both adult and larval stages of worms.
If it is effective only against adult worms it is repeated to eliminate adult worms that were unaffected during the first dose. 100% removal of worm load also eliminates the source of antigenic stimulation and animal looses the acquired resistance to parasite.
(ii) Wide therapeutic Index:
The anthelmintic compound should possess wide therapeutic index so that minor variation in calculation of dosage should not produce any toxicity in host. Since, the parasite and host shares some of the similar metabolic reactions and it may be the target for many drugs. Anthelmintics are much safer for hosts when their mechanism of action and biochemical pathways of worms do not share mutually.
(iii) Ease of Administration:
It should be easily administered. Most of the anthelmintics are administered orally in empty stomach. However, some of the anthelmintics are administered parenterally e.g. Ivermectin, ancylol etc.
(iv) Residue:
It should be eliminated from the body without any residual problems. The anthelmintics possessing a long withdrawal time will create human health hazards after consumption of milk, meat and other animals produce. The anthelmintics having a short withdrawal time are much safer.
Classification of Anthelmintics:
(i) Antinematodal
(ii) Antieestodal
(iii) Antitrematodal
Antinematodal Drugs:
Drugs that act against round worms are called antinematodals.
These drugs are classified as follow:
I. Simple Heterocyclic compounds e.g., Phenothiazine, piperazine etc.
II. Benzimidazoles e.g., Mebendazole, thiabendazole, cambendazole, albendazole, fenbendazole etc.
III. Imidazothiazoles e.g. Butamisole hydrochloride, levamisole etc.
IV. Tetrahydropyrimides e.g. Pyrantel and morantel.
V. Organophosphorus compounds e.g. Crufomate, haloxon, coumaphos, diclorvos, trichlorfon etc.
VI. Miscellaneous drugs e.g. Toluene, n-Butylchloride, tetrachloroethane, theniumclosylate, disophenol, phthalofyne, glycobiarsol, avermectins, hygromycin B.
Phenothiazine:
It is an old drug which was marketed as powder containing 95% pure phenothiazine (Phenovis). It was synthesized in 1885 and its anthelmintic activity was detected in 1938.
Chemistry: It is chemically thiodiphenylamine. The chemical structure is given in Fig. 35.1.
It is pale, green yellow powder, stable in dry condition and easily oxidizes when comes in contact with moisture. It is insoluble in water.
Anthelmintic Spectrum:
Ruminant:
It has wide range of activity against GI nematodes. It possess good anthelmintic activity for the large stomach worm (Haemonchus) and nodular worm (Oesophagostomum) of cattle, sheep and goats.
However, it is less effective against smaller stomach worm (Ostertagia, Trichostrongylus axei) and the hook worm (Bunostomum). It possess limited activity against roundworms of small intestine (Cooperia, Nematodirus and Trichostrongylus). It is not effective against larvae or immature round worms as well as against flukes and tape worms.
Horses:
Phenothiazine is 100% effective (Reffer Jone’s) against small strongyles and equine ascarids. It does not have efficacy against bots. The commercial preparations that contain piperazine and carbon disulfide along with phenothiazine are effective against ascarids, bots and strongyles in a single dose treatment.
Mode of Action:
Exact mechanism of action is not known. Resistant worms absorb the same quantity of phenothiazine equivalent to that of susceptible one but do not show any sign of toxicity. Therefore, the quantity of phenothiazine absorbed by the worms is not related with its mode of action. It is expected that the differences in the enzymatic system of worms are related with the mechanism of action of phenothiazine.
Pharmacokinetics:
Phenothiazine is converted to phenothiazine sulfoxide by the cellular enzyme of intestinal epithelium and then it is absorbed. Liver oxidizes it into two metabolites i.e. leucophenothiazone and leucothianol. The both metabolites are colorless and excreted in urine.
After excretion they are oxidized in air to brown red dyes i.e. thianol and phenothiazone. The red coloration of urine should not be confused with haematuria because sometimes the owners of the animals complain the clinicians that blood is coming with urine after phenothiazine administration.
Toxicity:
Horses are more susceptible to phenothiazine toxicity than cattle, swine, sheep and goat but birds are resistant. It should not be used in dogs and cats because of their high susceptibility to phenothiazine.
Toxicity Symptoms (Horse):
(i) Anaemia, weakness, dullness, anorexia, oliguria, colic, fever and rapid pulse.
Caution:
(i) Debilitated and anaemic cattle are more susceptible to poisoning.
(ii) It causes hemolysis of R.B.C. which may leads to anaemia and death.
Side Effects:
Photosensitization especially in calves but may also be observed in sheep, goats and fowl. Horses do not suffer with photosensitization. The high doses of phenothiazine is responsible for producing photosensitization because phenothiazine sulfoxide is not converted to leucophenothiazone and leucothianol by liver completely, and diffuses into general circulation to produce photosensitization. When phenothiazine sulfoxide reaches in aqueous humor of the eye, it produces photosensitization keratitis.
Ulceration of cornea occurs in 5 to 36 hours and cause blindness in cattle which is enhanced in bright sunlight.
Treatment of phenothiazine toxicity:
(i) Transfusion of blood.
(ii) Saline cathartics.
Contraindication:
(i) Weak, anaemic and emaciated animals.
(ii) Constipation.
(iii) Should not be given with organophosphates because it potentiates the toxicity of organophosphates.
(iv) Advance pregnancy.
Other Disadvantages:
(i) Pink coloration of milk and urine.
(ii) Hair and wool permanently discolored.
Administration:
It is administered through oral route.
Dose:
Single dose treatment:
Sheep and goat-Over 27 kg, 25 to 30G.
Cattle- 10 G/45 kg (the total dose should not exceed 70G, minimum of 10G in calves).
Horse- 3 G/45kg.
For small strongyles-5G/45 kg.
For large strongyles- The dose is divided and one half is given on each of 2 days.
Chickens- -0.5G/tM
Turkey- 1G/bird.
Daily Prophylactic Dose:
Sheep and goat- 0.25- 0.5G/animal.
Cattle – 0.5- 5G at the dose of 0.5G/45 kg.
Horse- Adult-2-5G.
Cattle – 1G.
Piperazine:
It is a drug of choice for ascarid and nodular worm infections of all species of domestic animals. It is moderately effective in pinworm infections. However, it does not have any effect for other parasites of gastrointestinal tract.
Chemistry:
It possess a simple ring structure and chemically it is diethylene diamine. The structure is given in Fig. 35.2
It is insoluble in ether but soluble in water and glycerol. It is a strong base and absorbs atmospheric water. Therefore, when stored, the container should be tightly closed and protected from light. It forms hexahydrate of Piperazine with moisture.
Salts of Piperazine:
(i) Piperazine adepate
(ii) Piperazine citrate
(iii) Piperazine phosphate
(iv) Piperazine sulfate
(v) Piperazine tartarate
(vi) Piperazine hydrochloride
The above salts of piperazine are more stable than piperazine base. The anti-parasitic activity of these salts depends on the piperazine base that varies in various salts (di-hydrochloride-50-53%, chloride -48%, adepate- 37%, sulfate-44%, hexahydrate- 44%, phosphate-42%, and citrate- 35%).
Dosage of salts of piperazine are expressed in terms of the hydrate equivalents i.e. 100 mg piperazine hydrate is approximately equal to 120 mg piperazine adepate, 104 mg piperazine phosphate and 125 mg piperazine citrate.
Anthelmintic Spectrum:
Dogs and Cats:
It is 100% effective in Ascaris infection. Efficacy increases after combining theniumclosylate and anti-tape worm drugs with piperazine. Piperazine is also effective against whipworm and tapeworms.
Horses:
It has excellent activity against ascarids. The activity against strongyles and pinworm is limited. Because it possess less efficacy against pinworms, therefore, the treatment is repeated after 21 days. It does not possess activity against stomach worms (Habronema) and tapeworms of equine. Combination of carbon disulfide (Piperazine and thiabendazole) provides activity against gastrophilus bots or strongyles respectively.
Ruminants:
Piperazine is active against nodular worms (oesophagostomum) and ascarid infection. It does not possess activity against abosomal and small intestinal nematodes.
Swine:
It has excellent efficacy for common ascarids and nodular worms in swine.
Chickens:
It possess high efficacy for Ascaridia galli. The caecal worm (Heterakis gallinarum) is not susceptible.
Mechanism of Action:
It produces neuromuscular block in susceptible worms. In addition to the above action, it inhibits succinic acid production in worms. Due to narcotic and paralytic effects produced by piperazine, worms loose their ability to maintain then- position in gastrointestinal tract and are eliminated due to peristaltic movement.
Administration:
It is convenient to give tablets of piperazine in dogs and cats. In other animals it is given in bran mashes. In poultry the powder or suspension is given in drinking water.
Doses:
Dogs and cats – 45-65 mg/kg.
Horses- 110 mg/kg.
Poultry – 32 mg/kg.
Toxicity:
(i) It possess good margin of safety in all animals,
(ii) Young animals can also be treated.
(iii) Large doses may produce vomiting, diarrhoea, incoordination and head pressing in cats and dogs.
(iv) Doses four times more than therapeutic dose can produce transitory diarrhoea, tympany and anorexia in calves.
Contraindication:
Animals suffering from hepatic and renal disorder should not be treated.
Benzimidazoles:
Thiabendazole, albendazole, cambendazole fenbendazole, mebendazole, oxfendazole, oxbendazole, parbendazole etc. are considered under Benz imidazole group of anthelmintics.
Thiabendazole:
It is a white crystalline compound having no taste and is stable. It is commercially available as powder, suspension and in tablet form.
Anthelmintic Spectrum:
Thiabendazole is a broad spectrum anthelmintic and is used for G.I. parasites in cattle, sheep, goat, horses and birds. It is larvicidal and ovicidal.
Ruminants (sheep, cattle and goats):
It has excellent efficacy against all major G.I. nematodes except whipworm, lungworms and filarial parasites. It is also effective against Haemonchus, Trichostrongylus, Bunostomum, Chabertia, Oesophogostomum and Stongyloids.
Dose:
50-110 mg/kg (Repeat the treatment after 14-21 days)
Ostertagia, cooperia and Nematodirns are less susceptible.
Horses- Eliminates 90% mature Oxyurids, Strongylus and Triodontophorus species. Immature forms of the above worms are also eliminated at high percentage.
Dose:
50- 110 mg/kg
Poultry- It is used in poultry against gape worms
Dose:
0.1% for 2-3 weeks in drinking water.
Mode of Action:
Thiabendazole inhibits fumerate reductase in helminths which is an essential component of fermentation. Because fermentation IS the main process of energy generation in worms, they lack their energy and die.
Pharmacokinetics:
It is rapidly absorbed by the gastrointestinal tract and is distributed throughout the body. The peak concentration is obtained within 4-7 hours after oral administration. It is quickly metabolized into 5-hydoxy-thiabendazole or sulfate of glucuronide of the 5-hydroxy derivatives. The drug metabolites are excreted in urine and faeces. It is completely excreted within 3 days of an oral administration. Less than 1% is excreted as thiabendazole.
Toxicity:
It is very safer anthelmintic and ruminants can tolerate 20 times therapeuitc dose. Pregnant ewes do not tolerate the high dose. When given at the dose of 100 mg/kg in piglets, it can reduce glycogen level, RNA, ascorbic acid and increase succinate dehydrogenase activity.
Mebendazole:
It is yellowish powder and is insoluble in water and most solvents. The chemical structure is given in Fig. 35.3.
Mode of Action:
It inhibits irreversibly the uptake of glucose and worms die due to starvation.
Anthelmintic Spectrum:
It possess broad spectrum activity and mainly used in equine against Ascaris, Strongyloids, Triodontophrous, Trichonema, Oesophagostomum and Oxyuris species. In poultry it is used against Syngamus trachae.
Dose:
Horse 5-10 mg/kg b.w.
Dogs and cats 5-10 mg/kg b.w.
Toxicity:
It is a safer compound and therapeutic index is higher than 40. However, the drug should not be used in pregnancy.
Pharmacokinetics:
It is poorly absorbed and 90% remains in the stomach and intestine. It is excreted unchanged in feces. The absorbed mebendazole is broken down in liver and excreted in urine. Its tissue penetration is sufficient to have possible effects on hydatid disease.
Albendazole:
It is better absorbed from G.I. tract and its active metabolites albendazole sulfoxide is concentrated 100 times more than mebendazole in blood.
Fenbendazole:
It is effective against round worms of cattle, sheep, goats, horses and pigs. It also eliminates lung worms and tape worms and kill all mature and immature worms.
Dose:
5 mg/kg b.w. for cattle, sheep, buffaloes, goats, horses and pigs.
Butamisole Hydrochloride:
It is an injectable anthelmintic used in dogs for the treatment of whipworm and hookworm (Ancylostoma Caninum) infestations.
Dose:
2-4 mg/kg S/C (Single dose)
I.M injection is not advisable due to pain
Toxicity:
Vomiting, ataxia, tremor, lateral recumbancy and convulsion.
Contraindications:
(i) Debilitated and severely diseased animals
(ii) Renal and liver disorders
(iii) Heart worm positive dogs
(iv) Do not use within 24 hr with the cestocidal drug bunamidine.
Febantel:
It is a broad spectrum anthelmintic for use in horses. Pregnant mares can be safely treated by febantel.
Dose:
6 mg/kg orally.
Pyrantel:
It is a broad spectrum anthelmintic against gastrointestinal parasites of cattle, horse, dogs and pigs.
Chemistry:
It is imidazothiazole derivative, off white in colour. Three salts are available for use in animals.
(i) Tartarate
(ii) Pamoate
(iii) Embonate
Pharmacokinetic:
Pyrantel tartarate is readily absorbed from gastrointestinal tract of pigs and dogs and less in ruminant. It is rapidly metabolised and 40% of the dose is excreted in dog. The unchanged drug is excreted in feces especially in ruminants.
The pamoate salt of pyrantel is slowly absorbed from gastrointestinal tract. The slow absorption of pamoate is advantage because it acts against the parasites of the large intestine. Therefore, it is useful in dog and horses.
Mode of Action:
The action of pyrantel is similar to the action of acetylcholine and produces paralytic action in parasites.
Morantel:
It is the methyl ester analogue of pyrantel. Morantel is more effective and safer anthelmintic in ruminants than the pyrantel. It is rapidly absorbed from the abomasum and upper small intestine of sheep. It is rapidly metabolised by liver and excreted (17%) in urine as metabolites within 96 hours after dosing.
Pyrantel and morantel are primarily effective against adult gut worms and immature larval stages that remain in the lumen or on the mucosal surface. They are less effective against the worms found in the mucosa and arrested Ostertagia larvae. Sustained release of morantel bolus for use in cattle is more useful because this releases the morantel over 60-90 days. This is very useful in preventing buildup of ineffective larvae on pasture.
(i) Pyrantel tartarate – Horse- 11 mg/kg b.w. orally
(ii) Pyrantel pamoate-
Pups – 7.5 mg/kg orally at 2, 4, 6 and 8 weeks of age.
(iii) Morantel-
Cattle- 8.8 mg/kg orally
Sheep – 10 mg/kg orally
Tetramisole hydrochloride (Nilverm):
It is a white crystalline powder and is soluble in 5 parts of water.
Efficacy and uses:
It is active against main gastrointestinal worms of cattle, sheep and goats. It is also active against Dictyocaulus (lung worms). The drug is effective for both mature and immature worms.
In pigs it is used against:
(i) Ascaris
(ii) Hydrostrongylus
(iii) Oesophagostomum
(iv) Metastrongylus
In cat it is used against lung worm (Aelurostrongylus).
Dose:
Cattle, sheep, goat and pigs – 15 mg/kg b.w.
Cats:
5 mg/kg b.w. daily for 6 days
Toxicity:
Overdose in cattle and sheep causes head shaking, salivation and licking of the lips.
Levamisole Hydrochloride:
It is a broad spectrum anthelmintic and an immuno- modulator. It is also used in animals where immune system is depressed.
Pharmacokinetics:
It is rapidly absorbed and is distributed to all parts of the body. Peak blood concentration is obtained within 1 hour of injection. The tissue concentrations of levamisole persists for 5 days. It is mainly excreted through feces and urine.
Mode of Action:
Low concentrations of levamisole stimulates ganglion of worms and produce muscle paralysis. The higher concentrations have been reported to interfere with carbohydrate metabolism.
Efficacy Spectrum:
It is mainly active against adult and larva of Haemonchus, Oestertagia, Trichostrongylus, Cooperia, Metastrongylus, Ascaris, Hyostrongylus, Trichnris and Dictyocaulus (lung worms).
Dose:
Sheep, cattle and pig- 7.5 mg/kg b.w. orally.
Poultry:
18-36 mg/kg s.c. injection (18.2% solution, 2 ml/50kg bw).
Precaution:
Cattle treated orally should not be slaughtered within 48 hour of oral treatment and within 7 days after parenteral treatment. It is not used in animals of breeding age.
Miscellaneous Antinematodals:
n-Butyl-chloride:
It is a colourless liquid and can be administered in gelatin capsules to dogs and cats. It is effective against Ascarid and hookworm infections. However, it does not have efficacy against parasites of other domestic animals. Overnight fasting of cats and dogs and use of purgatives enhance worm expulsion.
Dose:
Dose and Administration:
It is administered in tablets form. Fasting or purgation is not necessary.
More than 4.5 kg Dog- 500 mg orally
Pups-125 mg b.i.d orally
Disophenol (Ancylol):
It is an injectable anti-hookworm compound used in dogs and cats. It can be given without fasting to severely parasitized animals without causing stress and can be used in very young puppies and kittens.
Chemistry:
The structural formula of disophenol is given in Fig. 35.4. It is supplied commercially as 4.5 % solution for administration by s.c. route.
Mode of Action:
It is readily absorbed after oral or parenteral administration and reaches in systemic circulation. The exact mechanism by which disophenol acts is not known. It is thought that hookworms are affected when they ingest blood containing disophenol. The parasites that do not consume blood are not affected.
Anthelmintic Activity:
It is effective against canine hookworm (Ancylostoma caninum, Ancylostoma braziliense, Uncinaria stenocephala) and Ancylostoma tubaeforme of cat. It is also effective against adult Spirocerca lupi. It does not eliminate histotropic larva of the parasite. Therefore, the treatment is repeated after 21 days to remove the worms which were in larval form at the first dose.
Disophenol is not effective against ascarids, whipworms and lung flukes (Paragonimus) of dogs and cats. It is effectively used to treat wild animals especially, Leopards, lions, black panthers and golden cats against ancylostoma and Gnathostoma. It is also used to treat Gapeworms (Syngamus trachea) of turkey and poultry.
Administration:
Disophenol is administered as a powder by mouth or s.c. and i.m. injection. I.M. injection of disophenol is painful, hence s.c. route is preferred. The fasting of dogs is not essential.
Dose:
Dog- 10 mg/kg s.c.
Leopards, lions and black panthers – 6.6 mg/kg
Toxicity:
It is very safer for dogs and cats because it possess three fold margin of safety. Even 2 days puppies can be given the drug without any adverse effect. However, the following toxicities in dogs may be noticed.
(i) Occasional opacity of the lens may be observed at less than 4 months of age, which regresses within 7 days.
(ii) Tachycardia, polypnea, hyperthermia and early rigor mortis in fatal cases.
(iii) Vomiting at high dose.
Phthalofyne:
It is a whipicidal drug, used in dogs. It is administered orally in tablet form or i.v.
Dose:
Dog – 200 mg/kg orally
Glycobiarsol:
It is also used in whipworm infection of dogs
Dose:
Dog- 220 mg/kg daily for 5 days
Hygromycin B:
Hygromycin is an antibiotic produced from Streptococcus hygroscopicus. It is generally added in feed of poultry and swine for consumption over a period of several weeks.
Anthelmintic Activity:
It is effective against Ascaridia galli, Capillaria obsiguata and Heterakis gallinarum of poultry. Ascaris suum and Oesophagostomum of swine are effectively controlled.
Dose:
Swine -12 gm./900 kg of feed
Chicken – 8 gm./900kg of feed
Ivermectin:
Avermectins are produced by fermentation of an actinomycete known as Streptomyces avermitilis. Avermectins are complex of 8 components that are a group of macro-cyclic lactone derivatives. These complexes are A1a, A2a, B1a and B2a, A1b, A2b, B1b, and B2b. Each of the component has anthelmintic activity. These are not antibacterial or fungicidal as the macrolide or polyene antibiotics.
Ivermectin is the combination of B1a and B1b in ratio of 80% and 20% respectively.
Mechanism of Action:
Avermectins inhibit the motility and thereby causes paralysis of worms γ-aminobutyric acid (GABA) release is increased due to B1a from synaptosomes of the nervous system. Increased release of GABA causes hyperpolarization of post synaptic cells and inhibit contraction of muscle. Thus, worms are expelled in the similar fashion as ascarids following piperazine therapy.
Anthelmintic Activity:
Less than 1 mg/kg of avermectin antibiotic is required for anthelmintic activity by either oral or parenteral route of administration. It is active against nematodes and many arthropods. All gastrointestinal nematodes, lung nematodes, certain ectoparasites of cattle, horse, sheep and swine and sacroptic mange of dogs, heart worms are effectively eliminated.
Toxicity:
It possess 10 fold margin of safety in cattle, horse, swine and dogs. It produces mydriasis after a 10 fold oral dose in dogs. Horses show an impaired vision after two consecutive oral dosing. The acute toxicity symptoms include CNS depression, listness, ataxia, recumbancy. Death in horses has been reported after i.m. administration of 60 times of therapeutic dose. It is safer to pregnant animals.
Dose:
Cattle – 0.2 mg/kg s.c.
Sheep – 0.2 mg/kg orally
Horse – 0.2 mg/kg orally or i.m.
Swine – 0.3 mg/kg s.c.
Anticestodal Drugs:
Anticestodal drugs are also known as anti-tape worm or taeniacidal drugs. When these drugs cause the death of tapeworms they are referred to as taeniacidal and the drugs failing that, causes simply expulsion of worms by paralyzing them are referred to as taeniafuses.
Drugs available for tapeworm treatment in older days were mostly taenafuses. Therefore, purgatives along with taeniafuses were also incorporated in the prescriptions. The above drawback in the treatment of tapeworm infestations led to the search of taeniacidal agents.
Earlier Anticestodal Agents:
A. Natural Organic Compounds:
The earlier anti-tape worm drugs were mostly originated from plant.
Some of them are mentioned below:
(i) Pumpkin Seed:
The minsed seed of pumpkin is anticestodal. The active principle has been identified as Cucurbitine, which is completely safer and can be used in weak and debilitated patients even in young ones. However, it possessed low efficacy (55%) and could not be promoted for commercial production.
(ii) Male fern (Dryopteris felix mas):
The powdered rhizome of this plant was used in early period especially by Greek physician against cestodes. The active ingredients, filicic acid is responsible for anticestodal action which was thought to paralyse the muscle of tape worms.
(iii) Kamala:
It acts against cestodes of cats especially in Dipylidium caninum, Taenia taeniaeformis. Kamala is obtained from fruits of Mallotus philippinensis. The habitat of this plant is Philippines, India, China and Australia. It mainly acts by paralyzing the tapeworm muscle. However, this is obsolete now- a-days.
(iv) Nicotine:
Nicotine along with copper sulphate was extensively used in ruminants for elimination of tapeworms. It possessed low efficacy and has been replaced by new efficacious products.
(v) Arecoline:
Arecoline, an alkaloid obtained from betel nut has given birth to many more efficacious anticestodal drugs. The plant is abundantly grown in east and south India. Arecoline itself is not very suitable hence, its salts arecoline hydrobromide, arecoline acetarsol and arecoline carboxy phenylstibonate are used as anti-tape worm agent.
(a) Arecoline Hydro bromide:
It is a fine, white, bitter in taste and crystalline. Arecoline hydro bromide is used in the treatment against tapeworms infection in dogs. Echinococcus infestation in dogs can also be treated with it.
It has been observed that it is effective against infections of Taenia pisifortnis, T. hydatigena, T. ovis, T. multiceps and E. granulosus in dogs. The Echinococcus are eliminated intact and live. However, for complete elimination of Echinococcus, more efficacious recent drugs like praziquantel should be used.
Mechanism of Action:
The Arecoline paralyses worm musculature till the worms looses its attachment to the intestinal mucosa of the host. Besides this the arecoline hydro bromide increases the peristalsis so that detached worms are removed from G.I. tract.
As arecoline produces paralysis for a brief period, worms affected may recover and again make attachment with intestinal wall, if purgation, due to the local action, (due to its cholinergic effect) has not occurred within 2 hours of its treatment. In such cases saline purgatives are recommended.
Mode of Drug Administration:
The dog should be fasted for 12 to 13 hrs. before arecoline hydro bromide is administered. It is convenient to administer the tablet with meat through oral route.
Pharmacokinetics:
Tablets are absorbed readily from the stomach and the drug enters into portal circulation and is rapidly metabolised in the liver. It shows minimal signs of toxicity. It is also absorbed through oral mucosa when given in solution. In this case, systemic absorption is greater and signs of toxicity are more likely to occur.
The purgation starts 15 minutes after administration of arecoline and lasts for 30 to 40 minutes. However, it has been evidenced that some of the dogs do not defecate for several hours. In such situations, since the tapeworms must be expelled within 2.5 hours when they are paralyzed, purgatives are advised by the clinicians.
It has also been noticed that purgation is rapid when arecoline hydro bromide solution is orally administered.
Dose:
Dogs- 1 mg/kg orally
Toxicity:
Discomfort, incidence of vomiting and unconsciousness with high doses in dogs are observed. In some cases, vomiting and catharsis is noticed even after a therapeutic dose is given. Administration of a high dose i.e. 44 mg/kg in dogs shows symptoms of discomfort and convulsions.
During toxicity produced by Arecoline hydro bromide in dogs, atropine sulfate at the dose of 0.44 mg/kg is advised. Atropine does not show any effect on the paralyzing property on the worm musculature produced by arecoline hydro bromide.
Contraindication:
Arecoline is not advised in cats due to excessive bronchial secretion that may produce suffocation.
(i) Arecholine acetarsol:
It is white, tasteless and odorless powder, commercially it is available in tablet form and is readily soluble in water which is given promptly due to its un-stability in solution.
Arecoline acetarsol is given in dogs and cats against Taenia and Dipylidium infections. It does not possess activity against Echinococcus.
Pharmacokinetics:
After ingestion the tablet of arecoline acetarsol hydrolyses in stomach and releases arecoline. Similar to arecoline hydro bromide, it produces purgation that causes expulsion of paralyzed worms.
Toxicity:
It is not well tolerated and vomition may occur. Acute obstruction of upper respiratory tract by dipylidium vomited can lead to death of cats. Salivation, restlessness, ataxia and difficulty in respiration has been reported. Puppies less than 3 months of age and cats less than 1 year age should not be treated with arecoline acetarsol.
Contraindication:
It is contraindicated in febrile animals, G.I. tract disorders and cardiac disorders. In toxicity, atropine sulfate at above mentioned dosage proves to be an effective antidote.
Dose:
Dogs and cats: 4.9 mg/kg
(ii) Arecoline carb-oxy-phenylstibonate:
It is effective against Taenia and Dipylidium in dogs and is available in tablet forms.
Dose:
10.3 mg/kg orally. The maximum dose should not exceed 211.5 mg for a dog weighing 20.5 kg of more than this. The treatment may be repeated after 7 days if needed.
Toxicity:
Depression, nausea, vomition and colic.
Inorganic Compounds:
(i) Tin-Oxide or chloride of dibutyltin dilaurate were used 40 years ago for removal of cestodes in humans.
Mode of action:
Tin coats the cuticle of tape worms with its particles and renders the strobila susceptible to digestion. Now-a-days, the use of tin for removal of cestodes is obsolete due to its repeated dosing over a period of several days and its variable frequency of side effects.
(ii) Lead:
Arsenate salt of lead has been used to treat moniezia infections in lambs, calves and kids.
Mechanism of action:
It is hydrolyzed in the digestive tract to lead and arsenic. The lead is transformed to lead oxide and the pentavalent arsenic to toxic trivalent arsenic.
Synthetic Organic Compounds:
(i) Bunamidine:
Chiefly three salts of Bunamidine are in use:
(a) hydrochloride
(b) hydroxynaphthoate and
(c) p-toluene sulfonate
(a) Bunamidine Hydrochloride:
The chemical structure of bunamidine hydrochloride is given in Fig. 35.7. Chemically it is N, N-di-butyl- 4-hexyloxyl-1- naphthamidine hydrochloride. It is white, ordorless, crystalline solid and soluble in hot water.
Anti tapeworm spectrum:
It has efficacy against all tapeworm of dog and cat in a single dose. It is 86-99% effective against immature E. granulosus and 100% against its adult stages. It is 100% effective in Taenia and Mesocestoides corti. However, its activity against Dipylidium caninum varies from 56 to 90%. It should not be used for the treatment of Ascarids because of its very low efficacy.
Mechanism of action:
Salts of bunamidine are taeniacides, however, it do not produce purgation. It disrupts the integument of worms down to the level of the fibrous basal lamina. As a result, the glucose uptake is decreased and death results from starvation. The tapeworms are digested into the gut. In some cases, scolex is covered by mucous and disintegration of the scolex does not occur. Thus, the efficacy of bunamidine salts is reduced in such cases.
Administration:
Tablets are administered orally. The drug reaches quickly at the site of tapeworms especially located in the duodenal area of the small intestine. Because bunamidine is irritant to the mucus membrane of the oral cavity, tablets should not be crushed or dissolved before oral administration. In addition to the above, quick absorption results in high blood concentration and may lead to toxicity. The i.v. administration in dogs is not recommended due to the high degree of toxicity.
Toxicity:
Bunamidine causes death of the dog when given i.v. at the dose of 5 mg/kg. Fall in arterial pressure may be noticed if it is given i.v. at the dose of 1-2 mg/kg. Death does not results after oral administration at recommended dosage. The other toxicity symptoms include liver damage, ventricular fibrillation, vomition, transient diarrhoea and reduced spermatogenesis. However, it is safe to all stages of pregnancy in bitches.
Dose:
Dogs and cats-25 mg/kg orally. The above single dose after 3-4 hour fasting is sufficient to eliminate tapeworm in dogs and cats. The diet is generally given 3-4 hours after bunamidine treatment.
(ii) Bunamidine Hydroxynaphthoate:
It is a yellow, crystalline, solid compound and is insoluble in water.
Efficacy Spectrum:
It is effective against Moniezia expansa and M. benedeni in sheep and goats. It is not effective against Taenia pisiformis in empty stomach. However, its efficacy is increased against T. Pisiformis and T. hydatigena when given in food.
Dose:
Dogs: 25 mg/kg.
It is ineffective in dog if given in empty stomach. If given in food daily for 4 days it acts well in Echinococcus and Taenia infection. But it is unpalatable and difficult to administer by oral route.
Side Effect:
Produces vomition if given along with food.
(iii) Niclosamide:
It is a taeniacidal drug which is chemically 2, 5-di-chloro-4- nitrosalicylanilide. The chemical structure is given in Fig. 35.8. It is yellow, white tasteless powder and is insoluble in water.
Efficacy:
It is extensively being used for the treatment of tapeworm infections in animals. It is effective for the treatment of Dipylidiun caninum, Taenia pisiformis, T. hydatigena and T. laeniaeformis in dogs and cats. However, it possess poor efficacy against Echinococcus and variable efficacy for Dipylidium, Mesocestoides corti and M. lineatus in dogs.
It is also effective against Moniezia infections of cattle, sheep and goats. It is highly effective against Thysanosoma (fringed tape worm) of cattle, sheep and deer. It is also employed successfully in the treatment of equine tape worm (Anoplocephala magma, A. perfoliata, paranoplocephala mamillana.) and cestode infections in carp fishes (Bothriocephalus).
Mechanism of Action:
Niclosamide inhibits absorption of glucose by tape worms. It also inhibits uncoupling of the oxidative phosphorylation process in mitochondria of cestodes.
Ultimately it blocks the Krebs cycle which causes accumulation of lactic acid and thus results in death of tapeworm. It has also been suggested that overstimulation of ATP activity of mitochondria is related to cestodal action. The degree of cestodal action of this drug is directly proportional to the duration of action.
Pharmacokinetics:
It is poorly absorbed from G.I. tract. The small quantity absorbed is metabolised to an inactive compound known as aminoniclosamide.
Administration:
Tablets of niclosamide are administered orally in dogs and cats and as a drench in cattle, sheep and goats.
Dose: (single dose)
Cattle-50 mg/kg orally.
Dogs and cats: 100-57 mg/kg orally
Sheep and goats: 100 mg/kg orally
The above dosage should be given after overnight fasting in all species. The dead tapeworms are digested before it passes from the host and proglottis scolices are not identified when observed in feces.
Toxicity:
Niclosamide is a safer drug for the treatment of tapeworm infection because of its wide margin of safety. If the dose exceeds 40 times the recommended dosage, it does not produce any sign of toxicity in sheep and cattle. However, the limit of the safer drug dosage has not been yet established in dog and cats. The dosage higher than the recommended one causes damage to liver and kidney.
(iv) Dichlorophen:
It posses bactericidal and fungicidal activity and is used as taeniacidal agent in animal practices. Its properties are similar to niclosamide in many ways because both are phenol derivatives. It is chemically 2, 2-methylenebis (4- chlorophenol), white powder and insoluble in water. As it is insoluble in water, the absorption is limited from G.I. tract.
Anticestodal Efficacy:
It is effectively used in the treatment of Taenia and Dipylidium infection of dogs and cats. It possess very less activity in Moniezia expensa infection of sheep. The variable effects of dichlorophen is obtained when used for the treatment of Echinococcus in dogs and Thysanosoma in sheep.
Mechanism of Action:
Similar to niclosamide
Administration:
It is given orally in tablet or suspension form.
Dose:
Dogs: 300 mg/kg.
Cats: 100-200 mg/kg.
Sheep: 500 mg/2.5 kg b.w.
Overnight fasting in all species is required before dichlorophene administration. Purgation is not needed after treatment.
However, it is not a drug of choice for Echinococcus in dogs.
Toxicity:
Very low because it is not bioavailable to systemic circulation in sufficient amount.
(v) Resorantel:
In the recent years, its property was highlighted as anticestodal drug especially in ruminants.
Anticestodal Efficacy:
It is highly (95-100%) effective against Moniezia infection in sheep and cattle and is also used against rumen flukes especially of paramphistomum. It is 90% effective against rumen flukes in cattle and sheep against both adult and immature forms.
Pharmacokinetics:
The serum levels of resorantel is not detectable at 48 hours after treatment. It is rapidly excreted, and 3 days after administration, the total body residue approaches 0.10% if the total dose given.
Dose:
Cattle and sheep: 65 mg/kg as a drench
Side Effect:
Slight diarrhoea.
(vi) Bithionol:
It is bacteriostatic, fungicidal as well as anthelmintic. Chemically it is 2, 2-thiobis (4, 6- dichlorophenol). Its chemical structural formulla is given in Fig. 35.9. It is a white crystalline solid having a phenolic odor and is insoluble in water.
Efficacy:
Bithionol is effective against tapeworm infections of dogs, cats and poultry. It also possess activity against tapeworm and rumen flukes of sheep cattle and goats. It is highly effective against Taenia in dogs and cats. However, it is not used against Dipylidium caninum in dogs and cats.
It is also used clinically in cestodes infection in poultry. Most tapeworms of geese and quail are susceptible to this drug. Its efficacy against tapeworms in ruminants is good. However, it is less effective against tapeworms of adult sheep and lambs. It possess fairly good activity against paramphistomum of ruminants.
Pharmacokinetics:
Bithionol is not fairly absorbed from GI tract. Peak concentrations of bithionol is obtained within 2 hours after treatment. It is excreted through bile in sufficient concentrations as compared to that in blood. It exerts cholinomimetic action on the GI tract of host and induces purgation.
Administration:
Generally it is administered orally.
Dose:
(i) 200 mg/kg for dogs, cats, sheep and goats.
(ii) Geese- 600 mg/kg in a single treatment.
(iii) Chicken- 2 doses are given at the dose of 200 mg/kg at 4 days intervals in feed.
(iv) Quail- 200 mg/kg as a single dose.
Toxicity:
May produce vomition and diarrhoea in dogs.
Contraindication:
Carbon tetrachloride, sodium antimony tartarate, emetine hydrochloride, hexachloroethane or hexachloroparaxylene should not be given with bithionol. If the above drugs are given with bithionol the toxicity is enhanced.
(vii) Praziquantel:
It is an isoquinoline derivative for which the chemical structure is given in Fig 35.10.
It is colorless, odorless crystalline compound having a bitter taste. It is very less soluble in water.
Anticestodal Efficacy:
It is highly effective against all species of mature and immature tapeworms. It is highly effective against Taenia pisiformis, Taenia (Hydatigena) taeniaefomis, Taenia ovis and Taenia multiceps and Dipylidium caninum. It is also active against Mesocestodes corti, Echinococcus granulosus and E. multilocularis at higher dosage.
Lung flukes (paragonimus) infections in dog is treated successfully at high doses. It is also effective against tape worm infections in ruminants, poultry and snakes. Moniezia, Stilesia and Avitellina of sheep and goats are also susceptible. The pancreatic fluke (Eurytrema pancreaticum) of sheep and the intestinal flukes of swine (Fasciolopsis buski) are treated successfully with praziquantel.
It is also used for the treatment of ovine cenuriasis. It has a good result in human neurocysticercosis. However, it is not effective in hydatid cyst (larval stage) on the other hand it is highly effective against adult and juvenile forms of Echniococcus in carnivores.
Pharmacokinetics:
Praziquantel is quickly and completely absorbed from alimentary canal in animals. The Cp max of praziquantel is obtained at different time in different species e.g. 30-120 minutes in dog and 2 hours in sheep.
It is distributed to all organs and excreted through bile of dogs. Thorough distribution of praziquantel is a benefit in its activity against cestodes larval or adult forms that are located in various tissues like muscle, brain, peritoneal cavity, bile ducts and intestine.
Praziquantel is quickly metabolized in liver into inactive metabolites. After parenteral injections it presists in blood for a longer period as compared to the same dose given through oral route. The t1/2β of this compound in dog has been obtained equal to 3 hrs. It is fairly excreted through urine and feces.
Administration:
Praziquantel is administered through oral, s.c. or i.m. routes. The s.c. route is not preferred due to least efficacy.
Dose:
Dogs- A general dose of 5 mg/kg has been recommended. However, doses varies according to the species and nature of cestodes.
Dogs: 1 mg/kg by oral or parenteral route (Taeniaformis).
2 mg/kg (T. hydatigena, T. ovis, T. multiceps).
2.2-5 mg/kg (Dipylidium caninum).
5-10 mg/kg (Mesomultilocularis).
7.5 mg/kg on each of 2 consecutive days (Spirometra mansonoides and Diphyllobothrium erinacei).
25 mg/kg (paragoniums) on each of 3 consecutive days.
Cat: 1 mg/kg Taenia (hydatigena) taeniaformis.
Ruminants (sheep, goat): 10-15 mg/kg (Moniezia, Stilesia, Avitallina).
50-70 mg/kg single oral dose for pancreatic fluke.
30 mg/kg single oral dose (Fasciolopsis buski).
Toxicity:
It possess wide margin of safety. However, toxicity like increase in alkaline phosphatase, dermal and eye problem, teratogenic effects occur at high dosage in animals.
(viii) Benzimidazoles:
They are primarily used against infection of nematodes. Some of the substituted benzimidazoles show their efficacy against flukes and tapeworms. The benzimidazoles effective against cestodes are-mebendazole, oxfendazole, cambendazole and albendazole.
Efficacy:
The anticestodal activity of some benzimidazoles is dealt below.
Mebendazole:
It is active against Taenia, Echinococcus granulosus, Mesocestoides corti (rare canine tape worms), intermediate cyst of Taenia ovis T. hydatigina (sheep), cysticerci (cattle) and larvae stages of T. pisiformis (Rabbit) T. hydatigina (pigs) and E.multilocularis (mice).
Fenbendazole:
It is effective against Taenia (dog), Moniezia (cattle), Coenurus of T. muticeps (sheep), T. saginata (cattle) and hydatid cyst in mice.
Albendazole:
It is active against cestoides corti (dog), Moniezia and Thysanosama.
Cambendazole:
Acts against Avitellina centripunctata and moniezia, tapeworms and cysticerci (cattle).
Administration:
Benzimidazoles in clinical practices are administered through oral route in all species of animals.
Dose:
Mebendazole-Dogs and cats:
(i) 22 mg/kg/day for 5 days in Taenia infection.
(ii) 20 mg/kg at each of two treatments at 48 hrs.
(iii) 160 mg/kg single treatment.
Ruminants:
(i) 20 mg/kg single dose.
(ii) 50 mg/kg/day for 14 days for killing intermediate cysts of Taenia ovis and T. hydatigena.
(iii) 5 mg/kg for 10 days of cysticerci infection in beef cattle.
Albendazole (Dog):
(i) 50 mg/kg twice daily for 2 days.
(ii) 100 mg/kg, single dose.
Fenbendazole (Dog):
50 mg/kg/day for 3 days in Taenia infection.
Ruminant:
15 mg/kg in moniezia infection.
Cambendazole:
34 mg/kg in cysticerci infection in Beef cattle.
Antitrematodal Drugs:
Antitrematodal Drugs Affecting Adult Flukes:
(i) Carbon Tetrachloride:
It is the first effective drug for hepatica introduced in 1920s.
Chemistry:
Carbon tetrachloride (CC14) is obtained by chlorination of carbon disulfide or reaction of the disulfide with sulfur mono-chloride. It is volatile, colorless liquid and is insoluble in water. It smells like chloroform and has a burning taste. The chemical structure of carbon tetrachloride is given in Fig 35.11.
Antitrematodal Efficacy:
Carbon tetrachloride is very effective for the treatment of Fasciola hepatica in sheep. It is a cheap antitrematodal drug and is effective against adult flukes. It is effective against ascarid infections in chickens and dogs.
It has activity against blood-sucking nematodes including Ancylostoma in dogs and cats, Haemonchus and Bunostomum in cattle and sheep. Strongyles of horses are also susceptible to carbon tetrachloride. However, other more effective drugs are available in market against nematodal infection in animals and carbon tetrachloride is not preferred.
Pharmacokinetics:
Carbon tetrachloride is absorbed slowly from GI tract. Presence of fat and oil in stomach increases its absorption. The excretion is fairly through lungs, kidney and liver.
Administration:
It is administered orally as a drench mixed with rice gruel in cattle and sheep. In dog, it is given in gelatin capsules.
Sheep: 1-3 ml.
Dogs: 1-5 ml (0.1-0.2 ml/kg).
Poultry: 1-5 ml.
In practice, carbon tetrachloride is administered to animals before feeding.
Toxicity:
Liver damage, hyperaesthesia, convulsion followed by coma is evident in some animals. Death may occurs due to hepatic failure. The toxicity produced due to carbon tetrachloride is treated by calcium and dextrose administration by i.v. route. Protein feed is withheld to animals suffering from toxicity.
(ii) Hexachloroethane:
It is a simple chlorinated hydrocarbon for which the chemical structure is given in fig. 35.12.
Efficacy:
It is less toxic than carbon tetrachloride in cattle and is used against Fasciola. It is also effective against Haemonchus and Trichostrongylus axei. It has no activity against intestinal nematodes of ruminants. It possess activity only against mature flukes.
Administration:
It is administered orally.
Dose:
Cattle: 15-100g
Sheep -8- 15g
(Retreatment after one month is essential)
Toxicity:
Hepato toxicity
(iii) Hexachlorophene:
It is commercially available in the name of Distodin in market. Its chemical name is 2, 2- mthylenebis (3, 4, 6- trichlorophenol). The chemical structure is depicted in Fig. 35.13.
Efficacy:
It is an effective anthelmintic which is used in the treatment against liver flukes of ruminants and cestodes in canine. It is highly effective against adult F.hepatica and F. gigantica in cattle and sheep. It does not possess efficacy against immature flukes.
However, the immature flukes present in bile are susceptible. The immature flukes present in liver parenchyma are not affected because the drug is less available to immature flukes due to its plasma protein binding. Hexachlorophene is excreted in bile as a glucuronide metabolite which is an advantage and has highly effective against the adult flukes because they lodge in the bile ducts.
Administration:
Administered orally
Dose: (Cattle) 25 mg/kg
Toxicity:
Not toxic at above recommended dose, however, it possess a narrow margin of safety. Accurate calculated dosing is very essential in cattle. At high dose, it may produce excitability or depression followed by death and some animals can show vision problems.
(iv) Bithionol sulfoxide:
The chemical name of this compound is 2, 2′-thiobis (4, 6-di-chlorophenol).
Anthelmintic Efficacy:
In addition to its efficacy against liver flukes it also possess anticestodal properties. It is highly effective in the treatment of F. hepatica, F. gigantica, Fascioloides magma and Paramphisotmum. It is more effective against adult flukes than immature.
Administration:
In feed or boluses (orally)
Dose:
60 mg/kg for cattle, sheep and goats.
(v) Oxyclozanide:
It is marketed under the name of Zanil. This compound was introduced in 1966. The chemical name of oxyclozanide is 3, 3′, 5, 5′, 6-pentachloro-2′- hydroxysalicylanilide. It is a white crystalline substance insoluble in water. The chemical structure is given in Fig. 35.14.
Pharmacokinetics:
Oxyclozanide attains its highest concentrations in liver, kidney and intestines. It is excreted in the form of glucuronide into bile which is an active metabolite.
Mechanism of Action:
It is un-coupler of oxidative phosphorylation. It has been found that this interference by oxyclozanide is detrimental to F.hepatica.
Efficacy:
It is effective against adult flukes and does not possess efficacy against immature flukes. It has poor action against rumen flukes (paramphistomum). It is used in Duck farms for elimination of flukes (Notocotylus attenuatus).
Dose:
15 mg/kg orally for cattle and sheep. The same dose is given in duck by oral route.
Toxicity:
The therapeutic index of oxyclozanide is 4 and therefore, it is a safer compound.
(vi) Niclofolan:
It is nitro-substituted analog of hexachlorophene. Chemically it is 4, 4′- dichloride-6, 6′- dinitro-0, 0-bi-phenol. The chemical structure of niclofolan is given in Fig. 35.15.
Efficacy:
Niclofolan is used against mature forms of liver flukes in sheep, cattle and pigs. It is also effective against immature liver flukes which is an advantage.
Administration:
Niclofolan is generally administered by oral route in tablet form. It is also administered parenterally (s.c. or i.m.) to cattle.
Dose:
Sheep – 6 mg/kg
Cattle- (i) 4 mg/kg (Mature F.hepatica)
(ii) 16-20 mg/kg (Immature flukes)
(iii) 0.6- 1 mg/kg s.c. or i.m.
Pigs – 3-5 mg/kg, s.c.
Horse- 0.8 mg/kg, s.c.
Side Effects:
Fever, tachypnea
(vii) Rafoxanide:
It is a halogenated salicylanilide which is chemically 3′-chloro-4′- (P-chloro- phenoxy)-3, 5 diodosalicylanilide. The chemical structure of rafoxanide is depicted in Fig. 35.16. It is white crystalline powder available in market as a bolus and suspension for clinical use.
Efficacy:
It is principally used and effective against adult F. hepatica and F. gigantica in sheep and cattle. The efficacy is low against the immature flukes. It is also effective in haemonchosis, bunostomiasis and nasal bots of sheep.
Pharmacokinetics:
After oral administration rafoxanide is absorbed from GI tract and Cp max is obtained between 24 to 48 hours. It is not metabolised in cattle and sheep. The plasma half-life has been reported to range from 5 to 10 days in sheep. Following a recommended therapeutic dose rafoxanide is not detected in tissues of animals at 28 days post- administration.
Mechanisms of Action:
Not clear.
Dose:
Sheep and cattle 7-5 mg/kg orally
Toxicity:
The therapeutic index of rafoxanide approaches to 5 indicating a good margin of safety in all animals. No untoward effects are observed at recommended therapeutic doses. However, in-appetence and diarrhoea may occur in cattle after a high dose of rafoxanide. It may produce blindness and optic nerve degeneration in some animals.
Contraindications:
Lactating animals should not be treated with rafoxanide whose milk and milk products are consumed by human within 28 days.
Antitrematodals Used Against Immature Flukes:
Diamfenetide:
It possess high efficacy against the immature F.hepatica. As the flukes start aging, the activity of diamfenetide decreases. It is mainly used prophylactically against liver flukes in sheep. It also possess good efficacy for Dicrocoelium lanceolatum.
Chemical property:
It is chemically β, β’- bis (4-acetamidophenyloxy) ethyl ether. The chemical structure is given below in Fig 35.17.
Pharmacokinetics:
Diamfenetide is absorbed from GI tract after oral administration and is distributed to almost all body tissues. The highest concentrations of diamfenetide is obtained in gall bladder and liver after 3 days oral administration. The high quantity of this drug in gall bladder and liver is an advantage in the treatment of flukes because they lodge in these places.
The concentration of diamfenetide decreases to several folds in gall bladder and liver after 10 days oral administration. However, after 7 days of dosing milk and edible tissues of animals are not harmful if consumed by humans.
Mode of Action:
Diamfenetide acts by deacylases present in liver and is metabolised to an amine by de-acylation process. The metabolite, amine is active against the liver flukes. The rise of amine concentration in liver parenchyma causes rapid death of immature flukes.
Efficacy:
It is used clinically for the treatment of acute facioliasis due to immature flukes especially of F.hepatica in sheep. It is 100% effective against flukes of from 1 day to 9 weeks of age. It is not active for adult flukes located in bile ducts because the quantity of active amine reaching at this site is reduced due to dilution in blood of the affected animals.
Dose:
Sheep and goat: 100 ml/kg, orally.
Toxicity:
Temporary impairment of vision and loss of wool is evident at 4 times higher therapeutic dose.
Drugs Acting Against Paramphistomiasis:
Paramphistomum infection (paramphistomiasis) is very common in India. Animal suffering from paramphistomiasis show anorexia, increased water intake and watery fetid diarrhoea. It is observed that the drugs used against liver flukes and cestodes in ruminant give good result in parampohistomiasis.
Following drugs are successfully employed for combating paramphistomiasis in sheep and cattle:
(i) Tetrachloroethane (fasciolicide)
(ii) Niclofolan (fasciolicide)
(iii) Niclosamide (Anticestodal)
(iv) Resorantel, bithionol or bithionol sulfoxide.
Drugs Acting Against Paragonimiasis:
Paragonimiasis is caused due to lung infection by paragonimus in dog and cats.
The drugs used in the treatment of paragonimiasis are as below:
(i) Bithionol.
(ii) Praziquantal.
(iii) Albendazole and fenbendazole.