Benzimidazole anthelmintics (Continuation)
CAMBENDAZOLE
The most usual application
of cambendazole, isopropyl [2-( 4-thiazolyl)-1H-benzimidazol-5-yl] carbamate, is for treating pig roundworms.
ACTIVITY Cambendazole has good roundworm
activity and some activity against tapeworms.
DOSAGE
Horses 20 mg/kg.
Sheep 20 mg/kg.
Cattle 20 mg/kg.
Pigs
20-40 mg /kg.
Pigeons 75-150 mg/kg for 2 days.
METABOLISM The drug is readily absorbed, but
residues prevent treatment of dairy cows. It has a withdrawal period before
slaughter of 21 days.
TOXICITY Cambendazole is a fairly toxic benzimidazole. It may be
lethal to cattle at 2-3 times the recommended dose but sheep tolerate 10 times
the dose. The drug may be embryotoxic if dosed to pregnant animals.
FLUBENDAZOLE
Flubendazole, methyl[5-( 4- fluorobenzoyl)- 1H-benzimidazol-2-yl]carbamate,
is only used in pig (and human) roundworm therapy.
ACTIVITY Flubendazole
is used for treating roundworms of pigs.
INDICATIONS Gastro-intestinal roundworms and lungworms in pigs;
gastro-intestinal roundworms and tapeworms in dogs; gastrointestinal
roundworms, gapeworms, and tapeworms in poultry and game birds
DOSAGE
Pigs: by addition to
feed, 5 mg/kg body-weight as a single dose; 30
g/tonne feed for 5 or 10 days
Dogs: by mouth, 22 mg/kg for 2 or 3 days
Chickens: roundworms, 30 g/tonne feed for 7 days; Tapeworms,
60 g/tonne feed for 7 days
Turkeys: 20 g/tonne feed for 7 days
Geese: roundworms, 30 g/tonne feed for 7 days; Tapeworms,
60 g/tonne feed for 7 days
Game birds: 60
g/tonne feed for 7 days
METABOLISM Flubendazole is poorly absorbed from the gut and hence has low toxicity. It produces only one-tenth of the plasma levels of mebendazole (which is the unhalogenated
derivative). A 14-day withdrawal period
is required.
TOXlCITY Flubendazole is non-toxic at 40 times the recommended dose. It does not
appear to be embryotoxic.
SIDE-EFFECTS Occasional
transient vomiting and diarrhoea in dogs
LUXABENDAZOLE
Luxabendazole
methyl[5-(4-fluorophenylsulphoxyloxy)benzimidazol-2-yl]carbamate, is a novel
broad-spectrum drug.
ACTIVITY Luxabendazole has shown good efficacy against nematodes and adult and
6-week-old flukes in sheep.
DOSAGE Sheep 7.5 mg kg-I
(10 mg/kg for fluke).
METABOLISM After oral administration about 95% of absorbed drug is bound to serum
protein. Most of the dose (71%) is excreted in faeces as unmetabolized luxabendazole,
a further 12% occurring as metabolites. 13% is detected in urine of which 5% is
unmetabolized drug.
TOXICITY Doses of 100 mg/kg are not toxic in sheep, and tests have revealed no
mutagenic or teratogenic effects.
MEBENDAZOLE
Mebendazole,
methyl [5-(benzoyl)-1H-benzimidazol-2-yl]
carbamate, is not generally used for cattle.
ACTIVITY Mebendazole is effective against roundworms, tapeworms
and also tapeworm larvae. It has some antifiIarial activity.
INDICATIONS Gastro-intestinal roundworms in horses, donkeys and
sheep; lungworms in donkeys and sheep; tapeworms in sheep
CONTRA-INDICATIONS Administration
during first 4 months of pregnancy in donkeys for treatment for Dictyocaulus. Manufacturer
does not recommend administration to pigeons or parrots.
DOSAGE
Sheep 10-15 mg/kg.
Horses 5-10
mg/kg.
Donkeys Dictyocaulus
arnfieldi, 15–20 mg/kg daily for 5days
Pigs 30 ppm for up to 10 days.
Dogs 25-50 mg/kg twice daily for 5 days.
Poultry 10 mg/kg for 3 days (not pigeons)
METABOLISM The bulk of mebendazole is excreted unaltered in the faeces. The drug has
a withdrawal period of 7 days in sheep.
TOXICITY Mebendazole is well tolerated with a safety index in excess of 20 times the
recommended dose. The drug is not embryotoxic in target species, but
teratogenicity has been demonstrated in rodents.
SIDE-EFFECTS Occasional mild diarrhoea.
OXFENDAZOLE
Oxfendazole,
methyl[5-(Phenylsulphinyl)-1H-benzimidazol-2-yl]carbamate,
is a useful ruminant roundworm remedy which may also be injected
intraruminally, or be used in rumen boluses.
ACTIVITY Oxfendazole is active against roundworms, their inhibited larvae, and
tapeworms.
PHARMACOKINETICS Limited
information is available regarding this compound’s pharmacokinetics. Unlike
most of the other benzimidazole compounds, oxfendazole is absorbed more readily
from the GI tract. The elimination half-life has been reported to be about 7.5
hours in sheep and 5.25 hours in goats. Absorbed oxfendazole is metabolized
(and vice-versa) to the active compound, fenbendazole (sulfoxide) and the
sulfone. Oxfendazole is the sulphoxide metabolite of fenbendazole,
and is probably the derivative responsible for the activity of both these
anthelmintics.
Most of the drug and its metabolites are excreted in the faeces within
48 h of treatment. A withdrawal period of 14 days is required for meat.
INDICATIONS Gastro-intestinal roundworms, lungworms, and tapeworms
in ruminants; Type II Ostertagiosis. Oxfendazole is
indicated in cattle for the removal and control of lungworms, roundworms including
inhibited forms of Ostertagia ostertagi) and tapeworms. Oxfendazole was indicated for the removal of the
following parasites in horses: large roundworms (Parascaris equorum), large strongyles (S. edentatus, S. equinus, S. vulgaris), small
strongyles, and pinworms (Oxyuris equi). Oxfendazole has also been used extra-label in sheep, goats, and swine;
DOSAGE Dose. By mouth.
CATTLE: For susceptible parasites: 4.5 mg/kg either PO or via intraruminal injection
(22.5% only). May repeat in 4 – 6 weeks.
SHEEP: For susceptible parasites: 5 mg/kg PO, as a single
dose
GOATS: For susceptible parasites: 7.5 mg/kg PO
DOGS: For Oslerus osleri: 10 mg/kg PO once
daily for 28 days.
HORSES: For susceptible parasites: 10 mg/kg PO,
SWINE: For susceptible parasites: 3 – 4.5 mg/kg PO
TOXICITY
The safety index is greater than 10 times the recommended
dose but high dose levels may be embryotoxic to to pregnant ewes. Overdosage/Acute Toxicity Doses of 10 times those recommended elicited no adverse reactions in
horses tested. It is unlikely that this compound would cause serious toxicity
when given alone.
ADVERSE EFFECTS When used
as labeled, it is unlikely any adverse effects will be noted. Hypersensitivity
reactions secondary to antigen release by dying parasites are theoretically
possible, particularly at high dosages.
CONTRA-INDICATIONS Administration of ruminal boluses to non-ruminating
cattle or calves less than 12 weeks of age, concurrent administration of other
ruminal boluses (except as specified by manufacturer). Not to be used in horses intended for food purposes. Not approved for lactating dairy cattle.
WARNINGS If cattle are vaccinated against lungworm, the ruminal
bolus should not be administered until 10 to 14 days after the second dose of
vaccine. Not for use in female dairy cattle of breeding age. A
7 day slaughter withdrawal is required when using at labeled doses.
CONTRAINDICATIONS There are
no contraindications to using this drug in horses, but it is recommended to use
oxfendazole cautiously in debilitated or sick horses.
DRUG INTERACTIONS The
following drug interactions have either been reported or are theoretical in
humans or animals receiving oxfendazole and may be of significance in
veterinary patients: BROMSALAN FLUKICIDES (dibromsalan, tribromsalan): Oxfendazole should
not be given concurrently with these agents; abortions in cattle and death in
sheep have been reported after using these compounds together.
OXIBENDAZOLE
Oxibendazole, methyl[5-(n-propoxy)-1H-benzimidazol-2-yl]carbamate,
employed as a horse anthelmintic.
ACTIVITY Oxibendazole is effective against gastrointestinal roundworms and
lungworms.
USES/INDICATIONS Oxibendazole
is indicated for the removal of the following parasites in horses: large
roundworms (Parascaris equorum), large strongyles (S. edentatus, S. equinus, S. vulgaris), small strongyles, threadworms, and pinworms (Oxyuris equi). Oxibendazole has also been used in
cattle, sheep, and swine.
METABOLISM Peak plasma levels occur 6 h after dosing, and about 40% of the drug is
excreted in the urine in the 9 days post-treatment. A 14-day withdrawal period is advised following treatment, but milk may now
be used 48 h after dosing.
DOSAGE
HORSES: For susceptible parasites: 10 mg/kg PO; 15 mg/kg PO for strongyloides;
horses maintained on premises where reinfection is likely to occur should be
retreated in 6 – 8 weeks. CATTLE: For susceptible parasites: 10 – 20 mg/kg PO (Some may suggest 5 – 10 mg/kg)
SWINE: For susceptible parasites: 5 – 15 mg/kg, PO
SHEEP: For susceptible parasites: 10 – 20 mg/kg PO (Some may suggest 5 mg/kg)
TOXICITY A therapeutic index of 60 times the recommended dose has been quoted for ruminants,
but high doses are embryotoxic.
CONTRAINDICATIONS/PRECAUTIONS/WARNINGS Oxibendazole is stated by the manufacturer to be contraindicated in
severely debilitated horses or in horses suffering from colic, toxemia, or
infectious disease.
ADVERSE EFFECTS When used
in horses at recommended doses, it is unlikely any adverse effects would be seen.
Hypersensitivity reactions secondary to antigen release by dying parasites are
theoretically possible, particularly at high dosages. Oxibendazole in
combination with diethylcarbamazine was implicated in causing periportal
hepatitis in dogs when it was marketed (1980’s).
OVERDOSAGE/ACUTE TOXICITY Doses of 60 times those recommended
elicited no adverse reactions in horses tested. It is unlikely that this
compound would cause serious toxicity when given alone to horses.
PARBENDAZOLE
Parbendazole, methyl[5-butyl-1H-benzimidazol-2-yl) carbamate, was the
first of the benzimidazole carbamates, but is less widely used today.
ACTIVITY Parbendazole is effective against most (but not all) gastrointestinal
nematodes and lungworms.
DOSAGE
Cattle 30 mg/kg.
Sheep 20-30 mg/kg.
Pigs 30 mg/kg.
Horses 2.5-20 mg/kg.
METABOLISM After dosing orally to sheep absorption is rapid and plasma
levels are reached in about 6 h. The drug rapidly metabolized and excreted.
Most of the dose excreted in the first 24 h, and drug levels in tissues are
minimal after 6 days. Only 26% of the dose is excreted in urine. The withdrawal
period is relatively short (only 6 days).
TOXICITY Parbendazole has a safety index of over 30 times the recommended dose in
healthy animals, but may be teratogenic at
doses only slightly higher than recommended one. It was parbendazole that first
altered scientists to the embryotoxicity of benzimidazoles.
THIABENDAZOLE
Thiabendazole,
2-(4-thiazolyl)-1H-benzimidazole, the
first of this generation of anthelmintics, is still widely used.
ACTIVITY Thiabendazole is active against
adult and larval roundworms.
USES/INDICATIONS Thiabendazole
has been used for the removal of the following parasites in dogs: ascarids (Toxocara canis, T. leonina), Strongyloides stercoralis, and Filaroides.
It has been used systemically as an anti-fungal agent in the treatment of nasal
aspergillosis and penicillinosis. Topical and otic use of thiabendazole for the
treatment of various fungi is also commonly employed.
Thiabendazole is indicated (labeled)
for the removal of the following parasites in cattle: Haemonchus spp., Ostertagia spp., Trichostrongylus spp., Nematodirus spp., Cooperia spp. and Oesophagostomum radiatum.
Thiabendazole is indicated (labeled)
for the removal of the following parasites in sheep and goats: Haemonchus spp.,
Ostertagia spp., Trichostrongylus spp., Nematodirus
spp., Cooperia spp., Chabertia spp., Bunostomum spp. and Oesophagostomum spp.
Thiabendazole is indicated (labeled)
for the removal of the following parasites in horses: Strongylus spp., craterstomum
spp., Oesphagodontus spp., Posteriostomum spp., Cyathostomum spp., Cylicocylus spp., Cylicostephanus spp., Oxyuris spp., and Parasacaris spp.
Thiabendazole is indicated (labeled)
for the removal or prevention of the following parasites in swine: large
roundworms (Ascaris suum) (prevention), and in baby pigs infested with Strongyloides ransomi.
Although not approved, thiabendazole
has been used in pet birds and llamas. In many geographic areas, significant
thiabendazole resistance problems have developed and, for many parasites, other
anthelmintics would be a better choice for treatment. When used topically, thiabendazole has
antidermatophytic properties.
PHARMACOKINETICS
Thiabendazole is relatively well absorbed (for a benzimidazole)
and is distributed throughout body tissues. Peak levels occur in approximately 2
– 7 hours after dosing. Absorbed drug is rapidly metabolized in the liver by
hydroxylation, glucuronidation and sulfate formation. Within 48 hours of
dosing, 90% of the drug is excreted in the urine (as metabolites) and 5% in the
feces. Less than 1% of the drug is excreted in the urine unchanged. Five days
after a dose, the drug is virtually eliminated from the body.
METABOLISM Thiabendazole is readily absorbed
and rapidly eliminated from the body. The major metabolite is
5-hydroxythiabendazole which becomes conjugated with glucuronic acid or a
sulphate. 90% of the dose is excreted in the urine and 5% in the faeces within
48 h, mostly as metabolites. Less than 1% is unchanged drug. Its zero-day
withdrawal period ensures its popularity with farmers. It may also be dosed to
cows producing milk for human consumption.
DOSAGE
SHEEP & GOATS: For susceptible parasites: a) 44 mg/kg PO; 66 mg/kg PO for severe
infections in goats b) 50 – 100 mg/kg PO (sheep)
CATTLE: For susceptible parasites: a) 66 mg/kg PO; 110 mg/kg PO for Cooperia and
severe infections of other susceptible nematodes. Retreat treatment in 2 – 3
weeks if indicated. b) 50 – 100 mg/kg PO
HORSES: For susceptible parasites: a) 44 mg/kg, PO; b) 44 mg/kg; 88 mg/kg for
ascarids; c) 50 – 100 mg/kg PO
SWINE:
For susceptible parasites: a) For baby
pigs with Strongyloides ransomi: 62 – 83 mg/kg PO, retreat in 5 – 7 days if necessary. To prevent
Ascaris suum: Feed at 0.05 – 0.1% per ton of feed for 2 weeks, then 0.005 –
0.02% per ton for 8 – 14 weeks; b) 75 mg/kg, PO; c) 50 mg/kg, PO
POULTRY 1000 mg/kg.
BIRDS:
For susceptible parasites:
a) For ascarids: 250 – 500 mg/kg PO
once. Repeat in 10 – 14 days.
For Syngamus trachea: 100 mg/kg, PO
once a day for 7 – 10 days
b) For ascarids, Capillaria, gapeworms:
Chickens, pheasants, turkeys, and
pigeons: Mix 0.5% in feed for 10 days or administer orally at 44 mg/kg as a
single dose.
Psittacines: 44 mg/kg PO; do not exceed
this dose.
Falcons: 100 mg/kg PO as a single dose
c) For thorny headed worms in waterfowl
and raptors: 250 mg/lb
DOGS:
As an antiparasitic agent:
a) For
treatment of Strongyloides stercoralis: 50 – 60 mg/kg PO
b) For treatment of Filaroides (now
called Oslerus) infections: 35 mg/kg PO twice daily for 5 days, then 70 mg/kg
PO twice daily for 21 days. Prednisone can also be given at 0.55 mg/kg, PO
twice daily every other day
As an antifungal agent:
a) For treatment of nasal
aspergillosis/penicillinosis infections: 30 – 70 mg/kg divided q12h PO in food
for 20 – 45 days
b) For the treatment of aspergillosis:
20 mg/kg PO, once a day or divided twice daily; (with or without ketoconazole:
20 mg/kg PO, once a day or divided twice daily). Maintenance therapy: 10 – 20
mg/kg PO once a day
c) For penicillinosis: With appropriate
adjunctive surgical curettage and topical therapy, thiabendazole: 20 mg/kg/day
PO for 4 – 6 weeks
d) For aspergillosis: Administer 10
mg/kg as nasal flush. Dilute in 10 – 20 mL of water. Flush twice daily for 10
days. Orally: 20 mg/kg/day divided twice daily for 6 weeks
e) For treatment of nasal
aspergillosis: 20 mg/kg divided q12h PO for 6 – 8 weeks. If anorexia or nausea
develops, may withdraw drug and then gradually reintroduce to the full dosage. Administer
with food to enhance absorption and reduce anorexia.
May be
effective in 40 – 50% of dogs treated.
RABBITS, RODENTS, SMALL MAMMALS:
a) Rabbits: For pinworms: 50 – 100 mg/kg PO for 5
days or 50 mg/kg PO, repeat in 3 weeks
b) Mice, Rats, Gerbils, Hamsters, Guinea pigs: 100 mg/kg, PO for 5 days.
Chinchillas: 50 – 100 mg/kg
PO for 5 days
c) For pinworms in Mice, Rats,
Hamsters, Gerbils and Rabbits: 50 mg/kg, PO once
LLAMAS:
For susceptible parasites:
a) 50 – 100 mg/kg PO for 1 – 3 days.
Use higher dosage rate over several days when animal is severely parasitized.
b) 66 mg/kg PO
TOXICITY Thiabendazole has a safety index of 16-27 times the recommended dose.
OVERDOSAGE/TOXICITY Thiabendazole
has a safety margin of at least 20 times the recommended dose in horses. Doses
of 800 – 1000 mg/kg are necessary to cause anorexia and depression in sheep.
The minimum lethal dose is 700 mg/kg in cattle and 1200 mg/kg in sheep. It is
unlikely that a modest overdose would cause significant problems. If a massive
overdose occurs, treat supportively and symptomatically.
ADVERSE EFFECTS At
recommended doses, thiabendazole is usually well tolerated in approved species.
In dogs, vomiting, diarrhea, hair loss, and lethargy are possible side effects,
notably with high dose or long-term therapy. Dachshunds have been reported to
be particularly sensitive to thiabendazole. Toxic epidermal necrolysis (TEN)
has been reported in dogs receiving thiabendazole, but the incidence appears to
be very rare.
REPRODUCTIVE/NURSING SAFETY Thiabendazole has not been demonstrated to be a teratogen and is
considered generally safe to use during pregnancy. However, in high doses it
has been implicated in causing toxemia in ewes. It is not known whether this
drug is excreted in milk, but it is unlikely to be of clinical concern in
nursing patients.
DRUG INTERACTIONS The
following drug interactions have either been reported or are theoretical in
humans or animals receiving thiabendazole and may be of significance in
veterinary patients:
THEOPHYLLINE: Thiabendazole may compete with xanthines for metabolizing sites in the
liver, thereby increasing xanthine blood levels.
TRICLABENDAZOLE
Triclabendazole,
5-chloro-6(2,3-dichlorophenoxy)-2-(methylthio)benzimidazole, is a recently
launched benzimidazole with a very different spectrum of activity-directed
against liver flukes.
ACTIVITY Triclabendazole is very potent
against liver fluke (Fasciola hepatica) from 1 day old to adult. It is
poorly effective against Dicrocoelium and has no anti-nematode activity.
INDICATIONS Immature and
adult Fasciola in horses and ruminants
DOSAGE
Sheep and Goats 10
mg/kg.
Horses,
Cattle 12 mg/kg.
METABOLISM The major metabolites of
triclabendazole in sheep are the corresponding sulphoxide and sulphone. Both
are found in plasma and the former (both free and conjugated) is the major
metabolite in bile. Of the dose 40.5% is secreted in bile and 6.5% in the
urine. Triclabendazole has a withdrawal period of 28 days and should not be
given to animals providing milk for human consumption.
TOXICITY Triclabendazole is well tolerated
in sheep and cattle at 200 mg/kg orally. There is no evidence of teratogenicity
or embryotoxicity in rats.
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