Closantel: A review of its antiparasitic activity

Preventive Veterinary Medicine, 2 (1984) 317--327

317

Elsevier Science Publishers B.V., Amsterdam -- Printed in The Netherlands

CLOSANTEL:

A REVIEW OF ITS ANTIPARASITIC ACTIVITY

Jorge Guerrero Pitman-Moore, Inc. ~ , P.O. Box 344, Washington Crossing, New Jersey 08560, U.S.A.

INTRODUCTION Closantel

(N-5-chloro-4-[(4-chlorophenyl)

hydroxy-3,5-diiodobenzamide)

cyanomethyl]-2-methylphenyl-2

is a salicylanilide antiparasitic compound dis-

covered at Janssen Pharmaceutica, Beerse, Belgium and patented by Janssen and Sipido (1977).

This compound has been found to have surprising anthelmintic

and ectoparasiticidal activity in different animal host species (Hall et al, 1981; Guerrero et al, 1982; Guerrero et al, 1983; Chaia et al, 1981a). As other salicylanilides, coupler

of oxidative

closantel has been proven to be a potent un-

phosphorilation

(Van den Bossche et al, 1979).

of

mitochondria

of

This activity of closantel

Fasciola

hepatica

is not observed

in vivo in mitochondria isolated from uninfected rat heart and liver.

On the

other hand it has been observed that the presence of ~. hepatica in the liver tissue of the host severely affects the liver mitochondria producing uncoupling of oxidative phosphorilation.

Yet the elimination of the parasite from

the liver and bile duct by the activity of closantel results in a normalization of the mitochondrial activity (Van den Bossche et al, 1980). The objective of the present paper is to present a brief review of the antiparasitic effects of closantel in nematodes, trematodes and some arthropod parasites of economic importance of cattle, sheep and horses. The antiparasitic activity of closantel was studied through a series of controlled and critical studies in which experimentally and naturally infected and/or infested cattle, sheep and horses were utilized.

In order to limit the

length of this presentation only the most relevant references will be quoted to support this review.

n An a f f i l i a t e

company of J a n s s e n P h a r m a c e u t i c a , N . Y . , B e e r s e , B e l g i u m .

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© 1984 Elsevier Science Publishers B.V.

318 TABLE 1 Activity of Closantel Against Adult Helminth Parasites in Cattle

Dose in mg--g-/K8

Route of 'l'reatment

Haemonchus placej

2.5

IM

18

99.4

Bunostomum phlebptomum

2.5

IM

47

99.9

Oesophagostomum radiatum

2.5

IM

18

99.5

Capillaria boris

5.0

SC

l0

I00

Fasciola hepatic~

2.5 or 5

SC

15

i00

Fasciola gigantica

2.5

IM

18

Species o£ Helminth

No. o£ An~m--i-~5-Kg

% Eff-i-cacy

99.4

TABLE 2 Activity of Closantel Against Larval Helminth Parasites in Cattle.

Species of Helminth

Larval S-f~se

Dose in

m~.--/~

Route of

~

t

No. of

~

%

E£fTcacy

L3

2.5

IM

18

100

L4

2.5

IM

16

99

L3

5

IM

20

L4

5

IM

20

L3

5

IM

20

99.9

L4

2.5

IM

16

94.7

Fasciola hepatica

6 weeks

7.5

SC

12

80.8

Fasciola gisantica

6 weeks

2.5

IM

18

55.8

Haemonchus placei

Bunostomum phlebotomum

Oesophasostomum radiatum

99.6 i00

319 Antinematode A c t i v i t y Summary r e s u l t s of several s t u d i e s performed to determine the antinematode e f f i c a c y of c l o s a n t e l are presented in Tables 1 to 4 and are discussed i n the following paragraphs. In a l l these s t u d i e s , c l o s a n t e l was found to have an a n t h e l m i n t i c e f f e c t which is s p e c i f i c a l l y d i r e c t e d towards hematophagous nematode p a r a s i t e s of a v a r i e t y of hosts. against

third

Closantel has demonstrated e x c e l l e n t antinematode a c t i v i t y

and fourth

larval

and a d u l t

stages

of

Haemonchus plagei

in

c a t t l e , when administered by intramuscular i n j e c t i o n a t doses of 2.5 mg/kg of

body weight (Van der Westhuizen et al, 1977c).

This regimen was similarly ef-

fective against the adult stage of Bunostomum phlebotomum (Van der Westhuizen et al, 1977c).

Against the third and fourth larval stages of ~. phlebotomum

the preferred dose was found to be 5 mg/kg of body weight by intramuscular injection (Van der Westhuizen et al, 1978a). in the removal

of fourth-stage

Closantel was also very effective

(L4) and adult

stages of Oesophasostomum

radiatum when administered to cattle by the intramuscular route at dosage of 2.5 mg/kg (Van der Westhuizen et al, 1977c).

The optimal intramuscular dose

of closantel against third-stage larvae (L3) of O. radiatum was found to be 5 mg/kg (Van der Westhuizen et al, 1978b). One subcutaneous injection of closantel at a dosage o£ 5 mg/kg effectively cleared adult Ca~illaria boris infections in cattle (Rassier et al, 1980). In sheep, closantel was effective either at 2.5 mg/kg by intramuscular injection or at 5 mg/kg orally, in the removal of adult Haemonchus contortus (Janssen

Pharmaceutica

1975).

Against

the

fourth

larval

stage

of

H. c o n t o r t u s , the 2.5 mg/kg intramuscular route was found to be most e f f e c t i v e (Van Schalwyk 1974). and

adult

stages

of

Closantel demonstrated e x c e l l e n t e f f i c a c y a g a i n s t l a r v a l 6aiseria

pachyscelis

(Van der Westhuizen e t a l , 1977b).

at

an

oral

dose

of

10

mg/kg

The same dose regimen was also found to be

optimal a g a i n s t l a r v a l and a d u l t Chabertia ovina (Van der Westhuizen e t a l , 1978b). The antinematodal a c t i v i t y of c l o s a n t e l i n horses was determined by t e s t ing t h i s compound as an oral formulation a g a i n s t n a t u r a l and experimental i n f e c t i o n s of Stronsylus v u l s a r i s .

During t h i s

trial

i t was determined t h a t

c l o s a n t e l a t 20 mg/kg of body weight c o n s i s t e n t l y cleared a d u l t S. v u l g a r i s infections.

Larval stages of ~. v u l s a r i s p r e s e n t i n the mesenteric a r t e r i e s

were also completely e l i m i n a t e d using t h i s regimen. oral dose of c l o s a n t e l demonstrated e x c e l l e n t

Furthermore, the 20 mg/kg a c t i v i t y against adult

S. edentatus and Triodontophorus spp. i n horses (Guerrero e t a l , 1985).

320 TABLE 3 Activity of Closantel Against Adult Helminth Parasites in Sheep.

Species, of Helminth Haemonchus contortus

Dose in m~--'/~

Route of Treatment

No. of

% EfYYcacy

2.5 5

IM PO

18 18

99.9 i00 I00

~

Gai$eria pachyscelis

I0

PO

20

Chabertia ovina

I0

PO

20

99.9

Fasciola hepatica

i0 5 5

PO PO IM

41 18 18

99.9 96.9 99.6

Fasciola gigantica

5 7.5 i0

PO PO PO

9 9 9

i00 99.5 99.5

TABLE 4 Activity

of C l o s a n t e l A g a i n s t L a r v a l H e l m i n t h P a r a s i t e s

Species o£ Helminth

Larval Stage

Dose in m ~

Haemonchus c o n t o r t u s

L4

Gai~eria pachyscelis

L3

i0

L4

i0

L3 L4

Chabertia ovina

Fasciola hepatica

Fasciola gigantica

2.5

i n Sheep.

Route o£ Treatment IM

No. of Animals

% EffTcacy

I0

99.1

PO

20

94.7

PO

20

99.9

10

PO

20

96.6

10

PO

20

96.8

4 weeks

10

PO

22

82.9

6 weeks

10

VO

22

98.4

8 weeks

10

PO

9

95.9

321

Prolonged Antinematode Activity Prolonged

antiparasitic

the exploratory

activity

of closantel

phases of research utilizing

was observed early during

laboratory

animals.

Later on

tests on larger animals were undertaken to better define this activity. As such the prolonged antinematode

activity of closantel was measured in

cattle and sheep by treating animals at various times prior to artificial infection with a variety of nematode parasites. In sheep,

the prolonged

activity

of closantel

against

L 5 H. contortus

was optimal with an oral dose of l0 mg/kg either 5, 6 or 7 weeks prior to infection (Van der Westhuizen et al, 1978d).

The i0 mg/kg oral dose was also

very effective against L 3 ~. pachyscelis when given 4, 5 or 8 weeks prior to infection

(Van der Westhuizen et al, 1978d).

effective

against

L30.

columbianum

when

I0 mg/kg 2 weeks before the experimental

Closantel was only marginally

administered

orally

to sheep

at

infection (Van der Westhuizen et al,

1978c). In cattle,

a single

intramuscular

treatment

of 2.5 mg/kg,

administered

either 2 or 3 weeks prior to infection, effectively prevented the development of L 3 ~. placei (Van der Westhuizen et al, 1977e). By the subcutaneous route, the treatment of 5 mg/kg was most effective against L 3 ~. placei, when

administered

1979b).

5 weeks

prior

Closantel prevented

to infection

the development

(Van der Westhuizen

of L 3 ~. phlebotomum

et

al,

in cattle

when administered subcutaneously at a dosage of 5 mg/kg, either 2 or 5 weeks prior to infection (Van der Westhuizen et al, 1979b).

Closantel demonstrated

excellent prolonged activity against L 3 H. radiatum when administered taneously

at

5

mg/kg

either

1

or

2

weeks

prior

to

subcu-

infection

(Van der Westhuizen et al, 1979b). Antitrematode Activity The antitrematodal primary

screenings

of

activity of closantel was early determined during the efficacy.

against liver and intestinal cattle and sheep.

Later

on

the

efficacy

of

this

flukes was determined by controlled

compound

studies in

A summary of antitrematode efficacy results is presented in

Tables 1 to 4. In a study performed by Rassier et al (1980) adult Fasciola hepatica infections in cattle were completely cleared by a closantel treatment of either 2.5 mg/kg, using the subcutaneous route of injection. Closantel, at a dosage of 7.5 mg/kg administered by subcutaneous injection was moderately effective against 6-week ~. hepatica larvae in cattle (Oakley 1976). Against adult [. gigantica in cattle, the dose of 2.5 mg/kg was found to be optimal using the intramuscular route (Van der Westhuizen etal,

1977c).

322 TABLE 5 Prolonged Anthelmintic Activity of Closantel against Helminth Parasites in Cattle.

Dose in ~

Species of Helminth

Route of Treatment

No. of Animals

% EffTqacy

Treatment PreInfection

Haemonchus placei

2.5 2.5 5

IM IM SC

16 16 18

98.5 97.5 96.9

2 weeks 3 weeks 5 weeks

Bunostomum phlebotomum

5 5 5

SC SC SC

18 20 18

i00 96.5 81.0

2 weeks 3 weeks 6 weeks

5

SC SC

18 18

94.1 94.5

1 week 2 weeks

O~sophagostomum radiatum

5

TABLE 6 Prolonged Anthelmintic Activity of Closantel Against Helminth Parasites in Sheep.

Species of Helminth

Dose in

Route of

No.

~

Treatment

~

of

%

EffTcacy

Treatment Fre-

In~F~-~-ion

Haemonchus contortus

i0 i0 i0

PO PO PO

29 40 40

i00 99.9 97.8

3 weeks 6 weeks 7 weeks

Gaigeria pachyscelis

I0 I0 i0

PO PO PO

20 20 20

i00 i00 97.3

4 weeks S weeks 8 weeks

Oe~ophasostomum columbianum

I0

PO

20

75.8

2 weeks

323

On the other hand this dose did not demonstrate

any appreciable activity

against 6-week old ~. 8igan.~ic.a larvae in cattle (Van der Westhuizen et al, 1977d). In sheep, closantel demonstrated excellent activity against [. hepatica, when administered orally at 5 mg/kg; although a I0 mg/kg oral dose was slightly more effective. The efficacy of a 5 mg/kg intramuscular dose against adult [. hepatica was found to be as effective as the I0 mg/kg oral dose (Janssen Pharmaceutica

1975).

Closantel

was

also

effective

against

4-week

old

[. hepatica larvae and very effective against 6-week old larvae when administered to sheep orally at i0 mg/kg (Reinecke et al, 1976). The i0 mg/kg oral dose was also found to be very effective against 8-week old F. gigantica in sheep (Van der Westhuizen and Hatt, 1976). Anticestode and Antiarthropod Activity The anticestode activity o£ closantel was studied by Chevis et al (1980). These

investigators demonstrated

that closantel

orally, or at 20 mg/kg, administered against metacestode

at 40 mg/kg,

administered

intramuscularly, was highly effective

stages of Taenia pisiformis

in experimentally

infected

rabbits. In one other study, closantel administered orally at 20 mg/kg was found to be effective in the removal of .A~.oplocephala perfoliata in horses (Guerrero et al, 1983). The antiarthropod

activity

of closantel

has

been reported

in horses

against Gasterophilus nasalis and G. intestinalis (Guerrero et al, 1983), Boophilus microplu.§ in naturally infested cattle (Lombardero and Luciani, 1982), Amblyoma americanum in experimentally infected cattle (Drummond, 1982); Dermatobia hominis in cattle (Chaia, 1981a and b), H)rpod~rma boris in cattle (Thienpont et al, 1982), Oestrus ovis in sheep (Van der Westhuizen et al, 1977g), Cochlzomia hominivorax in sheep (Ochoa et al, 1982), Psoroptes communis vat ovis in sheep (Perez Arrieta et al, 1982), and demodectic mange in dogs (Losson and Benakhla, 1980).

A summary of the antiarthropod activity

of closantel is presented in Table 8. Concluding Remarks The m u l t i p l e a n t i p a r a s i t i c a c t i v i t y of c l o s a n t e l seem to have the c o ~ o n denominator of being expressed a g a i n s t p a r a s i t e s which are e i t h e r contact with c i r c u l a t i n g blood ( i . e . t0phagous i n n a t u r e (Guerrero e t a l , of

this

antiparasitic

compound i s

i n close

l a r v a e of ~. v u l g a r i s ) or t h a t are hema1982). its

The other marked c h a r a c t e r i s t i c

prolonged e f f e c t

which i s

depending on the host species (Hall e_~_ta_~=l, 1981; Guerrero e t a l , 1982)o

variable

324 TABLE 7 A c t i v i t y of Closantel Against Endoparasites in Horses. Dose in ~

Specie,> of P a r a s i t e s

Route of l~eatment

No.

% EffTcacy

of

Gasterophilus intestinalis

20

PO

9

I00

Strongylus vulgar.is (adults)

20

PO

9

i00

Strongylus v u l g a r i s (larvae)

20

PO

9

i00

Strongylus e d e n t a t u s

20

PO

9

I00

Triodontophorus spp.

20

PO

9

I00

Anoploceph~la p e r f o l i a t a

20

PO

9

86.6

TABLE 8 Activity of Closantel Against Arthropod Parasites in Domestic Animals.

Arthropod Sp,eci,es

Dose in ~

Route of Treatmeht

Regimen of Treatment

No. ~

%

of

EffYcacy

Boophilus microplus

20 25 25

PO PO PO

Day 0 and 20 Day 0 and 20 Every 7 days (3)

2 2 16

92.7 99. I i00

Dermatobia hominis

I0

IM or SC

Single

13

98.9

H~poderma boris

5

IM

Single

7

i00

Oestrus ovis

5 5

10

PO PO PO

Single Single Single

5 6 6

I00 97.3 96.6

Cochlyomia hominivorax

I0

PO

Single

Psoroptes communis var ovis

i0 15

SC SC

Day 0 and 7 Day 0 and 7

i00 i00

S

SC

Followed by 2.5 mg/kg 7 days (2)

100

Demodex c a n i s localized lesions

92.3

325

Yet in spite of this and its characteristic

activity on a biochemical mecha-

nism common to many parasitic and free living animal species, the safety of closantel has been demonstrated by diverse studies performed in sheep, cattle and laboratory rodents (Desplenter, 1982).

Its effect on the host reproduc-

tive functions have also been studied, establishing closantel in animals in reproduction

the safety of the use of

(Chevis, 1977).

The ultimate safety to

the consumer of the meat of closantel treated animal has been shown by determination of tissue residues in carcasses of animals treated with this antiparasitic compound (Michiels et al, 1980). The variety of actions and antiparasitic

activity

of closantel

seem to

indicate that in the future the control of many types of parasites may be possible

through

the use of compounds

which affect

biochemical

mechanisms

which are common to parasitic agents regardless of taxonomical classi£ication or animal host species.

These compounds

may then become extremely

tools for the veterinarian to practice preventive veterinary medicine.

useful

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