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Antiminth (Pyrantel Pamoate) : The Clinical Evaluation of a New Broad-Spectrum Anthelminthic

Norman E. Pitts and Joseph R. Migliardi CLIN PEDIATR 1974 13: 87 DOI: 10.1177/000992287401300116 The online version of this article can be found at: http://cpj.sagepub.com/content/13/1/87

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THERAPY

Antiminth
The Clinical Evaluation of a New

(Pyrantel Pamoate)

Broad-Spectrum Anthelminthic
Norman E. Pitts, M.B., Ch.B., D.C.H.,* Joseph R. Migliardi, M.D.†

A new broad-spectrum anthelminthic, antiminth (pyrantel pamoate), has been evaluated in 1,506 patients, mainly children. Single doses of 5/mg/lb/body weight (base activity) showed high overall efficacy against Enterobius vermicularis (97.2%) and Ascaris lumbricoides (97.5%). In tropical locations, in patients with multiple infestataons, single doses of 10 mg/lb/day for three consecutive days achieved a cure rate of 86.4 per cent with Necator americanus. With a smaller number of patients, a lower dosage of 5 mg/lb/day for three consecutive days was also effective (90.7%). At recommended doses (5 mg/lb/day), Antiminth (pyrantel pamoate) was well tolerated and free of adverse effects upon hematologic, renal, and hepatic function. There was not the troublesome staining seen with certain other anthelminthics. The safety profile was further substantiated by clinical experience with doses in excess of 5 mg/lb/body weight, at times carried on for several weeks.

tetrahydropyrimidines.1 Anti6-tetrahydro-1-methyl2-[2-(2-thienyl)vinyl]-pyrimidine hydrogen pamoate (Fig. 1). It is the salt of the tetrahydropyrimidine base and pamoic acid. It is not chemically related to currently availchemically
as

minth is trans-1, 4, 5,

able medications utilized for Enterobius

ver-

micularis, Ascaris lumbricoides, Ancylostoma duodenale or Necator americanus (Fig. 2, Table 1 }.

Animal Studies
The agent evaluated and described in this clinical research program has been Antiminth, the sparingly soluble pamoate salt of pyrantel (34 per cent free pyrantel base). Other water-soluble salts of pyrantel, e.g., pyrantel tartrate (58 per cent free base), are also effective; the level of activity is proportional to the amount of free base. 2,3 The tartrate salt of pyrantel dissolves readily in the gastric and intestinal juices (Table 2) whereas the pamoate salt is almost insoluble in either of these fluids. The form preferred for veterinary applications is the tartrate. Dogs given radiolabeled tartrate achieve higher plasma levels and excrete greater quantities of pyrantel in the urine than do dogs given radiolabeled

broad spectrum anthelminthic, Antiminth$ (pyrantel pamoate), represents a

9

ANEW

new

class of anthelminthic agents classified

* Executive Director, Department of Clinical Research, Medical Research Laboratories, Pfizer Inc., Groton,

Conn. 06340.

&dag er; Formerly Associate Director, Department of Clinical Research, Medical Research Laboratories, Pfizer Inc.; presently Clinical Research Director, Beecham-Massengill Pharmaceuticals, Bristol, Tenn. 37620.

pamoate.
The physicochemical and pharmacokinetic differences are reflected in the animal toxicology relating to the two salts. For inDownloaded from cpj.sagepub.com at University of Otago Library on August 1, 2011

87

The broad spectrum of anthelminthic activity of pyrantel pamoate (Antiminth) has been demonstrated in several laboratory models of infection. In tests carried out with mice and dogs, the compound exhibited a high order of activity against intestinal nematodes representative of those found in man, such as pinworm, large roundworm, and hookworm.

stance, the oral LD50t for mice, rats, and dogs ranges between 2 and 5 gm/kg of the pamoate

salt, whereas the oral LD50 for mice is 175 ( 152-~O l ) mg/kg of the tartrate salt-approx-

imately 30 times less than that of the pamoate

salt

(Table 3).

Pyrantel tartrate (Banminth: Pfizer Ltd., England) has been extensively evaluated in a variety of farm animals-sheep, cattle, swine, horses, and poultry, as well as dogs. When given as a single dose, this is highly active against both adult and immature
nematodes in the abomasum and small intestine of both cattle and sheep. In swine, excellent prophylactic and therapeutic activity has been demonstrated against Ascczris suum. In dogs, both the pamoate and the soluble salts exhibit excellent activity against Toxocara and hookworm species.
t That dose which kills 50 per cent of the animals when given as an acute single dose.
test

The studies in mice show that the sparing solubility does not affect the therapeutic activity of pyrantel. However, solubility does have a profound effect on its ED90 against species in various niches in the mouse. Solubility also has a significant effect on maximum tolerated dose (MTD). For instance, against Nematospiroides dubius in mice (duodenum) the ED9o** of pyrantel tartrate and pyrantel pamoate (Antiminth), respectively, are 6.8 and 17 mg/kg (pyrantel base). However, the MTD of pyrantel as the relatively insoluble pamoate salt (Antiminth) is 2,500 mg/kg (850 mg base); that of the soluble tartrate salt, 100 mg/kg (58 mg base). Thus, the therapeutic index of the pamoate (Antiminth) far exceeds (6 x) that of the tartrate. Against Syphacia obvelata (mouse cecum), the relatively insoluble pamoate (Antiminth) has
an

ED90 of 34 mg/kg (pyrantel base) compared with 116 mg/kg (pyrantel base) for
**

That dose which reduces the

worm

burden

by

90

per

cent.

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88

the

more

soluble

tartrate.

Thus, the insolucon-

bility

of

pyrantel pamoate (Antiminth)

presumably because remain in the intestinal tract. greater In dogs, whether administered as a soluble or insoluble salt, pyrantel is effective against hookworms and ascarids but not against whipworms and tapeworms. Just as with A. suum in mice, the ED90s of the soluble and insoluble salts are essentially the same. However, as the insoluble pamoate salt, pyrantel has an MTD >5 times its MTD as the soluble tartrate salt (34 mg/kg base). As a result, its therapeutic index (TI) is >130. Because of the potential margin of safety this affords, and its effectiveness at low levels, it was the logical choice for evaluation in man. Clinical studies have confirmed the findings in the laboratory.
amounts

fers a potency advantage,

so that it remains in This property can favorably act against the side effects and toxicity, particularly when the drug is also rapidly metabolized when absorbed. Such is the case with Antiminth, as illustrated by considering pyrantel in conjunction with two other recently introduced agents-methyridine and tetramisole. Veterinary clinical trials with methyridine and tetramisole have shown a pattern of toxicity which reflects their pharmacodynamic effects.5-9 Tetramisole and methyridine also possess the novel feature of being effective both orally and subcutaneously. 10 The toxicity

slowly

or

incompletely
tract.

the intestinal

However, Antiminth is 1,000 times

more

Mechanism of Anthelminthic Action The anthelminthic activity of Antiminth and its analogues is attributable to an inhibitory action on neuromuscular transmission. This pharmacologic mechanism of action of pyrantel has been explored in detail with the nematode Ascaris lumbricoides and with vertebrate neuromuscular preparations .4 Piperazine, a commonly used anthelminthic, was also studied and, like Antiminth, is highly specific forAsccaris l~crra~rricoides. However, Antiminth is 1,000 times more effective than piperazine in terms of the concentration required to produce an effect.

effective than piperazine in terms of the concentration required to produce

an

effect.

Pharmacokin~tics
lished the

as

Related to

Toxicity

Studies in both animals and man have estabpharmacokinetics of the sparingly soluble pyrantel pamoate (Antiminth) and are supportive of its incomplete absorption. In one study (Table 4), single oral doses of 5 mg/lb gave rise to very low plasma levels of unchanged drug 0.05--0.13 /ig/ml), too low to be quantitatively measurable. Of the
amounts

and efficacy patterns of these two agents are the result of their being both rapidly absorbed and slowly or incompletely metabolized, i.e., the active forms of these drugs achieve a systemic concentration sufficient to elicit a clinical effect. Pyrantel tartrate, in contrast, when given orally in veterinary medicine, is well absorbed but shows an absence of a pharmacodynamically determined spectrum of toxicity.&dquo; In addition, it is ineffective when administered parenterally. Both the absence of a distinctive toxicity pattern and a systemic anthelminthic effect reflect the fact that it is

rapidly

metabolized.&dquo;

Antiminth, being much less soluble than

administered, approximately 1 per

cent is

excreted

3 per

cent as

unchanged in the urine and drug-related substances (Table

5).

Therapeutically, a desirable feature of an anthelminthic intended for oral use against intestinal nematodes is that it be absorbed

pyrantel tartrate, is much more slowly absorbed. 13 This feature, combined with the rapid metabolism of pyrantel, accounts for its remarkable safety profile. For instance, in 1,506 patients treated with Antiminth, there has been complete freedom from limiting side effects or organ toxicity. The customary clinical dose is a single administration of 5 mg/lb/ body weight up to a maximum of 1,000 mg. Additional confirmation of the safety of Antiminth is provided by the observations made in Phase I evaluation, during which subDownloaded from cpj.sagepub.com at University of Otago Library on August 1, 2011

89

of diarrhea and nausea when the daily dosage was in excess of 2,500 mg.

Design

of Studies in Humans

Because preclinical evaluation had indicated the broad spectrum of anthelminthic activity of Antiminth, an extensive program of clinical studies was initiated to evaluate activity in man against Enterobius vermicularis, Ascaris lumbricoides, and Necator americanus. These studies, involving mainly children, were carried out in the United States and Puerto Rico. Single infections were the rule in the United States, whereas the Puerto Rican patients had multiple infections with Enterobius vermicularis, Necator americanus, Trichuris trichiura, and Giardia lamblia. Additional studies were carried out in the Cook Islands and Costa Rica with both adults

Antiminth, being much less soluble than

pyrantel tartrate, is much more slowly absorbed. This feature, combined with the rapid metabolism of pyrantel, accounts for its remarkable safety profile.
and children.
two or more

Virtually all were infected

with

helminths, e.g., 4scarfs lumbricoides, Necator americanus, Trichuris trichiura,

and often also with Giardia lamblia. Malnutrition was the most commonly associated condition ; in one survey, approximately 52 per cent of patients had a significant degree of baseline anemia. Antiminth (pyrantel pamoate) was given in two formulations in these clinical studiesian oral suspension and a tablet. Dosage consisted for the main part of a single dose calculated on the basis of 5 mg/Ib/body weight. A total of 1,388 patients were treated with the suspension of Antiminth. Of these, 379 were adults and 1,009 were children. The breakdown by age and sex is given in Table
6.

jects received intensive continual dosing as opposed to the single-dose administration employed therapeutically. Totals of 8,750 mg were given in divided doses over a seven-day period, and 15,000 mg over a ten-day period, with no untoward systemic toxicity whatsoever, but only local gastrointestinal effects
90

A total of 610 patients were treated with tablets of Antiminth. Of these, 1 &dquo;77 were adults
All doses are expressed as mg/Ib/body weight pyrantel, base.
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and 433 were children. The breakdown by age and sex is given in Table 7. With patients treated in an institutional setting, the nursing staff were responsible for the collection of fecal specimens and their conveyance to the laboratory. In outpatient studies and field trials, the patients themselves brought in the fecal specimens for the investigator to transmit to the laboratory of the hospital where the study was based. With Entearobius vermicularis infections, the Scotch

TABLE 4. Plasma L.evets of Unchanged Drug in 1 ~ Subjects Following Antiminth (Pyrantel Pamoate) Administration in Oral Suspension

Plasma Levels of

Unchanged Drug
5 hr 24 hr**
-

(~,g/ml)* after Dose

Subject
1 2 3
4 5 6 7 8 9 10 11 1 12 13 14 1 hr

3 hr <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.05 <0.05 <0.05 <0.05 <0.05 0.05 <0.05 <0.05

Tape slides ing staff.

Criteric~

were

prepared by

trained

nurs-

<0.05 <0.05 0.05 <0.05 <0.05 <0.05 0.10

0

<0.05
<0.05 <0.05 <0.05 <0.05

0
-

<0.05
<0.05 <0.05 0.05 <0.05 <0.05 <0.05 <0.05 0.06

0
-

of Effic&dquo;y

The criteria for

assessing

the clinical

<0.05 <0.05 0 <0.05 <0.05 <0.05

0
-

0 0

responses were as follows: l. Enterobius vermicularis

For

&dquo;cure,&dquo; five

Tape follow-up commencing after dosing.

(5) consecutive Scotch slides should be negative, with

seven

(7) days

* Predose (0 hour) samples from each subject presented no background interferences in the assay. Drug levels reported as less than 0.05 jU-g/ml showed an assay response (0.025-0.05 .Lglml) but could not be quantitated. Drug levels reported as zero were indicative of levels less than 0.025 E.cgfml. ** Only selected 24-hour samples were assayed; the remainder are designated
-.

The troublesome staining of clothes associated with other anthelminthic agents was not observed with Antiminth. 2. Ascdris lumbricoides, Necator americanus, or Trichuiis trichiurr~ For &dquo;cure,&dquo; follow-up egg counts of the stools should be zero. The egg count was termed &dquo;reduced&dquo; when there was at least a 2-log decrease in egg count. The procedures used were the Formalin-Ether Sedimentation Method (Ritchie) and the Modified Stoll Technic or Beaver Direct Smear for worm burden. These efficacy indicators were assessed by laboratories well versed in these procedures.

TABLE 5. The

Urinary Excretion of tlnchanged Drug and Drug-Related Substances (Containing N-a441ethyl-1, 3-propanediamine) in 14 Subjects Following A ntiminth (Pyrantel Pamoate) in Oral Suspension Drug-Related Substances Unchanged Drug
in 48 Hours (% of Dose) 2.9 0.8 1.6 2.5 1.7 5.4 0.9 3.2 5.6 5.6
1.4

Subject
1

in 48 Hours (% of Dose)
0.4 0.2 1.6 0.4 0.7 i.3 0.3 1.0*

Result-Efficacy All patients were included in the analyses of safety, regardless of whether they were excluded from the efficacy analyses because of loss to follow-up, or because their stool examinations were not performed according to protocol, or because they received doses in excess of 5 mg/lb. As shown in Table 8, single doses of 5 mg/

2 3 4 5 6 7 8 9 10 1 11 12 13 14 Mean -!- S.D.

1.6 0.7
0.4 1.4 0.2 1.5

3.5 2.6 2.7

2.9 l.7%

a.8 a.5,~0

* Mean of four determinations: 1.07:t 0.05% S.D.,

4.7% R.S.D.

in both children and adults resulted in very high efficacy with Enterobius vermicularis and Ascaris lumbricoides infections. With Necator americanus infectic~ns, with a

lbibody weight

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91

TABLE 6. Sex and Age

with Antiminth

Range Distribution of Patients Treated (Pyrantet Pamoate) Suspension

Males Females
Not Recorded

TABLE 8.

Therapeutic Response

to

~4ntimirath

(Pyrantel

Pamoate) Suspension in a Single Dose of 5 mgllb (Base Activity)

Response
Cure

Age Range (years)

Antiminth

Total

Cure

Egg Count
Reduced

Diagnosis
Antiminth

I Dose 2 Doses

Not Effective

Per Cent Cured

suspensionadults <20 21-40

41-60

>60
Not

161 128 59 31 0

84 48 24 17 0

60 59 25 9 0

17 21 10 5 0

suspensionadults
Enterobius

vermicularis
Ascaris lumbricoides

19 9
47

specified

Necator ar~eerzcartu.s Tricfauras Crichaura

18 8
1

0 fl 3 I

0
0

100.0
i0(1.t? 60.0

9 51 1

1.9

Amimimh

Antiminth

suspensionchildren
Enterobius vermiculaii,~ Ascaris lumbricoities 226
1 291

suspensionchildren
<2 67

2
t) 0

3-5 6-8 9-12

Not

specified

174 330 422 i6

29 84 159 220 9

35 80 154 192 6

3 10 17 i 10 1

2
3 1
0

0 16 6

100.0

Necator americanus
Trichuru trichiura

31 1
1 13

27
158 3

94.2 2 5().$
0.6
C1

0
0

Giardia lamblia

children) received Antiminth in tablet form. Except for two who received two doses, all
received

dose of 5 mg/lb/body weight the cure reached 50-60 per cent. Other dosage regimens (Table 9) appeared to indicate optimum activity (90.7%) with 5 mg/lb/body weight given daily for three consecutive days. At single doses of 5, 10, and 20 mg/lbibody weight, negligible activity was demonstrable against Trichuris ~richiuru in both adults and children, and no activity against Giardia lamblia in a few cases (Tables 8, 10). A total of 610 patients (177 adults, 433

single
rate

single dose based upon 5 mg/lb/body weight (base activity). With Enterobius
a

vermicularis and Ascaris lumbricoides infections, a pattern of efficacy comparable to that obtained with the suspension was seen (Table

1 (l).

TABLE 7. Sex and Age Range Distribution of Patients Treated with Antiminth (Fyrcantel Farnoate) Tablets

Age Range (years)

Antiminth tabletsadults <20 21-40 41-60 >60
Not

Total

Males

Females

Not Recorded

Results~--,Safety Throughout the entire clinical research program comprising a total of 1,5t?fi patients evaluated for efficacy, Antiminth, whether as suspension or tablet, was well tolerated-in terms of both subjective side effects and laboratory parameters of safety. The troublesome staining of clothes associated with other
anthelminthic agents rlntiminth.
TABLE 9.
was

not

observed with

111 l 50 13 3 0

79 25 6 2 0

32 25 7
1

0 0 0 0
0

Therapeutic Response
Cure

to

Antiminth

Pamoate) Suspension
Dosage Schedule Single dose:
Mean dose 5 zngllb Mean dose 10 mgllb Mean dose 20 mgllb
Two consecutive

in Necator ~crmericanus

(Pyrantel * Infection*
Per Cent

Significant
Reduction

Not

Effective

Cure

specified

49 0
1

Antiminth tabletschildren

6 2 1

36
15

53.2

0
5.9

15 5

daily

<2
3-5 6-8

9-12
Not

32 77 134 190

15 29 66 112

15 48 68 78

2 0 0 0
0

doses: Mean dose 5

mgllb

100.0

Three consecutive daily doses: Mean dose 5 mg/lb Mean dose lf) 0 mg/16

39 127

0 1

90.&dquo;i

15 5

86.4

specified

* Adults and children.

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92

TABLE 10. Therapeutic; Response in Parasitic Infections Antiminth (Pyrantel Pamoate) Tablets Single Dose of 5 rTagllb (Base ~9ctivity) Response Diagnosis
Antiminth tabletsadults
Enterobius Cure Cure I Dose 2 Doses

to

Egg Count
Reduced

Not

Per Cent

Effective

Cured

vermicularis ~2scari.s lumlrrieoides Trichuris triehiura Grczrclia lamblia Antiminth tabletschildren

47
21 1
I

0 0
0

7 0 7 1

87.5 L()f7.0 0
12.5 0

absence of any other serious clinical side effects ascribable to the pharmacologic action of Antiminth. Certain laboratory variables were also monitored. Laboratory studies were carried out prior to and on the first or second day after the drug was given. These included complete blood count, urinalysis, and serum determinations of SGOT, alkaline phosphatase, BUN, and bilirubin. Every value outside the range of normal for the reporting laboratory
was

Enteroltiu,s
vermiculari. Ascaris tumbricoit~es Necatllr americanus Trichuris trichura Giardia lamblia 170
154 1 1 0 (7

0 ()

0 (3 t7 0

3
C7 1

98.2 () 100.() 33.3 3

0
0

deemed probably drug related unless it fell in one of the following categories:
1. Baseline value abnormal line for comparison.
or no

30
~a

base-

t)

Side effects in the total of 1,506 patients who received either the suspension or the tablets were thoroughly looked for. Qualitatively and quantitatively, the two formulations showed the same side effect profile. At the recommended dose of 5 mg/Ib (or less), the side effects most frequently reported were gastrointestinal symptoms,usually mild (Table 11). Other side effects were very infrequent, other than an occasional headache. Additional extensive experience in man has shown the

2. Evidence of a concurrent illness likely to cause the abnormality. 3. Abnormality so small as to be clearly

insignificant.
4. Documented

laboratory error.

The overall laboratory results with regard the total number of patients receiving either suspension or tablet formulation are given in Table 12. No effects of significance on
to

hematologic, renal, were recognized.

or

hepatic functioning

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93

TABLE 12. Overall Incidence of ftbnormcalities in Laboratory Parameters in Patients Treated with Antiminth (Pyrantel Pamoate) in Suspension or Tablets
Number of Number of

(thus falling into the category of possibly drug related) (Table 13). These changes were
encountered only in patients treated for Enterobius. None of those with Necator had such changes. Since the incidence levels in both groups were within ranges which might occur purely by chance (Fishers exact test never results in a p value less than 0.20), the presence of intestinal mucosal lesions did not appear to influence the safety profile of Antiminth.
References

Laboratory Test
Hemoglobin
Hematocrit WBC

Patients Tested
612 755
944

Patients with Abnormalities*

0 0

Per Cent
-

Neutrophils
Lymphocytes Monocytes Urinalysis
SGOT SGPT Alkaline phosphatase Serum bilirubin BUN
*

944
944

9
9

609
671 1 851 1 51 118 62

2
0 15 5

0.60 0.95 0.95 o.so

-

1.80
-

0
0 0 1

816

0.10

May be related

to

pyrantel pamoate.
1.

TABLE 13. Incidence of Posttreatment Laboratory Abnormalities Following Treatment of Enterobius vermicularis and Necator americanus Infection with Antimircth

(Pyrantel Pamoate) Suspension

Enteroius aermictslrztis Number of Patients Tested Number with
Laboratorv

2.

Necator americanus

Number of Number with Patients Laboratory

Tested
-

Abnormalities
0 0

Abnormalities
-

3.
4.

Hematocrit

Hemoglobin
WBC

249 360 384

384

35

3
2

38
43

0
0

Neutrophils Lymphocytes Eosinophils

Monocvtes

384
384

2
0

43 43
43 43

0 0
0 0 0 0 0 0

5. 6.

Basophils
SGOT
BUN

384 384 361 362

2
0

6
0

38
3 1

Bilirubin

27 i
362

0
1)

Urinalysis

42

7.

The character of the infections in the

8.

patients provided a further approach to the search for drug toxicity. Since gastrc~intestinal mucosal lesions of some degree are an almost invariable accompaniment of Necator infecof interest to determine whether or not the presence of Necator had any influence on the side-effect profile. One group of patients had Enterobius or Ascaris infestation or both. Another group had Necator americanus infection with or without concomitant Enterobius or ~is~czris infestation or both. A tabulation was made of all patients treated with a single dose of 5 mg/lb whose baseline laboratory results were normal and whc~ had abnormal values following therapy
was

: al. Pyrantel tartrate, a new anthelmintic effective against infections of domestic animals. Nature (Lond) 212: 1273, 1966. Howes, H. L. and Lynch, J. E.: Anthelmintic studies with pyrantel. I. Therapeutic and prophylactic efficacy against the enteral stages of various helminths in mice and dogs. J. Parasit. 53: 1085, 1967. Cornwell, R. L. and Jones, R. M.: Activity of pyrantel against Parasceris equorum. Vet Rec. 85: 196, 1969. : Aubry, M. L., Cowell, P., Davey, M. J., et al. Aspects of the pharmacology of a new anthelmintic: pyrantel. Brit. J. Pharmacol. 38: 332, 1970. Broome, A. W. J.: Studies on the mode of action of methyridine. Brit. J. Pharmacol. 17: 327, 1961. Catarsini, O. and Gagliano, I.: II. Behavior of some serum enzymes in sheep with gastrointestinal parasites and treated with methyridine. Atti. Soc. Ital. Sci. Vet. 17: 690, 1963. Forsyth, B. A.: Tetramisole: a new anthelmintic for 412, sheep. Aust. Vet. J. 42: 1966. Walley, J. K.: Tetramisole (dl 2,3,5,6-tetrahydro-6phenyl-imidazo(2, 1-b) thiazole hydrochloride&mdash;
et

Austin, W. C., Courtney, J. C., Danielewicz, D. H.,

Nilverm)
worms

in the

treatment

of

gastrointestinal

9.

tions, it

10.

11.

12.

13.

and lungworms in domestic animals. 1. Sheep and goats. Vet. Rec. 78: 406, 1966. Eyre, P.: Some pharmacodynamic effects of the nematocides: methyridine, tetramisole and pyrantel. J. Pharm. Pharmacol. 22: 26, 1970. Broome, A. W.J. and Greenhalgh, N.: A new anthelmintic with unusual properties. Nature (Lond) 189: 59, 1961. Cornwell, R. L.: Controlled laboratory trials in sheep with the anthelmintic pyrantel tartrate. Vet. Rec. 79: 590, 1966. al Faulkner, J. K., Figdor, S. K., Monro, A. M., et. .: The comparative metabolism of pyrantel in five species. J. Sci. Food Agric. 23: 79, 1972. McFarland, J. W.: The chemotherapy of intestinal nematodes. In E. Jucker, Ed: Fortschritte der

Arzneimittelforschung. Basel, Birkh&auml;user Verlag,

1972, Vol. 16, pp. 157.

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94