IVERMECTIN
First draft prepared by
Dr K.N. Woodward
Veterinary Medicines Directorate
Ministry of Agriculture, Fisheries and Food
Weybridge, Surrey, United Kingdom
1. EXPLANATION
Ivermectin (a mixture of > 80% 22,23-dihydroavermectin B1a
(H2 B1a) and no more than 20% 22,23-dihydroavermectin B1b
(H2 B1b) had previously been evaluated at the thirty-sixth
meeting of the Joint FAO/WHO Expert Committee on Food Additives
(Annex 1, reference 91), when an ADI of 0-0.2 µg/kg bw was
established based on a NOEL of 0.1 mg/kg bw/day for maternal
toxicity in the CF1 mouse and a safety factor of 500.
Since that time, additional data have become available which
are summarized and discussed in the following monograph. Where
necessary, data presented in the original monograph (Annex 1,
reference 92) are also discussed in this updated version.
2. BIOLOGICAL DATA
2.1 Biochemical Aspects
2.1.1 Absorption
2.1.1.1 Mice
Radio-labelled ivermectin (3H-H2 B1a mixed with
unlabelled ivermectin to give a specific activity of 544 µCi/mg) was
administered in a single oral dose to CF1 mice, 7 weeks old, as a
solution in sesame oil, by gavage at 0.4 mg/kg bw. Blood samples
were taken at 0.5, 1, 2, 6, 8, 12, 48 and 96 h after dosing.
Greater than 62% of the dose was absorbed as indicated by
comparison of the plasma concentration-time curves with those
obtained from a group of mice given intravenous doses. Peak plasma
concentrations (80-100 ng/ml) occurred between 6 and 12 h after
administration, but levels of 2-3 ng/ml were present at 96 h. The
area under the curve (AUC) was 2733 ng-h/ml (Merck & Co. Inc.,
1987a).
2.1.1.2 Humans
Healthy male volunteers were given 6, 12 or 15 mg tablets as
single oral doses of ivermectin (approximately 100, 200 or 250 µg/kg
bw). Mean peak plasma concentrations were 18, 31 and 49 ng/ml,
respectively, at a mean time of approximately 4 h after dosing. Mean
AUCs were 247, 513 and 820 ng-h/ml, respectively (Merck & Co. Inc.,
1987b).
2.2 Toxicological Studies
2.2.1 Comparative toxicity: CF1
mouse vs rat and rabbit
The toxicity of ivermectin in animals was discussed
comprehensively in the previous monograph (Annex 1, reference 92).
The data clearly demonstrated that the CF1 mouse is more
sensitive to the toxic effects of orally administered ivermectin in
a number of studies than the rabbit, rat or dog. These include
acute, subacute and reproductive studies. These differences are
evident in the teratogenicity studies with ivermectin (and with the
related compound, abamectin), as shown in Table 1.
2.2.2 Comparative toxicity : ivermectin vs abamectin
Ivermectin differs from abamectin in that it lacks a double
bond in one of the lactone rings at C22-C23. Several studies,
but notably subchronic (13-18 weeks) studies in dogs, teratogenicity
studies in mice, rabbits and rats, and multigeneration studies in
Table 1. Results of teratogenicity studies with ivermectin and abamectin
CF1 mouse rabbit rat
abamectin ivermectin abamectin ivermectin abamectin ivermectin
Maternal
toxicity
NOEL 0.05 0.1 1.0 3.0 1.6 5.0
MEL 0.075 0.2 2.0a 6.0 2.0a 10.0
Developmental
toxicity
NOEL 0.2 0.2 1.0 1.5 1.6 5.0
MEL 0.4 0.4 2.0a 3.0 3.0 10.0
NOE = no-observed-effect level in mg/kg bw per day.
MEL = minimum effect level in mg/kg bw per day.
a effect (cleft palate) not seen at maximum dose tested (2.0 mg/kg bw).
rats, suggest that abamectin and ivermectin have a similar order of
toxicity (Annex 1, reference 92; Merck & Co. Inc., 1976, 1977a,b;
1982a,b). In fact, abamectin appears to be marginally more toxic
than ivermectin in all these studies. Consequently, the negative
mutagenicity studies on ivermectin and the negative carcinogenicity
studies with abamectin indicate that ivermectin has no carcinogenic
potential. The main signs of toxicity in the 94-week study in mice
with abamectin were tremors; the NOEL was 4 mg/kg bw/day. In the
105-week study in rats with abamectin, tremors were again the main
treatment-related effect. The NOEL was 1.5 mg/kg bw/day (Annex 1,
reference 92; Merck & Co. Inc., 1983a).
2.2.3 Acute toxicity studies
2.2.3.1 Cattle
Groups of 6-month old male and female Friesan calves were given
subcutaneous injections or oral treatments with 4 mg/kg bw
ivermectin (20 times the therapeutic dose). A third group was given
a micelle formulation by subcutaneous injection at 1.4 mg/kg bw (7
times the therapeutic dose).
The main signs of toxicity in animals given ivermectin orally
or by subcutaneous injection were depression and ataxia. Animals
given the oral dose became incoordinate and recumbent. Of the 6
animals treated (3 male, 3 female) in this way, one died. The death
appeared to be partly due to a long-standing lung condition. The
remainder recovered. All the animals given ivermectin subcutaneously
recovered (Merck & Co. Inc., 1983b).
2.2.3.2 Sheep
A group of 6 (3 male, 3 females) German merino lambs (8 months)
were given a single oral treatment of 4 mg/kg bw. Approximately 5-8
h after treatment, the ewes produced dark brownish-red urine. Signs
of depression including recumbency and incoordination were noted.
All the animals recovered within 7 days (Merck & Co. Inc., 1981a).
2.2.3.3 Horses
In this study, 6 thoroughbred mares (5-12 years), 8 Arab cross
and quarterhorse cross stallions (2-8 years) and 8 Arab cross foals
(3-5 months) were given 2 mg/kg bw ivermectin as an oral paste on
two consecutive days (10 times the therapeutic dose). Depression and
impairment of vision were the main signs seen following drug
administration. All the affected horses recovered within 5 days
(Merck & Co. Inc., 1982c).
2.2.4 Reproduction studies
2.2.4.1 Comparison of reproductive effects in laboratory species
An examination of the mouse, rat and rabbit reproductive data
and the teratology studies reviewed in the original monograph (Annex
1, reference 92) shows that birth defects occur only at maternally
toxic doses of ivermectin. Moreover, the types of defect, typically
cleft palate, are those usually associated with maternotoxic effects
rather than frank teratogenicity (see Table 1).
2.2.4.2 Cattle
Pregnant hereford or hereford/angus cows received 400 µg/kg bw
ivermectin at monthly intervals for a total of 6 treatments. The
first treatment was at day 90 of pregnancy. A group of 7 pregnant
cows were given no treatments. All the treated animals calved
normally and no abnormalities were noted in the calves. There were
no significant differences in weights between calves from control
and treated cows (Merck & Co. Inc., 1981b).
Jersey heifers (126) were given either vehicle control or
ivermectin at 400 µg/kg bw (twice the therapeutic dose)
subcutaneously, on the following days after insemination:
7, 19 and 35
or 10, 22 and 42
or 13, 25 and 49
or 16, 28 and 56.
Fifty-two pregnancies were confirmed in the treated groups and
53 in the controls. There were no significant differences in the
treated groups when compared with controls for the numbers of calves
carried to term, perinatal deaths or 3-month survival. No
treatment-related effects were seen (Merck & Co. Inc., 1981c).
A similar study was conducted with a total of 42 Friesian and
12 Jersey heifers. These were treated in the same way with 400 µg/kg
bw ivermectin at the same time intervals after insemination as those
in the study described previously. There were no significant
differences between treated animals and controls in the numbers of
animals carrying pregnancy to term, fetal anomalies, the numbers of
dead calves or in the birthweights of calves (Merck & Co. Inc.,
1981d).
2.2.4.3 Pigs
Six groups of 7 Yorkshire crossbred sows were given vehicle
control or 600 µg/kg bw ivermectin by subcutaneous injection on days
1 and 18, or 6 and 24, or 12 and 30 of gestation. Animals were
examined during gestation, at birth and until 35 days of age. At
this time, 25% from each litter were necropsied for examination for
terata.
There were no significant increases in the incidence of any
effect that could be attributed to compound administration (Merck &
Co. Inc., 1982d).
2.2.4.4 Sheep
Coopworth ewes (326) were treated orally with vehicle or with
400 µg/kg bw (twice the therapeutic dose) with one of 3 regimens:
day 0 of gestation to day 7 and day 21 to day 28
day 7 of gestation to day 14 and day 28 to day 35
day 14 of gestation to day 22 and day 35 to day 43.
All lambs born alive were weighed and clinically examined after
birth and at 3 and 6 months. All dead fetuses, stillborn lambs and
lambs dying after birth were necropsied and most of these were
radiographed.
No effects which could be attributed to ivermectin treatment
were noted (Merck & Co. Inc., 1981e).
2.2.4.5 Horses
A total of 32 pregnant Welsh pony-type mares were either
untreated or given ivermectin (600 µg/kg bw) as an oral paste using
the following regimes:
- on the first Monday following day 0 and every two weeks
thereafter for 6 treatments total;
- on the second Monday following day 0 and every two weeks
thereafter for 6 treatments total;
- on the first Monday following day 0 and every week
thereafter for 12 treatments total.
There were no significant differences between untreated and
treated groups with respect to foal birth weights or anatomical and
clinical abnormalities, except for two foals in the treated group
that showed transitory weakness. At 3 months of age, there were no
differences between foals from treated or untreated mares. At age
4-6 months, 3 cases of cryptorchidism were noted in foals born to
treated mares compared with one of the untreated animals. However,
because of the small numbers involved, statistical analysis was not
possible, and the condition is common in colts. The results do not
suggest a major effect of ivermectin in the pregnant mare (Merck &
Co. Inc., 1982e).
Groups of 4 pregnant mares (variety of breeds) were treated
orally with ivermectin (600 µg/kg bw) in the same manner as that
described in the preceding study.
There were no significant differences in the number of live
offspring produced by ivermectin-treated animals when compared with
controls. Foals from ivermectin-treated mares were similar in all
respects clinically to those from untreated mares. Cryptorchidism
was only seen in controls (Merck and Co. Inc., 1982f).
2.2.4.6 Adverse reproductive reports following ivermectin use
Ivermectin has been widely used in veterinary medicine for a
number of years. Although the number of pregnant animals treated is
unknown, the incidence of adverse reproductive effects following
clinical use is extremely low in all species (Table 2).
2.3 Observations in humans
In humans infected with Onchocerca volvulus or other
parasites, the major effects following the administration of
ivermectin are attributable to the Mazzotti reaction, a severe
inflammatory response. Symptoms include an intense pruritus,
erythema, oedema, vesicle and
Table 2. Incidence of adverse reproductive reports following use of
ivermectin in animals*
Adverse reproductive reports
Species Doses sold No. of reports No. of animals
(million)
Pigs 61 10 46
Cattle 1213 11 67
Horses 63 25 30
Dogs 340 3 4
Sheep 820 5 58
TOTAL 2497 54 205
* includes animals with known clinical problems which may affect
reproductive function (parvovirus, brucellosis, equine rhinopneumonitis,
trauma, etc.); adverse reproductive effects include abortion,
stillbirth, and infertility) (Greene, 1991).
papule formation and scaling. Adenitis, fever and hypotension may
occur and severe inflammatory changes may be noted in both the
anterior and posterior segments of the eye. The reaction is thought
to be due to an acute exacerbation of the host immune responses to
microfilariae, associated with migration of microfilariae into the
blood and other body fluids (Ackerman et al., 1990).
2.3.1 Observations in children
In a trial to investigate the safety and efficacy of ivermectin
in the treatment of Onchocerca volvulus in children, 103 subjects
aged 6-13 years were given a single oral dose of 150 µg/kg bw. The
major adverse reaction was a Mazzotti-type response. Cases of oedema
and peripheral oedema were classified as being "probably" due to the
drug and myalgia and headache as "possibly" related. None of the
effects was serious (Lariviere, 1988).
2.3.2 Observations in adults
Reports on studies of over 26 000 patients treated with
ivermectin for parasitic diseases, largely onchocerciasis, suggest
that single oral doses of up to 200 µg/kg bw produced no major
effects except for those resulting from effects on the parasite
(Table 3). Symptoms also included headaches which may be due to the
Mazzotti reaction but it should be noted that these have also been
reported in healthy volunteers given the drug at approximately 100
µg/kg bw (Annex 1, reference 92). Similar findings were made when
the combined results from 8 community trials were analysed (De Sole
et al., 1989b). A total of approximately 1.5 million people have
been treated with ivermectin worldwide and no deaths attributable to
the drug have been noted (Greene, 1991).
2.3.3 Observations in pregnant women
In a 3-year study in Liberia, 203 children born to women
inadvertently treated with ivermectin during pregnancy were
identified. There was no increased incidence of birth defects when
compared with untreated mothers in the same population or in a
reference population (Pacque et al., 1990).
2.3.4 Effects on prothrombin time
Two patients were found to have prolonged prothrombin times
after treatment with ivermectin (Homeida et al., 1988). However
in vitro and in vivo studies in humans have failed to reproduce
this effect (Hay et al., 1990; Richards et al., 1989), and it
seems unlikely that the reported cases were due to ivermectin
treatment.
2.3.5 Adverse reactions in humans following accidental exposure to
ivermectin
There are approximately 40 reports of self-injection with
ivermectin solutions intended for animal use. The major effect noted
was pain at the injection site but nausea, paresthesia, variable
blood pressure, urticaria and cellulitis have been reported.
Dermatitis was the main reaction following dermal exposure. There
were approximately 10 reports of accidental ingestion of ivermectin
solution or tablets by adults; adverse effects noted included
mydriasis, vomiting, tachycardia and somnolence. (Greene, 1991).
Table 3. Observations in patients orally treated with ivermectin
Number of Dose, Main effects noted Reference
patients µg/kg bw
86 50-200 Pruritus Pappayliou et al., 1987
50 50-200 Arthralgia, fever, pruritus Jacobsen & Aziz, 1987
1278 100-200 Well tolerated. Myalgia and Neu & Aziz, 1987
headache incidence higher at
highest dose
85 150-200 Well tolerated White et al., 1987
14 200 Well tolerated White et al., 1987
49 100-200 No serious adverse reactions Greene et al., 1985
32 5-50 Well tolerated Aziz et al., 1982
50 150 No major effects Addiss et al., 1991
19 50-200 Transient ischemia, Awadzi et al., 1984, 1985
delayed choroidal perfusion
59 200 Tachycardia, hypotension Awadzi et al., 1986
Ocular changes Dadzie et al., 1987, 1989
14911 130-200 13 cases of severe fever De Sole et al., 1989ab,
2 cases of life threatening 1990
dyspnea
30 200 Mazzotti reactions Diallo et al., 1986
32 (mean 150 No significant effects on Dukuly et al., 1990
age 61) electrocardiogram
30 200 Well tolerated Greene et al., 1985
40 25-200 Sore throat and cough at 100 Kumaraswani et al., 1988
and 200 µg/kg bw but only in
patients with high
microfilaria burden
Table 3. cont'd Observations in patients orally treated with ivermectin
Number of Dose, Main effects noted Reference
patients µg/kg bw
7699 150 No severe reactions; 1.3% with Pacque et al., 1989a,b,
(15 yrs +) Mazzotti reaction 1991
35) 100-200 Well tolerated Richard-Lenoble et al.,
17) 1988
30 200 Headache and fever Richards et al., 1991
200+200
(consecutive
days)
30 200 No ocular effects Taylor et al., 1986
39 100-200 No ocular effects Taylor et al., 1989
200 100-200 No major adverse reactions at White et al., 1987
150 µg/kg bw. Hypotension
(1 case) at 200 µg/kg bw
1400 150 Mild-moderate reactions seen Paque et al., 1991
after first dose, most
ascribable to Mazzotti-type
reactions. Incidence less in
subsequent years
3. COMMENTS
The Committee reappraised the developmental toxicity of
ivermectin and reviewed the human data including a large amount of
new information made available since its thirty-sixth meeting. The
information clearly demonstrates that the CF1 mouse is extremely
sensitive to the toxicity of ivermectin. In no species are there
data to suggest that the drug is a teratogen in the absence of
maternal toxicity. Various toxicity studies in rats and rabbits in
addition to those in cattle, pigs, sheep, and horses emphasize the
particular susceptibility of the CF1 mouse to ivermectin toxicity.
Despite the extremely wide use of ivermectin, there is no evidence
of significant incidences of adverse effects on reproductive
performance in treated animals and the very limited data on
reproductive toxicity in humans indicate that ivermectin does not
increase the incidence of birth defects.
The main effects noted in field and community-based trials with
ivermectin in humans infected with Onchocerca spp. have been those
arising from the death of the parasites, the so-called Mazzotti
reaction, which is characterized by arthralgia, pruritus, fever,
hypertension, tachycardia, headache, and ocular changes. Neither in
these studies nor during ivermectic treatment of other parasitic
diseases in humans in Africa, South America, the Caribbean, and
certain other areas has a subset of atypically sensitive individuals
been detected. Furthermore, the adverse effects experienced by the
small number of persons accidentally exposed to doses (often of
veterinary preparations) higher than customary human doses are in
keeping with those noted in several test animal species.
4. EVALUATION
In the light of the above findings, the Committee decided to
amend its previous conclusions. Taking into account the absence of
major effects in humans, the data indicating that the compound was a
developmental toxicant rather than an overt teratogen, and the
extreme sensitivity of the CF1 mouse to these effects, The
Committee concluded that a safety factor of 100 was justified.
However, as the CF1 mouse was the most sensitive species studied,
the ADI should continue to be based on the NOEL of 0.1 mg/kg bw/day
for maternal toxicity in that species. On this basis, an ADI of 0-1
µg kg/bw was established.
5. REFERENCES
ACKERMAN, S.J., KEPHART, G.M., FRANCIS, H., AWADZI, K., GLEICH, G.J.
& OTTESEN, E.A. (1990). Eosinophil degranulation. An immunologic
determinant in the pathogenesis of the Mazzotti reaction in human
onchocerciasis. J. Immunol., 144: 3961-3969.
ADDISS, D.G., EBERHARD, M.L., LAMMIE, P.J., HITCH, W.L. & SPENCER,
H.C. (1991). Tolerance of single high-dose ivermectin for treatment
of lymphatic filariasis. Trans. Roy. Soc. Trop. Med. Hyg., 85:
265-266.
AWADZI, K., DADZIE, K.Y., SCHULZ-KEY, H., HADDOCK, D.R.W., GILLES,
H.M. & AZIZ, M.A. (1984). Ivermectin in onchocerciasis.
Lancet, ii: 921.
AWADZI, K., DADZIE, K.Y., SCHULZ-KEY, H., HADDOCK, D.R.W., GILLES,
H.M. & AZIZ, M.A. (1985). The chemotherapy of onchocerciasis X. An
assessment of four single dose treatment regimes of MK-933
(Ivermectin) in human onchecerciasis. Ann Trop Med Parasitol., 79:
68-78.
AWADZI, K., DADZIE, K.Y., SCHULZ-KEY, H., GILLES, H.M., FULFORD,
A.J. & AZIZ, M.A. (1986). The chemotherapy of onchocerciasis XI. A
double-blind comparative study of ivermectin, diethlycarbamazine and
placebo in human onchocerciasis in Northern Ghana. Ann. Trop. Med.
Parasitol., 80: 433-442.
AZIZ, M.A., DIALLO, S., DIOP, I.M., LARIVIERE, M. & PORTA, M.
(1982). Efficacy and tolerance of ivermectin in human
onchocerciasis. Lancet, ii: 171-173.
DADZIE, K.Y., BIRD, A.C., AWADZI, K., SCHULZ-KEY, H., GILLES, H.M. &
AZIZ, M.A. (1987). Ocular findings in a double-blind study of
ivermectin versus diethylcarbamazine versus placebo in the treatment
of onchocerciasis. Brit. J. Ophthalmol., 71: 78-85.
DADZIE, K.Y., AWADZI, K., BIRD, A.C. & SCHULZ-KEY, H. (1989).
Ophthalmological results from a placebo controlled comparative
3-dose ivermectin study in the treatment of onchocerciasis. Trop.
Med. Parasitol., 40: 355-360.
DE SOLE, G., AWADZI, K., REMME, J., DADZIE, K.Y., GIESE, J., KARAM,
M., F.M. & OPUKU, N.O. (1989a). A community trial of ivermectin in
the onchocerciasis focus of Asubende, Ghana. II. Adverse reactions.
Trop. Med. Parasitol., 40: 375-382.
DE SOLE, G., REMME, J., AWADZI, K., ACCORSI, S., ALLEY, E.S., BA,
O., DADZIE, K.Y., GIESE, J., KARAM, M. & KEITA, F.M. (1989b).
Adverse reactions after large-scale treatment of onchocerciasis with
ivermectin: combined results from eight community trials. Bull.
World Health Org., 67: 707-719.
DE SOLE, G., DADZIE, K.Y., GIESE, J. & REMME, J. (1990). Lack of
adverse reactions in ivermectin treatment of onchocerciasis.
Lancet, i: 1106-1107.
DIALLO, S., AZIZ, M.A., LARIVIERE, M., DIALLO, J.S., DIOP-MAR, I.,
N'DIR, O., BADIANE, S., PY, D., SCHULZ-KEY, H., GAXOTTE, P. &
VICTORIUS, A. (1986). A double-blind comparison of the efficacy and
safety of ivermectin and diethylcarbamazine in a placebo controlled
study of Senegalese patients with onchocerciasis. Trans. Roy. Soc.
Med. Hyg., 80: 927-934.
DUKULY, Z.D., PACQUE, M., NARA, A., TAYLOR, H.R., WILLIAMS, P.N. &
GREENE, B.M. (1990). A prospective study in high risk subjects of
electrocardiographic changes with ivermectin. Trop. Med.
Parasitol., 41: 73-74.
GREENE, B.M., TAYLOR, H.M., CUPP, E.W., MURPHY, R.P., WHITE, A.T.,
AZIZ, M.A., SCHULZ-KEY, H., D'ANNA, S.A., NEWLAND, H.S.,
GOLDSCHMIDT, L.P., AUER, C., HANSON, A.P., FREEMAN, S.V., REBER,
E.W. & WILLIAMS, P.N. (1985). Comparison of ivermectin and
diethylcarbamazine in the treatment of onchocerciasis. New Engl. J.
Med., 313: 133-138.
GREENE, B.M. (1991). Expert report on the safety of ivermectin. In:
Ivermectin - Report to JECFA, Volume 1, Unpublished report.
Submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
HAY, J., DUNCAN, N. & ARNOTT, M.A. (1990). Ivermectin and
coagulation: an in vitro study. Ann. Trop. Med. Parasitol., 84:
503-506.
HOMEIDA, M.M., BAGI, I.A., GHALIB, H.W., SHEIKH, H.E., ISMAIL, A.,
YOUSIF, M.A., SULIEMAN, S., ALI, H.M., BENNETT, J.L. & WILLIAMS, J.
(1988). Prolongation of prothrombin time with ivermectin.
Lancet, i: 1346-1347.
JACOBSEN, C.A., KO, A. & AZIZ, M.A. (1987). Clinical study report
MK-933. Phase IIB ivermectin. Unpublished report: submitted to WHO
by MSD Research Laboratories, Lauterbach, Germany.
KUMARASWARMI, V., OTTESEN, E.A., VIJAYASEKARAN, V., DEVI, U.,
SWAMINATHAN, M., AZIZ, M.A., SARMA, G.R., PRABHAKAR, R. & TRIPATHY,
S.P. (1988). Ivermectin for the treatment of Wuchereria bancrofti
filariasis. J. Am. Med. Assoc., 259: 3150-3153.
LARIVIERE, M. (1988). Clinical study report. MK-933. Phase III
onchocerciasis - pediatric study. Unpublished report: submitted to
WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1976). Eighteen-week oral toxicity study in dogs.
TT # 76-073-0. Unpublished report: submitted to WHO by MSD Research
Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1977a). Oral teratogenic evaluation in mice. TT #
77-705-0. Unpublished report: submitted to WHO by MSD Research
Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1977b). Ten-day oral toxicity study in pregnant
mice. TT # 77-717-1. Unpublished report by MSD Research
Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1981a). Sheep trial # 6746. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1981b). MK-933/Cattle/Safety/Reproduction.
Unpublished report: submitted to WHO by MSD Research Laboratories,
Lauterbach, Germany.
MERCK & CO., INC. (1981c). Cattle trial # 6466. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1981d). Cattle trial # 6483. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1981e). Sheep trial # 6455. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1982a). Fifty-three week dietary study in dogs.
TT # 82-104-0. Unpublished report: submitted to WHO by MSD Research
Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1982b). Oral multigeneration study in rats. TT #
82-9010. Unpublished report: submitted to WHO by MSD Research
Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1982c). Horse trial # 8907. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1982d). Swine trial # 4815. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1982e). Horse trial # 7266. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1982f). Horse trial # 7417. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1983a). Ninety-four week dietary carcinogenicity
and toxicity in mice. TT # 83-002-0/1/2/3. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1983b). Cattle trial # 8803. Unpublished report:
submitted to WHO by MSD Research Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1987a). Oral absorption study in mice TT #
87-069-0. Unpublished report: submitted to WHO by MSD Research
Laboratories, Lauterbach, Germany.
MERCK & CO., INC. (1987b). Clinical pharmacology. In: Ivermectin -
Report to JECFA. Volume 2. Unpublished report: submitted to WHO by
MSD Research Laboratories, Lauterbach, Germany.
NEU D.C., KO, A. & AZIZ, M. (1987). Clinical study report. MK 933.
Phase III ivermectin. Unpublished report: submitted to WHO by MSD
Research Laboratories, Lauterbach, Germany.
PACQUE M., DUKULY, Z., GREENE, B.M., MUNOZ, B., KEYVAN-LARIJANI, E.,
WILLIAMS, P.N. & TAYLOR, H.R. (1989a). Community-based treatment of
onchocerciasis with ivermectin: acceptability and early adverse
reactions. Bull. World Health Org., 67: 721-730.
PACQUE, M., MUNOZ, B., WHITE, A.T., WILLIAMS, P.N., GREENE, B.M. &
TAYLOR, H.R. (1989b). Letter to Editor. Lancet, i: 1140.
PACQUE, M., MUNOZ, B., POETSCHKE, G., FOOSE, J., GREENE. B.M. &
TAYLOR, H.R. (1990). Pregnancy outcome after inadvertant ivermectin
treatment during community-based distribution. Lancet, ii:
1486-1489.
PACQUE, M., MUNOZ, B., GREENE, B.M. & TAYLOR, H.R. (1991).
Community-based treatment of onchocerciasis with ivermectin: safety,
efficacy, and acceptability of yearly treatment. J. Infect. Dis.,
163: 381-385.
PAPPAYLIOU, E.S., JACOBSEN, C.A., COOK, T. & AZIZ, M. (1987).
Multicenter (Study No.5002): Double blind comparative studies of
ivermectin (MIC-933), diethylcarbamazine citrate (DEC-C) and placebo
in patients with onchocerciasis. Unpublished report: submitted to
WHO by MSD Research Laboratories, Lauterbach, Germany.
RICHARD-LENOBLE, D., KOMBILA, M., RUPP, E.A., PAPPAYLIOU, E.S.,
GAXOTTE, P., NGUIRI, C. & AZIZ, M.A. (1988). Ivermectin in loiasis
and concommitant O. volvulus and M. perstans infections. Am. J.
Trop. Med. Hyg., 39: 480-483.
RICHARDS F.O., McNEELEY, M.B., BRYAN, R.T., EBERHARD, M.L.,
MCNEELEY, D.F., LAMMIE, P.J. & SPENCER, H.C. (1989). Ivermectin and
prothrombin time. Lancet, i: 1139-140.
RICHARDS, F.O., EBERHARD, M.L., BRYAN, R.T., McNEELEY, D.F., LAMMIE,
P.J., McNEELEY, M.B., BERNARD, Y., HIGHTOWER, A.W. & SPENCER, H.C.
(1991). Comparison of high dose ivermectin and diethylcarbamazine
for activity against bancroftian filariasis in Haiti. Am. J. Trop.
Med. Hyg., 44: 3-10.
TAYLOR. H.R., MURPHY, R.P., NEWLAND, H.S., WHITE, A.T., D'ANNA S.A.,
KEYVAN-LARIJANI, E., AZIZ, M.A., CUPP, E.W. & GREENE, B.M. (1986).
Treatment of onchocerciasis. The ocular effects of ivermectin and
diethylcarbamazine. Arch. Ophthalmol., 44: 863-870.
TAYLOR, H.R., SEMBA, R.D., NEWLAND, H.S., KEYVAN-LARIJANI, E.,
WHITE, A., DUKULY, Z. & GREENE, B.M. (1989). Ivermectin treatment of
patients with severe ocular onchocerciasis. Am. J. Trop. Med. Hyg.,
40: 494-500.
WHITE, A.T., NEWLAND, H.S., TAYLOR, H.R., ERTTMANN, K.D.,
KEYVAN-LARIJANI, E., NARA, A., AZIZ, M.A., D'ANNA, S.A., WILLIAMS,
P.N. & GREENE, B.M. (1987) Controlled trial and dose-finding study
of ivermectin for treatment of onchocerciasis. J. Infec.
Dis., 156: 463-470.