Review

Oxford, UK
International
IJD
Blackwell
1365-4632
45 Publishing
Journal Ltd,
Ltd.
of Dermatology
2003

Ivermectin: pharmacology and application in dermatology

Dourmishev et al.
Ivermectin
Review

Assen L. Dourmishev, Lyubomir A. Dourmishev, and Robert A. Schwartz

From the Department of Dermatology and Abstract

Venereology, Medical University, Sofia, Ivermectin is a synthetic derivative of the antiparasitic class of compounds known as
Bulgaria, and the Department of avermectins. It is a macrolide endectocide with activity against both endoparasites with
Dermatology, New Jersey Medical School,
cutaneous tropism (Strongyloides stercoralis, Ancylostoma braziliense, Cochliomyia
Newark, NJ
hominivorax, Dermatobia hominis, Filaria bancrofti, Wucheria malayi, Onchocerca volvulus,
Correspondence Loa-loa) and ectoparasites such as Sarcoptes scabies, Pediculus humanus, Demodex
Prof. Assen L. Dourmishev, PhD, DSC folliculorum, and Cheyletiella sp. Ivermectin is of great interest in the treatment of patients with
Department of Dermatology and Venereology different forms of scabies, head lice, demodecidosis, cutaneous larva migrans, cutaneous larva
Medical University
currens, myiasis, and filariasis.
1 St. G. Sofiisky Street
1431 Sofia
Bulgaria
E-mail: Assen_Dourmishev@yahoo.com

In humans, ivermectin was introduced against Onchocerca

Introduction
Ivermectin (MK-0933, 22,23-dihydroderivative of avermec-
tin B1) is a synthetic derivative of a broad-spectrum antipara-
sitic class of macrocyclic lactones known as avermectins.
Avermectin B was first isolated by fermentation of a soil
microorganism, the actinomycete Streptomyces avermitilis.
Ivermectin has a structure similar to that of macrolide anti-
biotics, but without antibacterial activity (Fig. 1). It is used
against a wide range of endoparasites (nematodes) and
ectoparasites (insects, acarine) of animals and humans. The
interest of dermatologists in ivermectin therapy grew when
promising results were observed in the treatment of human
ectoparasitoses such as scabies.1
volvolus infestation by Aziz et al. in 1982.2 It has been used
extensively in humans since 1987 to control endemic
onchocerciasis in countries of Africa and Latin America. The
drug is highly effective for the treatment of loiasis and bran-
croftian filariasis, and other intestinal nematodes as
strongyloidiasis3 and scabies.49
Pharmacokinetcs
Pharmacokinetic study of ivermectin shows good bioavail-
ability. It is absorbed rapidly and given orally on an empty
stomach, metabolized in the liver and excreted in the feces
(98%) and urine (1%).10,11 Minimal concentration of this
drug has been observed in human milk. Concentration of
ivermectin in blood peaks at 30 46 ng /mL around 4 h post-
dose, and slowly decreases thereafter.10,11 Peak plasma con-
centration of metabolites remains longer than that of the
parent drug, suggesting enterohepatic recycling. Ivermectin
reaches peak plasma levels 5 h after oral administration and
has a half-life of 36 h.12 The peak concentration of the drug in
squames, sebum and sweat on the forehead and the antithenar
was 8 h after a signal 12-mg oral dose and decline after 24 h.13

Pharmacology, Toxicology, Carcinogenesis and

Teratogenicity

Ivermectin is relatively safe. It has been tested in vitro in

microbial and mammalian cell mutagenesis assays. No geno-
Figure 1 Structure of ivermectin toxic activity was identified. Acute oral toxicity studies with 981

2004 The International Society of Dermatology International Journal of Dermatology 2005, 44, 981988
982 Review Ivermectin
ivermectin in mice, rats, dogs, and monkeys have shown
clear species differences in sensitivity.14 Primates, including
humans, are clearly less sensitive than rodents, particularly
mice. The drug is more toxic in infant than young adult rats.14
Treatment with very high dosages of ivermectin caused
embryotoxicity in animals.15 Idiosyncratic toxicity has been
observed in collies and other herding breeds receiving off-
label doses.16 The adverse reactions include ataxia, tremors,
mydriasis, depression, and in severe cases, coma and death.
Ivermectin is considered toxic to Old English sheepdogs,
Shetland sheepdogs, and Australian sheepdogs.16 Before
receiving high doses of ivermectin, animals should be free of
Dirofilaria immitis (heartworm) microfilaria.17 The tera-
togenity was defined as LS FDA Cat. C in 203 newborns
exposed to ivermectin before their birth.18 There were no con-
genital malformations.
Mode of Action
Ivermectin acts by binding selectively to specific neurotrans-
mitter receptors that function in the peripheral motor synapses
of parasites. It has an endectocidal effect (simultaneously
against endo and ectoparasites) causing paralysis of nema-
todes, arthropods and insects by suppressing the conduction
of nervous impulses in the interneuronic (intermediary neu-
rons) synapses of nematodes and the nerve-muscle synapses
of the arthropods and insects.19 Specifically, ivermectin
blocks chemical transmission across the nerve synapses that
use glutamate-gated anion channels or -aminobutyric acid-
gated chloride channels. Stimulation of -aminobutiric acid
(GABA) release from presynaptic nerve endings and enhance-
ment of the binding to the postsynaptic receptors accom-
plishes this.20,21 Ivermectin does not affect synapses gated by
other transmitter substances, such as acetylcholine, norepine-
phrine, and serotonin.22 In this way nerve impulse conduction
ceases and paralysis and death of the parasites ensues (Fig. 2).
Figure 2 Ivermectin action of -aminobutiric acid (GABA)-gated
chloride channels in the interneuronic synapsis of a parasite (i.e.
increased release of GABA at the presynaptic nerve ending;
opening of the chloride ion channels; increased binding of
GABA at the motor neuron)
International Journal of Dermatology 2005, 44, 981988
Dourmishev et al.
In humans GABA and glutamate do not affect peripheral
motor function. Thus, ivermectin selectively paralyzes inver-
tebrates. Ivermectin is well tolerated by mammals because
glutamate-gated anion channels or GABA-gated chloride
channels are localized only in the central nervous system; the
drug cannot penetrate through the hematoencephalic barrier.
-Aminobutiric acid is a neurotransmitter in the spinal cord
and brain of mammals; glutamate is a neurotransmitter in
many sensory pathways and in the cortex.
Activities
Ivermectin is used for treatment of a wide range of endopar-
asites (Strongyloides stercoralis, Ancylostoma braziliense,
Cochliomyia hominivorax, Dermatobia hominis), filariae
(Filaria bancrofti, Wucheria malayi, Onchocerca volvulus,
Loa-loa) with cutaneous tropism, and ectoparasites as well as
Sarcoptes scabies, Pediculus humanus, Demodex follicularis,
Cheyletiella spp. in animals and humans.
Resistance
Parasitic resistance to ivermectin therapy has been reported in
nematodes of horses, sheep, and other animals after almost
20 years of extensive use.1,23,24 Two mechanisms of ivermec-
tin resistance are proposed: (a) alteration of P-glycoprotein,
which is a membrane protein that actively transports the drug
across cell membranes;24 and (b) alteration of the chloride
channel receptor.23 The lack of efficacy of a single oral dose of
ivermectin in some patients with scabies may result from its
lack of ovocidal action.25 Some believe that ivermectin may
act only at certain stages of the life cycle of the parasites.26
Application in Animals
Ivermectin is successfully used in veterinary medicine for
treatment of sarcoptic mange in cats,27,28 dogs,27,29,30 foxes,31
pigs,3234 wild boars,35 and camels.36,37 It is administered either as
a subcutaneous injection, orally with feed, or topically. It is highly
effective against acars in experimentally infected donkeys.38
Species of Cheyletiella mites are parasites hosted by dogs,
cats, foxes, and rabbits.39 These mites can also be successfully
treated with subcutaneous or oral administration of iver-
mectin.14,15,39 For these parasites, it is usually given every 7
14 days for a 4- to 6-week course of treatment.14 In humans,
they cause Cheyletiella dermatitis.3941 Mite dermatitis is not
a labeled indication for ivermectin;40 however, it is widely
used in animal vectors because it prevents recurrence of dis-
ease in humans.16,17,39
Systemic treatment of white-tailed deer with ivermectin-
medicated feed corn is effective in controlling free-living popu-
lations of the Lone star tick (Acaridae: Ixodidae); a good idea,
as it is difficult to exclude deer from residential areas.42
2004 The International Society of Dermatology
Dourmishev et al.
Mode of Application in Humans
Ivermectin is used in humans administered orally or topically.
It is effective in most patients with scabies after a single oral
dose of 200 g / kg body weight, but often the regimen is
repeated doses, two or three, separated by interval of 1 or
2 weeks. Reported relapses in patients with scabies and
observed recurrent scabies in domestic animals support the
concept of two oral doses with a 7-day interval.43,44 A second
oral dose of ivermectin 1 week after the initial treatment is a
more reliable treatment option,22 and shortened the time to
successful treatment. This scheduling is suitable for the fol-
lows reasons: (i) fertile tunneling scabietic mites feed by
ingesting keratinocytes and intercellular fluids within the
epidermis; (ii) their eggs hatch every 6 7 days; (iii) the plasma
half-time of orally administrated ivermectin is 36 h;12 and (iv)
the lack of ovocidal action of the drug is hypotized.25 It can be
assumed that a second dose of the drug is needed to eradicate
newly hatched scabietic nymphs.22 In patients with scabies,
the drug was found to have a curative effect after a single topi-
cal application, but in 50% of cases, another application was
needed 5 days later.45
Contraindications to ivermectin therapy are allergic sensi-
tization, nervous system disorders, pregnancy, and lactation.
Ivermectin therapy should not be recommended for children
younger than 5 years or less than 15 kg in weight.18
Application in Dermatology
Ivermectin is used in dermatology against some parasitic
infestations in humans with cutaneous tropism. The drug is of
great interest in the treatment of patients with different forms
of scabies, human body lice, head lice, demodecicosis, cuta-
neous larva migrans, cutaneous larva currens, myiasis, and
filariasis.
Scabies
Experience with oral ivermectin use has shown that doses less
than 200 g / kg were less than 100% efficacious.46 Approxi-
mately 70% of patients with scabies treated with 200 g/kg
of ivermectin had been cured, compared with 48% of those
treated with topical 10% benzyl benzoate.5 A double-blind
study showed that 79.3% of patients with scabies were cured
1 week after a single oral dose of 200 g / kg of ivermectin, as
compared with 15.4% patients in a placebo group.7 In an
open-label study the drug was administered in a single oral
dose of 200 g / kg in two groups: one of 11 otherwise healthy
patients with ordinary scabies and a second group of 11 HIV-
infected patients with scabies, the majority of whom had
AIDS.8 At 4 weeks follow up, evaluation of all patients in the
first group and eight of 11 (73%) of the HIV-positive patients
showed they had been cured. Two patients required a second
dose 2 weeks after the first treatment and were also cured. A
2004 The International Society of Dermatology
Ivermectin Review 983
single dose of 200 g/kg of ivermectin was enough for recov-
ery in two patients with crusted scabies.9
A single dose of ivermectin 150 g/ kg was given under
supervision to 1153 prisoners.46 The signs of disease resolved
after 1 week in 30% of patients, 88% after 4 weeks, and
95.5% after 8 weeks.46 Ivermectin therapy of scabies was
shown to be effective compared with placebo.7,47 Four com-
parative studies have shown that oral ivermectin is equivalent
in common scabies to a conventional topical scabicidal treat-
ments (benzyl benzoate, lindane, permetrin) after 1 or 2 oral
doses of 200 g/ kg.5,7,25,28 Only one report showed that a single
dose of ivermectin had a cure rate of 70%, which increased to
95% with two doses at 2-week intervals and was effective
as a single topical application of 5% permetrin cream
(97.8%).25 In four controlled and open studies the cure rate of
invermectin in scabies was between 70%, 80% and 100% of
treated patients.5,7,8,43 Other open noncontrolled studies have
also shown efficacy of ivermectin in scabies.43,49,50 Because
some authors achieved only 80% success rates with 200 mg/
kg of the drug, they increased the dosage to 250 g/ kg.22 Ran-
domized, controlled trials of treatment with ivermectin vs.
benzyl benzoate and ivermectin vs. lindane failed to demon-
strate significant differences in clinical cure rates.48 Two hun-
dred patients with scabies were randomly allocated to one of
two groups.51 One panel received oral ivermectin in a single
dose of 200 g/ kg body weight. The other received 1% lin-
dane lotion for topical application overnight. Patients were
assessed after 48 h, 2 weeks, and 4 weeks. After a period of
4 weeks, 82.6% of the patients in the ivermectin group
showed marked improvement; only 44.44% of the patients in
the lindane group showed a similar response.51
In patients with autoimmune bullous disorders such as
pemphigus, connective tissue diseases such as dermatomyosi-
tis, or infection with the human immunodeficiency virus
HIV-1 for which scabies is more difficult to treat, 200 g/ kg
of ivermectin also has been successfully used.8,9,43,44,50 Some
patients with both scabies and HIV infection required a second
dose after 1 or 2 weeks,8 or a combination with local benzyl
benzoate.52 Ivermectin has been successfully employed to
eradicate scabies in epidemic or endemic situations in insti-
tutions such as nursing homes18,5355 and prisons.46
Norwegian or crusted scabies, a severe form with a high
mite burden usually associated with underlying immunosup-
pression, has been effectively treated with ivermectin given
alone or in combination with topical scabicides.9,5663 Seven of
16 prisoners (44%) with crusted scabies treated with a single
150-g/kg dose still had the disease after 8 weeks.46 The ther-
apy of crusted scabies is effective after a 200-g/ kg single dose
of the drug,9,58,62 but some patients require a second dose after
1 or 2 weeks.8,43
Ivermectin has been successfully employed in recalcitrant
crusted scabies in children.58 Crusted scabies refractory to
topical scabicides was also treated with oral ivermectin and
International Journal of Dermatology 2005, 44, 981988
984 Review Ivermectin
topical permetrin.18,63 This combination was chosen because
ivermectin may not penetrate crusted scabies adequately.1 All
cases of clinical efficacy with ivermectin therapy were accom-
panied by rapid clearing of skin lesions and a marked decrease
in pruritus.44
Oral ivermectin treatment offers several advantages over
standard topical scabicides.43,44,6567 The benefits of oral iver-
mectin treatment of patients with scabies are high efficacy,
ease and rapidity of application, and treatment of the entire
cutaneous surface without neglected areas. It is also well tol-
erated. These factors afford maximal patient compliance.
This treatment is convenient for persons who are not self-
sufficient or are bedridden. It is also effective for the immuno-
compromized. The irritant dermatitis sometimes seen with
topical scabicides is thus avoided.43,44 That is, dermatitis
caused by topical treatment and confusion between the per-
sistence of scabies and scabicide-induced dermatitis are obvi-
ated. The drug appears to be the first-line treatment for cases
of scabies in adult nursing homes and institutions.64 Ivermec-
tin is an effective and safe treatment for scabies in a closed
community, such as a prison.46
Pediculosis
Ivermectin has systemic activity against human body lice,68
head lice,6972 and phtirus pubis.73 Two 200-g /kg oral doses
of ivermectin given a week apart has been shown to be effec-
tive in eradication of head lice6972 and phthiriasis palpe-
brarum.73 All adult lice were eradicated within 2 days, while
the nits remained attached to the eyelashes but then disap-
peared.73 It has also been administered orally for pediculosis
capitis in children older than 1 year.72 The drug is used a
0.8% topical (4000 g /kg or 1525 mL for each patient) for
pediculosis capitis in children.45
Demodecidosis
Demodex folliculorum is a normal inhabitant of human skin.
In immunosuppressed patients it causes facial or dissemi-
nated demodecidosis that can be a therapeutic challenge. Two
children with acute leukemia and disseminated demodecido-
sis were treated successfully with a single oral dose of 250 g/
kg of ivermectin.74 Relapses after 6 months were also treated
with a new dose.74 Treatment of papulopustular rosacea-like
facial demodicicosis with oral ivermectin and topical perme-
trin 5% was also successful.75
Cutaneous larva migrans
Cutaneous larva migrans is caused by cutaneous penetration
of larvae of animal hookworms (usually Ancylostoma bra-
ziliense). Patients with this disease have been successfully
treated with a single 12-mg oral dose (200 g / kg) of ivermec-
tin.7680 Pruritus resolved completely in every case, while the
progression of the larva tracts was stopped within 48 h.76 A
single 12-mg dose of ivermectin was more effective in 10
International Journal of Dermatology 2005, 44, 981988
Dourmishev et al.
patients (cure rate, 100%) than a single 400-mg dose of
albendazole (cure rate 46%).78 Sixty-four patients with cuta-
neous larva migrans were treated with a single 200-g/ kg
dose of ivermectin and 77% were cured.80 After one or two
supplementary doses, the overall cure rate was 97%.80
Cutaneous larva currens
Larva currens is a cutaneous manifestation of strongyloidia-
sis.81 Three patients with clinical manifestations of larva cur-
rens and a positive stool test for Strongyloides stercoralis
larvae were treated with a 12-mg oral dose of ivermectin.82
Three months later two patients had been cured. The third
patient who had not been affected by this treatment was given
a further 24-mg dose of ivermectin for two consecutive days.
Three months later she was asymptomatic. Ivermectin was
evaluated for treatment of strongyloidiasis in two compara-
tive trials.83,84 Ivermectin (150 or 200 g/ kg in single doses)
was used in a comparative randomized study with albendazol
(400 mg /24 h for three days). Twenty-four of 29 (83%)
treated with ivermectin were cured in comparison with nine
of 24 (38%) treated with albendazole.83 In another study
patients were divided into three groups: the first using iver-
mectin (200 g/kg /24 h), the second with 200 g/ kg for two
consequent days, and the third treated with thiabendazole
(50 mg /kg/24 h for three days). Only one of the 34 patients
employing ivermectin and two of the 19 treated with thiaben-
dazole did not have therapeutic success.84
Myiasis
Cutaneous myiasis is an infestation of humans by fly larvae.
Four cases of traumatic myiasis caused by Cochliomyia hom-
inivorax were topically treated with 1% ivermectin in a pro-
pylene glycol (400 g/kg) for 2 h.85 Within 15 min the pain
decreased and after 1 h most of the larvae died. After 24 h no
viable larvae remained. Twenty-nine patients with furuncular
myiasis from Dermatobia hominis were effectively treated
with topical ivermectin (10% solvent in propylene glycol) for
2 h.86 After local anesthesia the skin lesions were incised and
the parasite removed by digital compression.86 A single oral
dose of ivermectin (200 g/kg) in one patient with cutaneous
myiasis resulting from H. lineatum was also effective,87 and
led to spontaneous migration of the maggots.
Filariasis
Filariasis is an infestation by filarial worms (Filaria bancrofti,
Wuchereria malayi) whose vectors are mosquitoes (Culex,
Anopheles, Aedes and Mansonia). Clinical manifestations
commence after a long incubation period and include acute
lymphangitis of the legs, lymphadenitis, and orchitis, and
finally lead to elephantiasis. Patients with filariasis have been
treated with oral ivermectin; microfilaria rapidly disappear
but the efficacy is temporary, necessitating repeated courses.88,89
The combination of ivermectin and diethylcarbanazine
2004 The International Society of Dermatology
Dourmishev et al.
produced superior results in comparison with each individual
drug alone in the reduction of microfilariemia of F. bancrofti
and W. Malayi.88
Onchocerciasis (African river blindness)
Onchocerca volvolus infestation is characterized by dissemi-
nated prurigo, lichenification, and subcutaneous nodules
(onchocercomas) on the trunk and extremities.90,91 Infesta-
tion of the eye leads to blindness. Ivermectin was introduced
against Onchocerca volvolus,2 and has been used extensively
in humans to control endemic onchocerciasis.92 Thirty-one
patients with early infestations were treated with a single dose
of 150200 g /kg of ivermectin and two-thirds relapsed within
1 year.93 Second and third doses were given 1 and 2 months
later, respectively.94 There was a 50% reduction in the prev-
alence of severe itching after six monthly ivermectin treat-
ments of 4072 villagers in Ghana, Nigeria, and Uganda.95 If
there was a recurrence of pruritus, a typical rash, or eosinophilia,
the patients required further doses at 6 12-month intervals.
Loiasis
The vector of loa-loa is the horsefly. Chrysobs induces cuta-
neous manifestations such as a transient prurigo nodularis-
like swelling (Calabar swelling) on the upper extremities.
Ivermectin is highly effective for the treatment of loiasis.96
Others diseases with probably parasitic origin
In one case-control study of 33 patients with chronic urticaria
with antibodies to Toxocara canis, 14 had been treated with
thiabendazole or ivermectin, and after at 1 years follow up,
five (36%) were cured and four (29%) showed improve-
ment.97 No improvement occurred in the cases not specifically
treated. A patient with follicular, papulopustular rosacea-like
eruption with a long history of unsuccessful treatment also
responded to the ivermectin therapy.75
Safety and Adverse Reactions
The 20-year ivermectin history of effective control for mil-
lions of people suffering from microfilarial diseases indicates
that it is an extremely safe drug.98,100 The results from several
trials of ivermectin in the Onchocerciasis Control Programme
in West Africa show a low prevalence of adverse reactions,
most of which were mild and transient. Severe reactions were
observed in only 1.83% of 50,929 treated patients.98100 Tran-
sient and mild adverse reactions have been reported in 24%
of filarial disease patients, with signs and symptoms including
anorexia, asthenia, headache, arthralgia, myalgia, fever, and
eosinophilia. Mazzotti reactions and sudden death from
release of degradation products of microfilaria were observed
in patients with filarial diseases.99 Serious reactions after mass
treatment of onchocerciasis were reported in 1.1% of 10,000
patients.100
2004 The International Society of Dermatology
Ivermectin Review 985
Macular and papular rashes and pruritus (33%) between 2
and 4 days after oral ivermectin in patients with scabies has
been noted.18,44 Probably, this adverse reaction is the result of
the release of toxic products from dying or dead mites.
Hematomas and an increase in prothrombin time in a few
patients have been observed. Occasionally, nausea and a
decrease in blood pressure, as well as flat T waves or pro-
longed PR times on ECG, have been described.18
On the basis of a statistical study it was suggested that
death in 15 out of 47 elderly patients may have been associ-
ated with a single oral dose of ivermectin (0.150.2 mg / kg)
for treatment of scabies.54 According to some observations
the mortality rate 6 months after treatment did not differ sig-
nificantly from that seen 30 months before treatment.101,102
Patients with spasticity as a result of spinal cord injury
received subsequent injections at weekly or biweekly intervals
with doses of ivermectin up to 1.6 mg /kg without serious
reactions.103
Conclusions
Oral ivermectin treatment offers several advantages over
standard therapy of scabies, pediculosis, demodecidosis,
larva migrans, myiasis, filariasis, and other parasitic infesta-
tions with cutaneous tropism. More studies are required to
precisely define the optimal therapeutic uses for ivermectin in
dermatology.
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