Dourmishev - Ivermectin Pharmacology and Application in Dermatology

Review 45 BlackwellPublishingLtd,2003 1365-4632 InternationalJournalofDermatology IJD Oxford,UK BlackwellPublishingLtd.

Ivermectin: pharmacology pharmacology and application in dermatology Review Dourmishevetal. Ivermectin

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

From the Department of Dermatology and Venereology, Medical University, Sofia, Bulgaria, and the Department of Dermatology, New Jersey Medical School, Newark, NJ

Correspondence Prof. Assen L. Dourm ishev, PhD, DSC Department of Derm atology and Venereology Venereology Medical University 1 St. G. Sofiisky Street 1431 Sofia Bulgaria E-mail: [email protected]

Abstract Ivermectin is a synthetic derivative of the antiparasitic class of compounds known as avermectins. It is a macrolide endectocide with activity against both endoparasites with cutaneous tropism (Strongyloides stercoralis , Ancylostoma braziliense , Cochliomyia hominivorax , Dermatobia hominis , Filaria bancrofti , Wucheria malayi , Onchocerca volvulus , Loa-loa ) and ectoparasites such as Sarcoptes scabies , Pediculus humanus , Demodex folliculorum , and Cheyletiella  sp. Ivermectin Ivermectin is of great interest in the treatment of patients with different forms of scabies, head lice, demodecidosis, cutaneous larva migrans, cutaneous larva currens, myiasis, and filariasis.

Introduction

Ivermectin (MK-0933, 22,23-dihydroderivative of avermectin B1) is a synthetic derivative of a broad-spectrum antiparasitic class of macrocyclic lactones known as avermectins. Avermectin B was first isolated by fermentation of a soil microorganism, the actinomycete Streptomyces avermitilis. avermitilis. Ivermectin has a structure similar to that of macrolide antibiotics, 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

In humans, ivermectin was introduced against Onchocerca 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 brancroftian filariasis, and other intestinal nematodes as strongyloidiasis 3 and scabies.4–9 Pharmacokinetcs

Pharmacokinetic study of ivermectin shows good bioavailability. 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 ivermect in in blood peaks at 30– 46 ng/mL ng /mL around 4 h postdose, and slowly decreases thereafter.10,11 Peak plasma concentration 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

Figure 1 Structure of ivermectin © 2004 The International Society of Dermatology

Ivermectin is relatively safe. It has been tested in vitro in microbial and mammalian cell mutagenesis assays. No genotoxic activity was identified. Acute oral toxicity studies with International Journal of Dermatology  2005, 44, 981–988

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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 offlabel 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 teratogenity was defined as LS FDA Cat. C in 203 newborns exposed to ivermectin before their birth.18 There were no congenital malformations. Mode of Action

Ivermectin acts by binding selectively to specific neurotransmitter receptors that function in the peripheral motor synapses of parasites. It has an endectocidal effect (simultaneously against endo and ectoparasites) causing paralysis of nematodes, arthropods and insects by suppressing the conduction of nervous impulses in the interneuronic (intermediary neurons) 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 γ -aminobutyric acidgated chloride channels. Stimulation of γ -aminobutiric acid (GABA) release from presynaptic nerve endings and enhancement of the binding to the postsynaptic receptors accomplishes this.20,21 Ivermectin does not affect synapses gated by other transmitter substances, such as acetylcholine, norepinephrine, 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 γ -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, 981–988

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In humans GABA and glutamate do not affect peripheral motor function. Thus, ivermectin selectively paralyzes invertebrates. 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. γ -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 endoparasites (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 ivermectin 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,32–34 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 ivermectin.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.39–41 Mite dermatitis is not a labeled indication for ivermectin;40 however, it is widely used in animal vectors because it prevents recurrence of disease in humans.16,17,39 Systemic treatment of white-tailed deer with ivermectinmedicated feed corn is effective in controlling free-living populations 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 

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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 µg/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 follows 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 topical application, but in 50% of cases, another application was needed 5 days later.45 Contraindications to ivermectin therapy are allergic sensitization, 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, cutaneous larva migrans, cutaneous larva currens, myiasis, and filariasis. Scabies

Experience with oral ivermectin use has shown that doses less than 200 µg/kg were less than 100% efficacious.4–6 Approximately 70% of patients with scabies treated with 200 µg/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 µg/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 µg / kg in two groups: one of 11 otherwise healthy patients with ordinary scabies and a second group of 11 HIVinfected 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

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single dose of 200 µg / kg of ivermectin was enough for recovery in two patients with crusted scabies. 9 A single dose of ivermectin 150 µg/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 comparative studies have shown that oral ivermectin is equiva lent in common scabies to a conventional topical scabicidal treatments (benzyl benzoate, lindane, permetrin) after 1 or 2 oral doses of 200 µg/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 µg/kg.22 Randomized, controlled trials of treatment with ivermectin vs. benzyl benzoate and ivermectin vs. lindane failed to demonstrate significant differences in clinical cure rates. 48 Two hundred patients with scabies were randomly allocated to one of  two groups.51 One panel received oral ivermectin in a single dose of 200 µg/kg body weight. The other received 1% lindane 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 dermatomyositis, or infection with the human immunodeficiency virus HIV-1 for which scabies is more difficult to treat, 200 µg/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 institutions such as nursing homes18,53–55 and prisons.46 Norwegian or crusted scabies, a severe form with a high mite burden usually associated with underlying immunosuppression, has been effectively treated with ivermectin given alone or in combination with topical scabicides.9,56–63 Seven of  16 prisoners (44%) with crusted scabies treated with a single 150-µg / kg dose still had the disease after 8 weeks.46 The therapy of crusted scabies is effective after a 200-µg / 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, 981–988

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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 accompanied by rapid clearing of skin lesions and a marked decrease in pruritus.44 Oral ivermectin treatment offers several advantages over standard topical scabicides.43,44,65–67  The benefits of oral ivermectin 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 tolerated. These factors afford maximal patient compliance. This treatment is convenient for persons who are not selfsufficient or are bedridden. It is also effective for the immunocompromized. The irritant dermatitis sometimes seen with topical scabicides is thus avoided.43,44  That is, dermatitis caused by topical treatment and confusion between the persistence of scabies and scabicide-induced dermatitis are obviated. The drug appears to be the first-line treatment for cases of scabies in adult nursing homes and institutions. 64 Ivermectin 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,69–72 and phtirus pubis.73 Two 200-µg/kg oral doses of ivermectin given a week apart has been shown to be effective in eradication of head lice69–72  and phthiriasis palpebrarum.73 All adult lice were eradicated within 2 days, while the nits remained attached to the eyelashes but then disappeared.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 µg / kg or 15–25 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 disseminated demodecidosis that can be a therapeutic challenge. Two children with acute leukemia and disseminated demodecidosis were treated successfully with a single oral dose of 250 µg /  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 permetrin 5% was also successful.75 Cutaneous larva migrans

Cutaneous larva migrans is caused by cutaneous penetration of larvae of animal hookworms (usually Ancylostoma braziliense). Patients with this disease have been successfully treated with a single 12-mg oral dose (200 µg/kg) of ivermectin.76–80 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, 981–988

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patients (cure rate, 100%) than a single 400-mg dose of  albendazole (cure rate 46%).78 Sixty-four patients with cutaneous larva migrans were treated with a single 200-µg/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 strongyloidiasis.81 Three patients with clinical manifestations of larva currens 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 treatmen t 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 comparative trials.83,84 Ivermectin (150 or 200 µg/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 ivermectin (200 µg / kg/24 h), the second with 200 µg / 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 thia bendazole 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 hominivorax were topically treated with 1% ivermectin in a propylene glycol (400 µg/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 µg/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 

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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 disseminated prurigo, lichenification, and subcutaneous nodules (onchocercomas) on the trunk and extremities.90,91  Infestation 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 do se of 150–200 µg / 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 prevalence of severe itching after six monthly ivermectin treatments 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 cutaneous manifestations such as a transient prurigo nodularislike 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 year’s follow up, five (36%) were cured and four (29%) showed improvement.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 millions 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.98–100 Transient and mild adverse reactions have been reported in 24% of filarial disease patients, with signs and symptoms includin g 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

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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 prolonged 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 associated with a single oral dose of ivermectin (0.15–0.2 mg/kg) for treatment of scabies.54  According to some observations the mortality rate 6 months after treatment did not differ significantly 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 infestations with cutaneous tropism. More studies are required to precisely define the optimal therapeutic uses for ivermectin in dermatology. References

1 del Guidice P, Marty P, Ivermectin. A new therapeutic weapon in dermatology? Arch Dermatol  1999; 135: 705– 706. 2 Aziz MA, Diallo S, Diop IM, et al. Efficacy and tolerance of ivermectin in onchocerciasis. Lancet  1982; 2: 171–173. 3 Ottesen EA, Cambell WC. Ivermectin in human medicine.  J Antimicrob Chemother 1994; 195–203. 4 Dunne CL, Malone CJ, Whithworth J. A field of the effects of ivermectin on ectoparasites of man. Trans R Soc Trop Med Hyg  1991; 85: 550–551. 5 Glaziou P, Cartel JL, Alzieu P, et al. Comparison of ivermectin and benzoyl benzoate for treatment of scabies. Trop Med Parasitol  1993; 4: 331–332. 6 Kar SK, Mania J, Patnaik S. The use of ivermectin for scabies. Nat Med J India 1994; 7: 15–16. 7 Macotela-Ruiz E, Pefia-Gonzalez G. Tratamento de la escabiasis con ivermectina por via oral. Gaseta Med Mexico 1993; 29: 201–205. 8 Meinking TL, Taplin D, Jorge L, et al. The treatment of scabies with ivermectin. N Engl Med J  1995; 332: 26–30. 9 Aubin F, Humbert P. Ivermectin for crusted (Norwegian) scabies. N Engl Med J   1995; 332: 612. 10 Edwards G, Dingsdale A, Helsby N, et al. The relative systemic availability of ivermectin after administration as International Journal of Dermatology  2005, 44, 981–988

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capsule, tablet, and oral solution. Eur J Clin Pharmacol  1988; 35: 1–4. 11 Fink DW, Porra AG. Pharmacokinetics of ivermectin in animals and humans. In: Campbell WC, ed. Ivermectin and Abamectin , New York: Springer Verlag, 1989: 113–130. 12 Baraka OZ, Mahmoud BM, Marschke CK, et al. Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus. Eur J Clin Pharmacol  1996; 50: 407–410. 13 Haas N, Lindemann U, Frank K, et al. Rapid and preferential sebum secretion of ivermectin: a new factor that may determine drug responsiveness in patients with scabies. Arch Dermatol   2002; 138: 1618–1619. 14 Lankas GR, Gordon LR. Toxicology. In: Campbell WC ed. Ivermectin and Abamectin, New York: Springer Verlag, 1989: 89–112. 15 Paul JM. Effects of perinatal ivermectin on behavioral development of rats. Neurotoxicol Teratol   1988; 10: 267– 272. 16 Paradis M. Mite dermatitis caused by Cheyletiella blaklei.  J Am Acad Dermatol  1998; 38: 110–114. 17 Lewis D, Logas DB, Wojciechowski J. Bullous eruption in patient with systemic lupus erythematosus. J Am Acad Dermatol , 1998; 38: 1012. 18 Paasch U, Haistein U-F. Management of endemic outbreaks of scabies with allethrin, permetrin and ivermectin. Int J Dermatol  2000; 39: 463–470. 19 Bennet DG. Clinical pharmacology of ivermectin. JAMA 1986; 89: 100–104. 20 Turner MJ, Schaeffer JM. Mode of action of ivermectin. In: Campbell WC, ed. Ivermectin and Abamectin, New York: Springer Verlag, 1989: 73–88. 21 Dent JA, Wayne Davis M, Avery L. avr-15 encodes a chloride channel subunit that mediates inhibitory glutametric neurotronsmission and ivermectin sensitivity in Caenorhabditis elegans. EMBO J  1997; 16: 5867–5879. 22 Burkhard CN, Burjhart CG. Ivermectin: a few caveats are warranted before initiating therapy for scabies. Arch Dermatol  1999; 135: 1549–1550. 23 Walter PJ, Echevarria F, Eddi C, et al. The prevalence of antihelminthic resistance in nematode parasites of sheep in southern Latin America: general overview. Vet Parasitol  1996; 62: 181–187. 24 Xu M, Molento M, Blackhall W, et al. Ivermectin resistance in nematodes may be caused by alteration of Pglycoprotein homolog. Mol Biochem Parasitol   1998; 92: 327–335. 25 Usha V, Gopalakrishnan TV. A comparative study of oral ivermectin and topical permetrin cream in the treatment of scabies. J Am Acad Dermatol  2000; 42: 236 –240. 26 Campbell WC. Ivermectin, an antiparasitic agent. Med Res Rev 1993; 13: 61–79. 27 Campbell WC. Use of ivermectin in dogs and cats. In: Campbell WC, ed. Ivermectin and Abamectin, New York: Springer Verlag, 1989: 245–259. 28 Soll MD, d’Assonville JA, Smith CJ. Efficacy of topically applied ivermectin against sarcoptic mange (Sarcoptes

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