Ivermectindownload.xuebalib.com/7jjxKUPgB4z0.pdf · Ivermectin in Onchocerciasis: A Review Summary Synopsis 641 Ivermectin, a derivative ofavermectin E, is an orallyeffective microfilaricidal

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Drugs 42 (4): 640-658, 19910012-6667/91 /00 I0-0640/$09 .50/0© Adis International Limited . All rights reserved .

DRE153

IvermectinA Review of its Antifilarial Activity, Pharmacokinetic Properties andClinical Efficacy in Onchocerciasis

Karen L. Goa, Donna Mc'Tavisn and Stephen P. ClissoldAdis International Limited , Auckland, New Zealand

Various sections of the manuscript reviewed by: A.M. Breckenridge, The University of Liverpool, Liverpool,England; K.Y. Dadzie, Onchocerciasis Control Programme in West Africa, World Health Organization , AfricanRegion, Ouagadougou, Burkina Faso; S. Dial/o, Faculte de Medecine et de Pharmacie, Service de Parasitologie,Universite Cheikh Anta Diop de Dakar, Dakar, Senegal; B. Duke, River Blindness Foundation, Houston, Texas,USA; G. Edwards, Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, Eng­land; H. Fukuda, Department of Pharmacology, College of Pharmacy, Nihon University , Chiba, Japan; T. Itoh,Department of Clinical Pharmacology, Faculty of Medicine, Tottori University, Yonago, Japan; K. Matsumoto,Department of Pharmacology, College of Pharmacy , Nihon University , Chiba, Japan; H. Neu, Department ofMedicine, Division ofInfectious Diseases, Collegeof Physicians and Surgeons of Columbia University, New York,New York, USA; H. Newland, Department of Ophthalmology , Hinders Medical Centre, Bedford Park, SouthAustralia, Australia; E.A. Ottesen, Clinical Parasitology Section, National Institute of Allergy and Infectious Dis­eases, National Institutes of Health, Bethesda, Maryland, USA; H. Schulz-Key, Eberhard-Karls-Un iversitat Tub­ingen, Universitatsklinikum, Institut fur Tropemedizin, Tubingen, Federal Republic of Germany; H.R. Taylor,Department of Ophthalmology, Melbourne University, East Melbourne, Victoria, Australia; J. Whitworth , Trop­ical Health Epidemiology Unit, Department of Epidemiology and Populat ion Sciences, London School of Hygieneand Tropical Medicine, London, England.

Contents

641643643643645646646647648649650650651652652654654654

SummaryI. Pharmacological Propert ies

l.l Antifilarial Activity1.1.1 In Vitro and Animal Studies1.1.2 Human Studies1.1.3 Mechanism of Action

1.2 Pharmacokinetic Properties2. Clinical Efficacy

2.1 Dose-Finding Studies2.2 Comparisons with Diethylcarbamazine2.3 Mass Treatment in Large Scale Community Trials

2.3.1 Effects of Ivermectin on Skin and Ocular Microfilarial Loads2.3.2 Effect on Disease Transmission

3. Tolerability3.1 General Reactions3.2 Ocular Reactions

4. Dosage and Administration5. Place of Ivermectin in Therapy

Ivermectin in Onchocerciasis: A Review

SummarySynopsis

641

Ivermectin, a derivative of avermectin E, is an orallyeffective microfilaricidal agent. It is thecurrent drugofchoice for treating patientsinfected with the nematodeOnchocerca volvulus, whichis a major causeofblindness in inhabitants ofsome tropical areas.

Ivermectin is administered orallyas a singledoseof150p,g/kg givenannually. Skin and ocularmicrofilarial counts aredramatically reduced afterthefirst dose, withsome evidencefor a resultingdecrease in transmission of infection by the blackjly vector. With the exception of rare seriousreactions suchas severe systemicpostural hypotension, ivermectin is generally welltolerated. Thedrug has the clear advantages of ease of administration and better tolerability compared withdiethylcarbamazine and suramin, agents previously used to treat onchocerciasis.

Thus, ivermectin is suitablefor inclusion in mass treatment programmes and is the best ther­apeutic option presently available to combat onchocerciasis. As such it provides hopefor manythousands of people at risk of becoming blind, and represents a major contribution to tropicalmedicine.

Pharmacological Properties

Since 0. volvulus is difficult to maintain under laboratory conditions, the in vitro and in vivomicro- and macrofilaricidal activity of ivermectin has also been investigated in other filarialspecies of nematode. Ivermectin concentrations of 10 to 50 Itg/L had no significant effect on 0.volvulus microfilariae in vitro. Higher concentrations (5 to 30 mg/L) killed microfilariae with100%mortality achieved at 30 mg/L, In Vitro, low concentrations of ivermectin (3.14 X 10-8 toI X 10-7 mol/L) inhibited motility of O. gutturosa macrofilariae to a limited extent; immobilis­ation was achieved at a concentration of 1.25 X 10-5 mol/L,

In humans, a single oral 100 to 200 ltg/kg dose markedly reduced numbers of skin and oculartissue O. volvulus microfilariae and decreased microfilariae motility. After ivermectin treatment,most remaining viable microfilariae are found in the subcuticular skin layer; in untreated patientsmicrofilariae are found predominantly in the upper Imm of skin.

The mechanism of action of ivermectin is not fully understood but a number of possibilitieshave been proposed including a direct toxic effect (possibly mediated by potentiation of theinhibitory neurotransmitter GABA) and/or inhibition of intrauterine microfilarial developmentand release from female adult worms.

In healthy subjects peak plasma ivermectin concentrations of about 50 Itg/L are recordedapproximately 4 hours after the administration of a l2mg dose in either tablet or capsule form­ulation. There is evidence that absorption is greater if the drug is administered in an oral aqueousethanol solution. Little is known regarding the distribution and elimination of ivermectin al­though 2 metabolites have been identified in humans . The following pharmacokinetic variableshave been reported in healthy subjects: elimination half-life (28 hours), volume of distribution(46.9L), plasma protein binding (93%) and oral clearance (1.2 Lzh),

Clinical Efficacy

Large scale community trials in tens of thousands of patients with onchocerciasis, includingchildren older than 5 years, have demonstrated that ivermectin is effective and suitable for masstreatment. Skin microfilariae counts decreased by 85 to 95%when measured 2 months after singledose treatment with oral ivermectin 150 ltg/kg; such reductions are clinicallysignificant in patientswith heavy infestation.

Dose-finding and comparative trials indicate that parasite counts decrease rapidly within 2 to8 days of a 100 to 200 ltg/kg dose, and remain suppressed for several months . Although levelsrise gradually toward baseline thereafter, at 12 months skin microfilariae counts are only one­tenth of pretreatment values.

Reductions in ocular parasite counts (in the cornea and anterior chamber) tend to follow acourse parallel to that in skin, although the rate of decrease is slower. At 4 months ocular levelshad diminished by 80%in a large community trial. However, the finding that after several months

642 Drugs 42 (4) 1991

ocular microfilariae counts rose to about 30% of pretreatment levels led some investigators toadvocate a 6-monthly, rather than a once yearly, treatment programme.

'Ivermectin as a single dose is at least as effective as diethylcarbamazine administered in acomplicated multiple dose regimen, and is considerably better tolerated . Although both drugsproduce similar patterns of microfilarial elimination from skin and eyes, ivermect in causes amore sustained suppression of microfilariae counts.

By reducing the prevalence of microfilariae amongst a mass population, ivermectin therapyalso influences the rate of disease transmission. In one large trial the reduction in availability ofmicrofilariae for transmission was estimated to be 68 to 78%, consistent with a decrease in vectorinfection of 65 to 85% as evidenced by entomological results. These effects are reflected in re­ductions in overall microfilarial load in both treated and untreated patients in mass treatmentprogramm es and , in I trial , a decrease in the annual rate of new infections in children .

Tolerability

Almost all of the adverse effects which occur during ivermectin treatment are a result of thepatient's immune response to dead microfilariae, and usually appear within 3 days of the dose.The most common of these include myalgia, rash, node tenderness , swelling of nodes, joints,limbs or face, itching, fever and chills. These are usually of mild to moderate severity and gen­erally respond to analgesics or antihistamines. The severity of the response is directly related tothe initial degree of O. volvulus infestation.

The incidence of adverse effects among patients administered ivermectin is difficult to quan­tify because of variab ility in reporting methods. Although small samples have reported incidencerates of as high as 35%, this is probably not representative. In a mass treatment programmeinvolving > 50 000 subjects , 9% had an adverse effect after the first dose, and the rate was 15%amongst more than 7400 Ghanaian patients ina separate trial.

Ivermectin does not cause severe ocular complications in patients with onchocerciasis. Nochanges in visual acuity or appearance of punctate opacities have occurred with ivermectin, andin this respect it is superior to diethylcarbamazine. Similarly, ivermectin is much less likely tocause the potentially fatal Mazzotti reaction associated with diethylcarbamazine, although therehave been reports of severe postural hypotension (occurring in 37 of about 14000 patients in Ilarge trial) and other rare but serious reactions in patients receiving ivermectin.

Dosage and Administration

Ivermectin is administered as a single oral dose, usually ISO~gjkg. Annual re-treatment (usingthe same initial dosage) is required. There is some evidence from clinical trials that ivermectinmay be more effective in patients with heavy ocular involvement when given 6-monthly ratherthan yearly.

Ivermectin is an 80: 20 mixture of avermectin

Bla and avermectin BIb, monocyclic lactones pro­

duced by the actinomycete Streptomyces avermi­tilis (fig. 1). It is an orally effective antifilarial agent

which has been used in veterinary medicine since

1981. However, ivermectin has recently achieved

widespread acceptance for the treatment of oncho­

cerciasis (ri ver blindness) in humans - particularly

following its inclusion into the Onchocerciasis

Control Programme (OCP) in 1987. Onchocer­

ciasis is caused by the nematode Onchocerca vol-

vulus.Ivermectin has also shown activity against vari­

ous other nematodes including Wuchereria ban­crofti(Diallo et al. 1987; Kumaraswami et al. 1988;Ottesen et al. 1990; Raux et al. 1989), Loa loa(Richard-Lenoble et al. 1988) and the gastrointes­

tinal helminths Ascaris lumbricoides and Strongy­loides stercoralis (Datry et al. 1991; Freedman et

al. 1989; Naquira et al. 1989). It is also effective

in the treatment of cutaneous larva migrans

(Caumes et al. 1991). However, this review will

OH

Ivermectin in Onchocerciasis: A Review

HO··A

3

OCH3

,"cAo{o-x)0 -,

H3C 0 H -

H3C' /

H." ~CH3

B'a: R = -C-CH2CH3

643

Fig. 1. Structural formulae of avermectin Bla and avermectin Bib; these lactones are synthesised in an 80: 20 ratioby Streptomyces avermectilis to produce ivermectin.

concentrate on the use of ivermectin in patientswith onchocerciasis.

1. Pharmacological Properties1.1 Antifilarial Activity

The vector for onchocerciasis is a blackfly of thegenus Simulium which breeds in fast-flowingstreams. The blackfly ingests Onchocerca volvulusmicrofilariae (embryonic form) from humans, andacts as an intermediary for the development of in­fective larvae (fig. 2). Following an approximately2-week period these larvae can be transmitted backto the host during subsequent bites. It is this rein­fection that causes heavy parasite loads, since nei­ther the larvae nor the adult worm multiply in hu­mans. Over a period of 1 to 3 years the inoculatedlarvae mature into male or female adult worms(macrofilariae) that are usually coiled together infibrous subcutaneous or deep tissue nodules. Eachgravid female worm can live for as long as 15 years,and releases thousands of immature microfilariaedaily. These migrate to the subcutaneous layer ofthe skin and to the eyes, and degenerate or are in­gested by feeding Simulium to continue the cycle(Plorde 1987).

1.1.1 In Vitro and Animal StudiesA major obstacle facing investigators searching

for an effective treatment against onchocerciasis hasbeen the lack of suitable in vitro and in vivo screen­ing systems capable of identifying drugs with ac­tivity against O. volvulus. Because of the difficultiesinvolved in maintaining viable O. volvulus underexperimental conditions, altemativefilarial para­sites, notably Brugia pahangi, Acanthocheilonemaviteae, and other Onchocerca species (0. gutturosa,O. lienalis) have been substituted. However, re­sults obtained with these species should be extrap­olated to O. volvulus with caution because of wideinterspecies differences in susceptibility. Recently,successful cryopreservation of Onchocerca macro­filariae has facilitated long term storage and trans­portation of viable worms, and enabled further ex­perimental investigation (Townson 1988; Townsonet al. 1989).

Ivermectin has been examined as a microfilar­icidal and macrofilaricidal agent in several in vitroand animal models, and has proven to be an ex­tremely potent single dose microfilaricidal agentwithout significant macrofilaricidal effects.

In vitro, ivermectin is effective against O. lien­alis microfilariae (Bianco et al. 1986; Devaney &Howells 1984; Townson & Tagboto 1991; Town-

644

Infection with O. volvulus :micro filar iae (migrate intoeye to cause blindness);macrof ilariae (encaps ulated indermal and tissue nodu les)

Development oflarvae in vector

Human host

Microfilariae ingestedby vector (blackfly,Simulium spp.)

Drugs 42 (4) 1991

Fig. 2. Life cycle of Onchocerca volvulus (adapted from Dr H Schulz-Key, personal communication, and Townsend &Wise 1984).

son et al. 1988) and O. volvulus microfilariae (Cha­vasse & Davies 1990). Concentrations ofivermec­tin ranging from 10 to 50 /Lg/L had no significanteffect on 0. volvulus microfilariae mortality after24, 36 or 48 hours; however, at higher concentra­tions mortality after 24 hours was 24% at 5 mg/L,54% at 10 mg/L, 86% at 20 mg/L and 100% at 30mg/L (Chavasse & Davies 1990). Thus, only at anin vitro concentration approximately 1000 timeshigher than that typically achieved in plasma wereall O. volvulus microfi1ariae killed, indicating thatthe in vivo effect of ivermectin may not be due toa direct action of the drug on microfilariae, or thatthe observation time was not sufficient to show themaximal drug effect on mortality (Chavasse &Davies 1990).

In vivo. mean recovery of microfilariae frommice injected with O. lienalismicrofilariae was re­duced by 83, 94 and 99% within 12, 24 and 72hours, respectively, of an injection of ivermectin0.2 mg/kg compared with untreated control values(Bianco et al. 1986). In this model,ivermectin waseffective when administered up to 28 days prior toinjection of microfilariae, and it was superior todiethylcarbamazine, suramin and levamisole whenevaluated over 5 days (Townson et al. 1988).

The macrofilaricidal effects of ivermectin have

been investigated in vitro in adult O. gutturosaworms using worm motility as a reliable and quan­tifiable assessment method (Satti et al. 1988;Townson et al. 1987). In these studies ivermectininhibited macrofilariae motility at low concentra­tions: the minimum effective concentration for im­mobilisation of all worms was 1.25 x 10-5 mOI/L(Townson et al. 1987) while lower concentrationsof 3.14 x 10-8 to I X 10-7 mOI/L resulted in 50%inhibition of motility (IC50) after 7 days (Satti etal. 1988; Townson et al. 1987).

When ivermectin (3.13 x 10-6 mol/L) was ad­ministered with other antiparasitic agents (includ­ing levamisole, suramin and mefloquine) there waslittle or no increase in the effect on in vitro adultO. gutturosa motility compared with ivermectinmonotherapy (Townson et al. 1990). However,combination treatment with ivermectin and theseother antiparasitic drugs generally produced a cu­mulative effect on the viability ofadult worms. Us­ing cryopreserved female O. volvulus, these authorsdemonstrated that although both ivermectin andCGP6140 inhibited motility after 24 hours com­pared with controls, the combined use of theseagents was more effective than either drug givenalone (Townson et al. 1990). Thus, there is someevidence that a combination of ivermectin and

Ivermectin in Onchocerciasis: A Review 645

values and microfilarial emergence was reduced to74,67 and 61%, respectively.

Despite a dramatic reduction in skin microfi­larial density, and a simultaneous tendency for mi­crofilarial emergence (or migration) from the sam­pled subendothelial skin layers to decrease, thereis little evidence to support a clinically significantincrease in microfilariae in urine or blood (Rich­ards et al. 1989a). Migration of microfilariae intodeeper endothelial layers, subcutaneous fat, or thelymphatic system may explain the disappearanceof microfilariae from biopsy tissue (Duke et al.1991). Jurgens and Schulz-Key (l990), using a newtechnique for assessing viable and degenerative O.volvulus microfilariae in different skin layers, re­ported a dramatic decrease in the total number ofmicrofilariae (76%were found in the epidermal andbasement membrane layer), and an increase in theproportion of degenerated microfilariae, 2 days aftera single oral ivermectin dose. Furthermore, after28 days most of the few remaining viable O. vol­vulus microfilariae were found in the subcuticularlayer (3 to 5mm). By comparison, in patients whoreceived placebo, most (> 80%) microfilariae werefound in the epidermal and basement membranelayers. 1.2%of microfilariae were degenerated; thesewere also found predominantly in the upper skinlayers.

Initially, an oral ivermectin dose appears to haveno effect on adult O. volvulus worms (Albiez et al.1988a; Diallo et al. 1986; Greene et al. 1985; Lar­iviere et al. 1985). However, I month after admin­istration pronounced embryotoxic activity was ob­served, leading to a high (> 85%) proportion ofdegenerate microfilariae in gravid female worms;this became more pronounced after 6 months andpersisted for up to 12 months (Awadzi et al. 1986;Diallo et al. 1986; Lariviere et al. 1985). More re­cently, Duke et al. (1990) failed to show a universaleffect on O. volvulus macrofilariae in infectedpatients. Biopsies obtained 4 months after a finalivermectin 150 ltg/kg dose revealed no moribundor dead macrofilariae in patients who receivedivermectin monthly for 4 months. Biopsies from60% of patients who received the drug once­monthly for 8 or 12 months showed e I moribund

24

-------------0..--------------0

2.0 t-----,------.---r-----,o

3.5

xQ)u·~ 3 .0.'"~Es 2.5Q)

:;j;

other antiparasitic agents is advantageous in vitro;further research is needed before the practicalbenefits of such combined therapy are known.

1.1.2 Human StudiesIn patients infected with O. volvulus. ivermectin

100 to 200 ltg/kg administered as a single oral dosedramatically reduced microfilarial density in skinand the anterior chamber of the eye (see section 2for a detailed review). Additionally, it reduced mi­crofilarial motility in the anterior chamber of theeye as characterised by transient immobility, an ex­tended configuration and occasional spastic paraly­sis of the larvae (Newland et al. 1988; Soboslay etal. 1987). Analysis of microfilariae in skin samplestaken from infected patients also showed an iver­mectin-induced reduction in microfilarial motility12 and 24 hours after administration of ivermectin(fig. 3). Partial or complete immobilisation of mi­crofilariae would be expected to result in reducedemergence (or migration) of microfilariae from bi­opsy tissue samples. Indeed, Messinger et al. (1988)found that 80% of microfilariae emerged from skinsamples from patients infected with O. volvulusprior to a single oral ivermectin dose. However, 3days after administration of ivermectin microfilar­ial skin counts had decreased to 28 (100 ltg/kg), 19(ISO ltg/kg) and 14% (200 ltg/kg) of pretreatment

12Time after administration (hours)

Fig. 3. Effect of a single oral dose of ivermectin 100 ltg/kg(n = 16; .), 150 ltg/kg (n = 16; .), or 200 ltg/kg (n = 15; .&)and placebo (n = 16; 0), on mean motility index for micro­filariae obtained from patients infected with O. volvulus;o = immobile, 4 = extremely active (after Soboslay et al.1987).

646

or dead macrofilariae versus 6.5% of untreatedcontrols; however, wide variation (0 to 100%) wasseen between individual patients . After 12 months,12% of male adult worms were dead and 22% offemale adult worms were dead or moribund; theremaining adult worms were unaffected.

1.1.3 Mechanism ofActionDespite the widespread use of ivermectin there

is considerable uncertainty surrounding its mech­anism of action. However, several processes ap­pear to be involved which contribute to the de­layed accumulation of viable o. volvulusmicrofilariae observed following ivermectinadministration. The drug's microfilaricidal activityappears to be two-pronged. Firstly, within I to 3days, there is a dramatic reduction in microfilarialskin density which persists for up to 12 months.This may be the result of a direct toxic effect caus­ing immobility as observed in several studies (sec­tion l.l). It has been suggested that although iver­mectin may only slightly reduce microfilarialmotility, this may be sufficient to allow cytotoxiccells of the host to adhere to their surface with sub­sequent clearance by lymphatic drainage (Jurgens& Schulz-Key 1990).

Evidence for a direct effect has been providedby early studies in animals with gastrointestinalrather than blood dwelling parasites. In these ex­periments it was shown that ivermectin can act asan agonist of the inhibitory neurotransmitterGABA. Thus, ivermectin may potentiate GABArelease and modulate GABA and benzodiazapinebinding to the GABA receptor complex, resultingin postsynaptic blockade of neurotransmission withconsequent inhibition of motility, and paralysis ofthe microfilariae (Pong et al. 1980). More recentstudies have identified ivermectin binding sites onthe GABA-receptorcomplex; these are distinct fromGABA binding sites (Matsumoto et al. 1986; Ya­mazaki etal. 1989).

The second stage of activity, intrauterine de­generation of developing microfilariae, is observedabout I month after ivermectin administration andbecomes progressivelymore pronounced during thefollowing 12 months.

Drugs 42 (4) 1991

Duke et al. (1990) reported that the proportionof live female worms showing degenerated micro­filarie in utero increases with the duration of iver­mectin therapy ; more than half failed to resumeembryogenesis 4 months after the last ivermectindose; the authors suggested that although about one­third of these female macrofilariae had been re-in­seminated, fertilisation appeared to be preventedby the mass of degenerate microfilariae in the ut­erus.

Viable microfilariae present in uteroat the timeof ivermectin therapy appear to accumulate (thensubsequently degenerate and are resorbed) becauseof ivermectin's ability to inhibit their release fromfemale macrofilariae (Schulz-Key 1988, 1990).Themechanism(s) regulating microfilarial release is un­known but it seems that while production of mi­crofilariae is controlled within the adult 0. volvulusworm, release of microfilariae is more likely to beregulated by factors intrinsic to the host (e.g. viathe immunological system) [Schulz-Key 1990].

As a result of its microfilaricidal activity, iver­mectin also appears to interrupt transmission ofthe parasite by its blackfly vector (section 2.3.2). Asingle oral ivermectin dose substantially reduceduptake of O. volvulus by its vector, limited thenumber of microfilariae per fly and lowered meanfly thoracic microfilariae density (Cupp et al. 1986,1989).

1.2 Pharmacokinetic Properties

The pharmacokinetic profile of oral ivermectinhas been investigated in healthy subjects, usingvarious high performance liquid chromatographyassays (sensitive to 1 to 2 ~g/L) to measure iver­mectin concentrations in biological fluids (e.g.Chiou et al. 1987; Dickinson 1990).

Following administration of a single 12mg doseofivermectin to 12 healthy males there was no dif­ference in mean peak plasma concentration (Cmax)

between tablet and capsule formulations (46 vs 50~g/L). However, when ivermectin was admini­stered in an aqueous ethanol solution the Cmax wasvirtually doubled (81 ~g/L; fig. 4), and this was re­flected as an increased systemic availability as es-

1 I

Ivermectin in Onchocercias is: A Review

100

50

~~c.g 20eEOJ<Jc:8 10c:"'BOJE

.~ 5tilEIIItila::

2

iii I I I I10 20 30 40 50 60 70

Time (hours)

Fig. 4. Mean plasma ivermectin concentrations followingadministration of a single oral 12mg dose to 12 healthy malevolunteers; (0 = 2 x 6mg capsules; • = 2 x 6mg tablets ;... = as a 40% vlv aqueous ethanol solution) [after Edwardset al. 1988].

timated by the area under the plasma concentra­tion-time curve (855, 1034 and 1473 ~g/L· h forthe tablet, capsule and solution formulations, re­spectively). From these values the bioavailabilityof the tablet (relative to that of the solution) wascalculated to be 60% (Edwards et al. 1988).

Mean time to achieve Cmax is consistently about3.5 to 4 hours over the dosage range 6 to 15mg(Porras et al. 1987), and is independent of formu­lation (Edwards et al. 1988). Ivermectin exhibitslinear pharmacokinetics over this dosage range(Porras et al. 1987).

The distribution of ivermectin to areas of filar­ial concentration, such as skin, eyes and nodules,has not been characterised. However, ivermectinhas been reported to have a relatively large appar­ent volume of distribution (46.9L), indicating widetissue distribution (Ette et al. 1990). Plasma pro­tein binding of ivermectin was calculated to be 93%(Klotz et al. 1990).

647

The apparent terminal elimination half-life ofivermectin in humans was 28 hours after an oralsolution (Edwards & Breckenridge 1988), while oralclearance was reported as 1.2 Llh (Ette et al. 1990).The metabolite 3'-O-demethyl-22,23-dihydroaver­mectin Bla was detected in the urine and 22,23­dihydroavermectin Bla monosaccharide in thefaeces of 4 healthy subjects administered radiola­belled ivermectin (Fink & Porras 1989).

2. Clinical Efficacy

Of the estimated 20 million people in the trop­ics who are affectedby onchocerciasis(African riverblindness, blinding filariasis, Robles disease), 3 to4 million have skin involvement and I million havevisual deficits (WHO Expert Committee on Oncho­cerciasis 1987). A further 85 million are at risk ofacquiring the infection. The areas worst affectedare West and Central Africa, where 99% of all in­fected individuals reside, and parts of Latin Amer­ica (Duke 1990).

The major presenting symptoms of onchocer­ciasis are ocular, dermatological, lymphatic andsystemic in nature , arising from the infiltration ofmicrofilariae throughout body tissues. Ocular in­volvement is common and blindness (resultingfrom complications such as sclerosing keratitis, ir­idocyclitis, chorioretinitis and optic atrophy) is themost severe sequela, occurring particularly inpatients carrying a high microfilarial load for pro­longed periods.

The impact of the disease can be measured notonly by morbidity associated with blindness, butalso by the effect on socioeconomic standards: vil­lagers are forced to move from wet, fertile areas,where Simulium breed, to less productive regions;and heavily infected individuals who would other­wise contribute to villageeconomics die earlier thantheir uninfected counterparts (for a review see Duke1990).

The aims of comprehensive treatment/controlprogramme'S. to combat onchocerciasis are there­fore 3-fold:I. Reduce vector numbers through vector controlwith pesticides;

648

2. Reduce the microfilarial load in skin and eyesto prevent blindness , disfiguration and severe dis- .abling morbidity from chronic itching;3. Reduce the number of patients with high mi­crofilarialloads, thereby decreasing the availabilityof parasites for transmission.

Diethylcarbamazine and suramin, treatmentoptions used in the past against onchocerciasis , areeffective against the disease but must be admini­stered in multiple dose regimens and are associatedwith serious systemic and ophthalmic adverse ef­fects. Diethylcarbamazine is microfilaricidal butmay induce a severe, potentially fatal anaphylacticreaction (Mazzotti reaction) characterised by rash,fever, headache, itching, nausea and hypotension.The condition is thought to be provoked by an im­mune response to the dead microfilariae. An idio­syncratic toxic reaction may arise with suramin, anintravenously administered macrofilaricidal agent.Both drugs must therefore be administered undermedical supervision and are not suitable for masstreatment programmes. Severe reactions occurmuch less frequentl y with ivermectin than withother available therapy (see section 3).

The efficacy ofivermectin in onchocerciasis wasfirst demonstrated in 1982 by Aziz and coworkersin 32 Senegalese patients without ocular involve­ment. In those treated with single oral doses of 30or 50 ltg/kg, skin microfilariae counts were signifi­cantly reduced by day 2 after treatment, and mi­crofilariae were completely eliminated in 6 of 8 in­dividuals given the higher dose. Further dosefinding trials (section 2.1) and comparative studies(section 2.2) have provided compelling evidence ofthe efficacy of ivermectin and led to its inclusionin the Onchocerciasis Control Programme (OCP),which has now encompassed tens of thousands ofpatients (section 2.3).

Controlled trials investigating the use of iver­mectin in areas under vector control have neces­sarily included a placebo group, to allow for theincrease in natural mortality of adult worms afterseveral years of pesticide use :to eliminate theblackfly. Diagnosis of onchocerciasis has been per­formed by taking skin snips from regions such asthe iliac crest, calf or ankle, immersing the sample

Drugs 42 (4) 1991

in water and counting the emergent microfilariaeunder a microscope. Microfilarial counts have beenexpressed as the number of microfilariae per mil­ligram of skin (mf/mg) , or per skin snip (rnf/s).Examination for ocular damage or involvement hasusually included fundoscopy and fluorosceinangiography, and tests for visual acuity exceptwhere impractical in the field situation.

2.1 Dose-Finding Studies

Dose-finding trials conducted in patients inGhana (Awadzi et aI. 1989; Dadzie et aI. 1989), theIvory Coast (Lariviere et aI. 1989a,b), Togo (Hell­ing et aI. 1987) and Liberia (Greene et aI. 1991;Newland et aI. 1988) have established 100 to 200ltg/kg to be the optimal dosage range for treatingonchocerciasis. Single oral doses of 100, 150 or 200ltg/kg reduced the number of microfilariae in skinsnips by 60 to 80%within 3 or 4 days ofivermectintreatment, vs a decrease of 16% (Newland et aI.1988) or a slight increase (Lariviere et aI. 1989a)in placebo recipients. At month 3 the reduction was95 to 99% for patients receiving ivermectin vs 21to 46% for placebo (Awadzi et al. 1986; Lariviereet aI. 1989a; Newland et al. 1988).

Skin microfilarial counts remained suppressedfor at least 1 year (an average 83% reduction forthe 3 doses of ivermectin vs a decrease of 38% forplacebo compared with baseline) [Newland et aI.1988]. A small rebound increase at 12 months hasbeen documented, although skin counts were stillonly one-tenth of baseline levels (Heuschkel et aI.1989; Lariviere et aI. 1989a). A subset of Liberiansubjects who were retreated with the same dose ofivermectin at 12 and 24 months showed persistentsuppression of skin microfilariae counts at 36months (Taylor et aI. 1989), and at 2 years aftertreatment in patients from Togo levels were 30%of baseline (Heuschkel et aI. 1989). Administrationof ivermectin every 6 months resulted in greaterreductions than annual treatment (Greene et al.1991).

Importantly, the number of ocular parasites ,most commonly found in the anterior chamber of

lvermectin in Onchocerciasis: A Review 649

the eye and , to a lesser extent , in the cornea, alsodecreased after a single dose of ivermectin 100 to200 ~g/kg. Parasite burdens in the anterior cham­ber decreased within 3 days, were negligible at 3months (fig. 5; Newland et al. 1988), and then eitherstabilised at this low level or increased slightly dur­ing the 6 to 12 months after therapy (Dadzie et al.1989; Lariviere et al. 1989a; Newland et al. 1988).This reduction in parasite numbers in the eye oc­curred even in patients with severe ocular involve­ment (> 20 micro filariae in the anterior chamber)[Taylor et al. 1989]. There is some evidence thata decrease in ocular parasite burden may be betteraccomplished by repeat administration of iver­mectin at 6 rather than 12 months after the initialdose (Lariviere et al. 1989b; see also section 2.3.1),or even more frequently in heavily infected patientswith severe ocular involvement who dwell in areaswith no vector control (Rothova et al. 1990).

Ivermectin (100, 150 and 200 ~g/kg) also sig­nificantly reduced corneal microfilariae numbersand punctate corneal opacities ; this latter abnor­mality was virtually eliminated at 12 months, com­pared with a 50% reduction in the placebo group(Dadzie et al. 1989).

Some clinical signs have improved in tandem

with diminished skin microfilariae counts. The fre­quency and severity of reactive skin signs (e.g. pa­pules, lymphadenopathy) and the severity ofchronic skin signs (hyperkeratosis, atrophy, hang­ing groin) were reduced compared to placebo, 6months after ivermectin treatment in 507 subjectsin Sierra Leone. Skin microfilariae counts de­creased from a geometric mean of 4.30 to 0.77 mf/mg. As might be anticipated there was no effect onthe number of nodules, or prevalence of chronicskin lesions or visual loss. However general well­being and itching also did not improve, for reasonswhich remain unclear (Whitworth et al. 1991).

2.2 Comparisons with Diethylcarbamazine

Ivermectin asa single oral dose is at least aseffective as diethylcarbamazine administered in amore cumbersome regimen (usually 50mg orallyfor 2 days, then 100mg twice daily for 6 days), andcauses fewer and less serious systemic orophthalmic reactions (section 3). These conclu­sions are based on the results of well-designed pla­cebo-controlled trials comparing the 2 drugs in menfrom Ghana, Liberia, Senegal and Mali who hadmoderate to heavy infestation and ocular involve-

_---0------- - ------0----0--- -

0.5* -** **** **

.----:-rI **0 3 1 3 6 12

Time.-.... .. •days months

<ll

3l ~ 2.5.~ '0;Ci52.0 2.0.!:1E_E ~ Q;.5 ~ E 1.5<ll 0 ::l~ .~ cQ),ScB ~ m1.0<ll Eo.s~

3.0

Fig.5. Reduction in number ofmicrofilariae in theanterior chamber ofeyes of200Ghanaian patients treated with ivermectin100(.&), 150 (e), or 200 (.) /lg/kg, or placebo (0). Statistically significant difference from placebo; * p < 0.05; **p < om(after Newland et aI. 1988).

650

120c::i!<h

E90

! 60oo D~iethYICarbamaZine

~ 30Ol

~ 01,--"::~~S;;;;;;;;;;;;;;;;;;;::;::;;: I~ermec:=:-::24 8 14 20 2890 180 270 360

Time (days)

Fig. 6. Effect of ivermectin as a single dose, diethylcarbam­azine 1.3g total dose over 8 days or placebo on skin micro­filariae count in 30 men from Mali (after Lariviere et al. 1985).

ment (Awadzi et aI. 1986;Diallo et aI. 1986;Greeneet aI. 1985; Lariviere et al. 1985).

Skin microfilariae counts rapidly decreasedwithin 2 to 8 days of treatment with either drug,reaching a nadir at about I week for diethylcar­bamazine and 2 to 4 weeks for ivermectin (Dialloet al. 1986;Greene et aI. 1985; Lariviere et aI. 1985).During the following months skin microfilariaecounts rose gradually toward baseline. However,this increase tended to be less with ivermectin thanwith diethylcarbamazine at 6 months (Diallo et al.1986; Greene et al. 1985), and at 12 months thedifference between the 2 treatments was signifi­cant . Skin microfilariae counts at 12 months were4 to 9% of pretreatment for ivermectin vs 18 to45% for diethylcarbamazine (fig. 6) [Diallo et aI.1986; Lariviere et al. 1985].

Elimination of microfilariae from the anteriorchamber of the eye was rapid after diethylcar­bamazine, with near zero levels achieved within 8to 10 days, whereas ivermectin eliminated thesemicrofilariae more slowly (Dadzie et aI. 1987;Tay­lor et al. 1986). Dadzie et aI. (1987) noted a sig­nificant decrease at day 4 with diethylcarbamazinecompared with placebo. In contrast, ivermectincaused an initial increase in microfilariae countpeaking at day 4, then a gradual reduction . Im­portantly, by 3 to 6 months after ivermectintreat­ment microfilariae were virtually eliminated'(Dad­zie et aI. 1987; Diallo et aI. 1986;Taylor et al. 1986),but in some patients treated with diethylcarbam-

Drugs 42 (4) 1991

azine parasites had reappeared in the anteriorchamber within 6 months (Lariviere et al. 1985).

In the cornea, microfilarial counts significantlyincreased by day 4 after treatment with either drugcompared with placebo in patients studied by Dad­zie et al. (1987), then decreased to near zero levelsby about 3 months. However, Taylor et al. (1986)found an initial increase only in the diethylcar­bamazine group. Diethylcarbamazine is known tomobilise microfilariae from the skin and anteriorchamber to other ocular tissues, including the cor­nea (Dadzie et al. 1987), and this may also occurwith ivermectin, although to a lesser extent.

2.3 Mass Treatment in Large ScaleCommunity Trials

2.3.1 Effects of Ivermectin on Skin andOcular Microfilarial LoadsThere is now convincing evidence that iver­

mectin is an effective and well-accepted agent formass treatment of onchocerciasis. This has beendemonstrated in large scale community trials in­volving tens of thousands of patients in Ghana(table I; Remme et aI. 1989), which comprised partof the Onchocerciasis Control Programme (OCP)implemented in West Africa in 1987, and in Lib­eria (Pacque et al. I990a). Decreases in skin mi­crofilariae loads were similar in magnitude to thoseobserved in dose-finding and comparative trials. Inthe Ghanaian study skin microfilarie counts fell by96% 2 months after ivermectin treatment, as as­sessed in a sample population of 443 patients liv­ing in holoendemic villages (defined as centreswhere the geometric mean microfilarial load inadults aged> 20 years is 58 to 73 mf/skin snip)[Remme et al. 1989]. Dramatic reductions weredemonstrated even in patients with very high skinmicrofilariae counts ( > 64 mf/skin snip). 40 to44% of this group displayed zero microfilariaecounts at 2 months after treatment, and in 75% ofpatients microfilariae counts were .:E; 2 mf/sk in snip(fig. 7). During the 4 months after ivermectintherapy mean microfilariae counts did increase, butonly to 10% of pretreatment levels.

Likewise, the mean skin microfilarial load in

Ivermectin in Onchocerciasis: A Review 651

Table I. Summary of large-scale community trials invest igating the use of ivermectin 150 ltg/kg as a single oral dose in patientswith onchocerciasis

Country Total population No. of pts treated Reductions in skin Reference

of study area (% of total) microfilarial load

Ghana 24575 14991 (61.5%) 96%8 at 2 months Remme et al. (1989)

Liberia (in 1987) 13704 7699/7956 eligible (97%) 86% at 6 months ; Pacque et al. (1990a)

(in 1988) 13977 8062/8438 eligible (96%) 78% at 12 months

a In a sample of 443 patients in holoendemic villages (geometric mean load of 58 to 73 mlcrof llariae/skln snip).

Liberian subjects dropped from 5.25 mf/mg skinto 0.71 mf/mg skin (-86%) 6 months after treat­ment with ivermectin 150 ~g/kg, and rose slightlyto 1.18 mf/mg skin (-78%) at 12 months (Pacqueet a1. 1990a), at which time a second dose was ad­ministered.

Ocular levels of microfilariae in the anteriorchamber decreased to 20% of pretreatment values4 months after ivermectin therapy, but rose to 39%at 12 months (Oadzie et a1. 1990). Similarly, thenumbers of living and dead microfilariae in thecornea were 2% and 9% of baseline at 4 months,but had increased to 27 and 33% at 12 months(Oadzie et al. 1990). These investigators recom­mended that a 6-monthly, rather than yearly, dos­age regimen may be optimal in hyperendemic areaswhere ocular infestation is severe.

Of importance is the finding that there was a

50IIIC 40Q)

! 30'0

20"go

10

o 0o 0.5 2 4 8 ;;'16

No. of mf/skin snip 2 months after treatment

Fig.7. Assessment of severity of onchocerciasis, as measuredby microfilarial (mf) skin snip counts 2 months after treating256 Ghanaian patients with ivermectin 150 ltg/kg. Baselinemicrofilarial counts for the groups represented above were64 (0; n = 152), 128 (.; n = 108) or;;' 256 (~; n = 5) [afterRemme et al. 1989].

tendency for regression of early sclerosing keratitisin ivermectin recipients, and 70% of patients pre­senting with early iridocyclitis had no lesions at 4months. No significant changes could be detectedin lesions of the posterior segment or in visual acu­ities; however, in smaller sample populations cho­rioretinal changes have progressed despite iver­mectin treatment, particularly in those withadvanced scarring (Rothova et a1. 1990; Semba eta1. (1990). These results imply resolution of somepre-existing ocular defects, at least in the anteriorsegment, in line with reductions of ocular micro­filariae counts following ivermectin treatment, butthe effect of ivermectin on posterior segment le­sions is less clear.

Ivermectin was also effective in children aged 6to 14 years when administered in a dose of 150 ~g/

kg. Reductions in skin and ocular microfilariaecounts in 103 children living in the Ivory Coastwere very similar to those reported in adults (La­riviere et a1. 1989c).

2.3.2 Effect on Disease TransmissionRemme et a1. (1989) estimated a reduction of

68 to 78% in the availability of skin microfilariaefor transmission across all inhabitants living inholoendemic villages at 2 months after implemen­tation of the mass ivermectin treatment pro­gramme in Ghana, in which about 60%of the studypopulation received the drug. However, at 4 monthsthe prevalence of microfilariae approached pre­treatment levels. Entomological results demon­strating a 65 to 85% reduction in vector infectionduring the first 3 .months after ivermectin distri­bution are consistent with decreases in microfilar-

652

ial counts among the population (Remme et al.1989). Similar findings have been reported in Lib­eria (Trpis et al. 1990). This decrease in availablemicrofilariae is undoubtedly a contributing factorin the reduction in overall microfilarial load at 6and 12 months in the total population of sampleareas (Pacque et al. 1990a).

A more detailed analysis of the effect of iver­mectin on transmission of onchocerciasis is pro­vided by Taylor et al. (1990) in an extension of theLiberian study. The annual incidence of new in­fection in a previously non-infected group of child­ren living on a rubber plantation decreased by 35%.The age-adjusted reduction was 45% in 7- to 12­year-old children, 35% in 5-year-olds who had livedon the plantation a I year, and 21% in all 5-year­olds . Thus, ivermectin effectively reduces micro­filariae counts and contributes to reduction oftransmission rates amongst a mass population.

3. Tolerability3.1 General Reactions

Ivermectin is generally well tolerated. Almostall of the unwanted effects occurring during iver­mectin therapy appear to be a consequence of animmunological reaction to dead microfilariae,rather than being directly attributable to ivermec­tin per se. Adverse effects reported most com­monly include myalgia , rash, node tenderness andswelling, itching, fever and chills, and limb, jointor facial swelling. These are usually of mild tomoderate severity, and respond to analgesics orantihistamines. Adverse experiences almost alwaysappear during the first 3 days following treatment,and subside thereafter (de Sole et al. 1989, 1990;Rothova et al. 1989; Whitworth et al. 1988). Theseverity of these adverse events is directly relatedto the degree of parasitic infestation (de Sole et al.1989; Rothova et al. 1989; Whitworth et al. 1988).

Incidence rates are difficult to establish becauseofdifferences in trial design and reporting methodsused by investigators. Also, some treated subjectsmay not have been infected with O. volvulus andthus would not be expected to manifest an immuneresponse. While in some smaller trials the inci-

Drugs 42 (4) 1991

dence of unwanted effects in patients treated forthe first time has been as high as 35% (Pacque etal. 1990a; Rothova et al. 1989), this is in excess ofincidence rates reported in much larger samples.The total incidence of reactions among 7411Ghanaian patients administered ivermectin 150 J.tgjkg was about 15%, as depicted in figure 8 (de Soleet al. 1989). This agrees with the findings of themost extensive evaluation of adverse reactions,which was undertaken in conjunction with masstreatment of more than 50 000 patients in WestAfrica between May 1987 and August 1988 (de Soleet al. 1989, 1990). During a 72-hour monitoringperiod after ivermectin ingestion, 9% of subjectsexperienced an adverse event, ofwhich 2.38% were'moderate' and 0.24% 'severe'. After re-treatmentof a subset of patients living in heavily infestedareas (7717 in Ghana and 2388 in Guinea), the in­cidence of adverse effects was 4- to 6-fold less thanthat occurring after the initial dose (fig. 9). It islikely that reducing the parasite load contributedto this decreased rate ; however, the investigatorsfelt that patients may also have been less con­cerned about adverse effects than after the first dose,and may not have reported all events (de Sole etal. 1990).

Ivermectin is less likely than diethylcarbama­zine to cause serious adverse effects, although 2patients with reactive onchodermatitis ('Sowda')who were treated with ivermectin experienced sev­ere swelling, fever and pruritus similar to the Maz­zotti-type reaction seen with diethylcarbamazine(Guderian et al. 1991). Severe symptomatic pos­tural hypotension, an uncommon but potentiallydangerous condition, occurred in 37 of approxi­mately 14 000 patients treated in Ghana (de Soleet al. 1989), and was associated with faintness,sweating, tachycardia and, rarely , confusion. Treat­ment usually consisted of placing the patient in asupine position. Therapy with hydrocortisone wasinstituted in 4 patients but the requirements forsuch intervention were not clearly established.Other rare but serious events reported by de Soleet al. (1989) were dyspnoea and laryngeal oedema,although causality with ivermectin was not deter­mined. The potential for these serious adverse ef-

Ivermectin in Onchocerciasis: A Review 653

16

14

12

2!10c.,'0 8'u.S~ 60

4

2

0Pain Fever Swelling Skin Gland Eye Other TOTAL

+ (limbs, reactions pain, pain,chills face) swelling redness,

watering

Fig. 8. Incidence of adverse effects among 7411 Ghanaian patients administered ivermectin 150 ltg/kg (after de Sole et al.1989). 'Total' also includes severe symptomatic postural hypotension (n = 34; 0.46%) and dyspnoea (n = 6; 0,08%),

fects to occur suggests that a health worker shouldbe available for 36 hours after treatment.

Haematomatous swellings which developed 4weeks after ingestion of ivermectin have been de­scribed in 2 patients (Homeida et al. 1988). Theauthors related this effect to prolonged prothrom­bin time, but this finding has not been substanti­ated by other investigators (Pacque et al. 1989;Richards et al. I989b), and is not supported by datafrom animals (Ali 1990). No significant changes inelectrocardiographic parameters were observed in32 elderly men treated with ivermectin (Dukuly etal. 1991).

There is some evidence that expatriates livingin endemic areas experience more frequent un­wanted events. Reaction rates have been describedas 61% (17 of 28) in British expatriates despite lowskin microfilariae densities (Davidson et al. 1990),and 93%(25 of 27) in American expatriates (Bryanet al. 1991) who were living in West or CentralAfrica. Whether such an increase also occurs in in­digenous children is equivocal : reaction rates inchildren have been reported to be both higher (La­riviere et al. 1989c) and lower (Whitworth et al.1991) than in adults . While Davidson et al. (1990)postulated that such groups may have a lower nat­ural immune tolerance to O. volvulus infestationbecause of a shorter exposure time, it is also prob-

able that these individuals are more likely to reportadverse effects, and that reporting methods usedby investigators to assess such events differ.

The risk offetal damage in 200 pregnant womenwho were inadvertently treated with ivermectin wasnot greater than in control women (Pacque et al.1990b). The investigators recommended thatmonitoring of pregnant women treated with iver­mectin should continue.

Controlled comparisons with diethylcarbama­zine have consistently demonstrated a superior tol-

Ghana

1----- - ---------' n = 7411

n =7717

Guinea1- ...... n = 2327

••• n = 2388

o 2 4 6 8 10 12 14 16Patients with adverse reactions (%)

Fig. 9. Percentage of patients treated with ivermectin whoexperienced adverse reactions after the first dose (EI) and fol­lowing re-treatment (.; after I year in Ghana and after 6months in Guinea) [adapted from de Sole et al. 1990),

654

erability profile for ivermectin (Albiez et al. 1988b;Awadzi et al. 1986; Diallo et al. 1986; Greene etal. 1985; Lariviere et al. 1985). Overall reactionscores for diethylcarbamazine (as measured bysummarising 4-hourly individual scores for eachreaction over the study period) were twice those ofivermectin (Awadzi et al. 1986;Greene et al. 1985),and 3- to 6-fold more diethylcarbamazine recipi­ents received steroid therapy to treat severe reac­tions (Diallo et al. 1986; Lariviere et al. 1985).

3.2 Ocular Reactions

Drugs used to prevent or retard river blindnessideally should not produce or exacerbate ocularcomplications. In this regard ivermectin is superiorto diethylcarbamazine, and has been associated withfew deleterious ocular effects. A dosage of iver­mectin 100 to 200 ~gjkg did not elicit untowardreactions in patients with severe ocular involve­ment (Taylor et al. 1989), and no fundoscopicchanges occurred in those with 'moderate to heavy'infestation (Dadzie et al. 1989; Newland et al. 1988).Ocular inflammation observed in 6% of 116patients was not considered to be clinically im­portant (Dadzie et al. 1989). The possible cause­effect relationship between the development of ret­inal infiltrates in a few patients treated with iver­mectin is uncertain (Rothova et al. 1989; Semba etal. 1990).

In comparative studies, assessment of visualacuity and ocular complicat ions (using ocular re­action index and the incidence of punctate opaci­ties or limbitis) significantly favoured iverrnectincompared with diethylcarbamazine (Albiez et al.1988b; Dadzie et al. 1987; Lariviere et al. 1985;Taylor et al. 1986).

4. Dosage and Administration

The usual initial dosage of ivermectin for pre­vention and treatment of onchocerciasis is 150 ~g/

kg as a single oral dose. Annual re-treatrnent withthis dosage is necessary, to ensure suppression ofO. volvulus microfilariae . Patients with heavy ocu­lar infestation may require more frequent re-treat-

Drugs 42 (4) 1991

ment and repeat administration every 6 monthshas been advocated by some investigators . Child­ren aged 5 to 14 years have been treated success­fully with ivermectin 150 ~g/kg (Lariviere et al.1989c;Taylor et al. 1990), but there are insufficientdata to recommend its use in children younger than5 years, or in pregnant women. Ivermectin may beused in lactating women after the infant is 7 daysor older.

5. Place of Ivermectin in Therapy

Infection with the nematode Onchocerca vol­vulus is one of the major causes of blindness in theworld today, with millions of individuals in sometropical areas at risk of developing 'river blindness'(onchocerciasis). In 1974 the Onchocerciasis Con­trol Programme (OCP) initiated vector control us­ing pesticides to reduce disease transmission viathe blackfly Simulium; since 1987 ivermectin hasbeen included in the programme as the pivotal partof the therapeutic regimen, and it is supplied freeof charge by the manufacturer. I

At present ivermectin, a microfilaricidal ratherthan macrofilaricidal agent, is the drug of choicefor treating .patients afflicted with onchocerciasis.Although ivermectin is not the 'ideal' drug foronchocerciasis, because it is not macrofilaricidaland its use is not recommended in pregnant womenor young children, it is pre-eminent in comparisonwith other available therapy. Diethylcarbamazineand suramin, the 2 drugs used previously to treatonchocerciasis, have activity against O. volvulus butbecause of their cumbersome administration regi­mens and more frequent serious adverse effects,are not suitable for mass treatment programmes.

In contrast, ivermectin is easily administered asa single oral,dose calculated by bodyweight. Thedose is repeated annually to continue suppressionof microfilariae counts . The efficacy of ivermectin

I Ivermectin (trade name, Mectizan'P) is being donated world­wide without charge by its manufacturer for treating all personswith onchocerciasis for as long as the drug is needed. Informationabout obtaining ivermectin for community-based, mass treat­ment programmes should be addressed to the Mectizan® ExpertCommittee, One Copenhill , Atlanta , GA 30307, USA.

Ivermectin in Onchocerciasis: A Review

has already been proven in large scale communitytrials involving many thousands of patients underthe care of the OCP in West Africa, and in CentralAmerica, and the drug is now being administeredto hundreds of thousands of individuals in thesecountries. Skin microfilariae counts decrease tonegligible levels within a week of a single dose, andgenerally remain suppressed for at least 6 months.Ocular microfilarial load is also significantly re­duced; however, in some hyperendemic commun­ities ocular counts have returned to 30% of pre­treatment levels at I year; and a 6-monthly ratherthan yearly dosing regimen has been advocated bysome investigators for use in patients with severeocular involvement, to further protect against therisk of developing eye lesions.

Unlike diethylcarbamazine, ivermectin is welltolerated and is largely devoid of serious adversereactions such as Mazzotti reactions and ophthal­mological disturbances (e.g. punctate opacities). Forthe most part this obviates the need for a healthworker to be present during drug administration.However, the rare occurrence of severe reactions,including systemic postural hypotension , wouldsuggest that medical personnel should be availablefor 36 hours after ivermectin administration.

Iverrnectin treatment also appears to reduce thespread of infection by decreasing the availability ofmicrofilariae for transmission. This is an integralfacet of mass treatment programmes, which aimnot only to treat but to prevent onchocerciasis.

There is some in vitro evidence that combiningivermectin with a macrofilaricidal agent may pro­vide a rational and effective means of combatingonchocerciasis, but clinical support for such an ap­proach is lacking as yet. In the meantime, by virtueof its simple oral administration regimen, good tol­erability and high degree of efficacy iverrnectin isclearly superior to any other available treatment,and as such represents a milestone in the treatmentof onchocerciasis. It is therefore the present drugof choice for controlling onchocerciasis, thus pre­venting needless loss of sight in many thousandsof people living in tropical areas of the world.

655

References

Albiez EJ, Walter G, Kaiser A, Ranque P, Newland HS, et al.Histological examination of onchocercomata after therapy withivermectin. Tropical Medicine and Parasitology 39: 93-99,1988a

Albiez EJ, Newland HS, White AT, Kaiser A, Greene BM, et al.Chemotherapy of onchocerciasis with high doses ·of diethyl­carbamazine or a single dose of ivermectin: microfilaria levelsand side effects. Tropical Medicine and Parasitology 39: 19­24, 1988b

Ali BH. The effect of ivermectin on some haematological indicesin rabbits : influence of vitamin K treatment. Clinical and Ex­perimental Pharmacology and Physiology 17: 735·738, 1990

Awadzi K, Dadzie KY, Klager S, Gilles HM. The chemotherapyof onchocerciasis . XIII . Studies with ivermectin in onchocer­ciasis patients in northern Ghana, a region with long lastingvector control. Tropical Medicine and Parasitology 40: 361­366, 1989

Awadzi K, Dadzie KY, Schulz-Key H, Gilles HM, Fulford AJ, etal. The chemotherapy of onchocerciasis. XI. A double-blindcomparative study of ivermectin, diethylcarbamazine and pla­cebo in human onchocerciasis in northern Ghana . Annals ofTropical Medicine and Parasitology 80: 433-442, 1986

Aziz MA, Diallo S, Diop 1M, Lariviere M, Porta M. Efficacyandtolerance of ivermectin in human onchocerciasis. Lancet I: 171­173, 1982

Bianco AE, Nwachukwu MA, Townson S, DoenhoffMJ, MullerRL. Evaluation of drugs against onchocerca microfilariae inan inbred mouse model. Tropical Medicine and Parasitology37: 39-45, 1986

Bryan RT, Stokes SL, Spencer He. Expatriates treated with iver­mectin . Lancet 337: 304, 1991

Caumes E, Darry A, Paris L, Gaxotte P, Danis M, et al. Efficacyofivermectin in the treatment of cutaneous larva migrans. Pre­sented at the 31st International Congress of AntimicrobialAgents and Chemotherapy, Chicago, 1991

Chavasse DC, Davies JB. In vitro effects of ivermectin on Onch­ocerca volvulus microfilariae assessed by observation and byinoculation into Similium damnosumsensulato. Transactionsof the Royal Society of Tropical Medicine and Hygiene 84:707-708, 1990

Chiou R, Stubbs RJ, Bayne WF. Determination ofivermectin inhuman plasma and milk by high-performance liquid chro­matography with fluorescence detection . Journal of Chroma­tography 416: 196.202, 1987

Cupp EW, Bernardo MJ, Kiszewski AE, Collins RC, Taylor HR,et al. The effects of ivermectin on transmission of Onchocercavolvulus. Science 231: 740-742, 1986

Cupp EW, Ochoa 0 , Collins RC, Ramberg FR, lea G. The effectof multiple ivermectin treatments on infection of Simuliumochraceum with Onchocerca volvulus. American Journal ofTropical Medicine and Hygiene 40: 501-506, 1989

Dadzie KY, Bird AC, Awadzi K, Schulz-Key H, Gilles HM, etal. Ocular findings in a double-blind study of ivermectin ver­sus diethylcarbamazine versus placebo in the treatment ofonchocerciasis. British Journal of Ophthalmology 71: 78-85,1987

Dadzie KY, Awadzi K, Bird AC, Schulz-Key H. Ophthalmolog­ical results from a placebo controlled comparative 3-dose iver-

656

mectin study in the treatment of onchocerciasis. Tropical Med­icine and Parasitology 40: 355-360, 1989

Dadzie KY, Remme J, Alley ES, de Sole G. Changes in ocularonchocerciasis four and twelve months after community-basedtreatment with ivermectin in a holoendemic onchocerciasis fo­cus. Transactions of the Royal Society of Tropical Medicineand Hygiene 84: 103-108, 1990

Datry A, Mayorga R, Lyagouki M, Hilmarsdottir I, Gaxotte P,et al. Treatment of Strongyloides stercora/is infection withivermectin versus albendazole: results of a 44 case study. Pre­sented at the 31st International Congress of AntimicrobialAgents and Chemotherapy, Chicago, 1991

Davidson RN, Godfrey-Faussett P, Bryceson ADM. Adverse re­actions in expatriates treated with ivermectin. Lancet 336: 1005,1990

de Sole G, Awadzi K, Remme J, Dadzie KY, Ba 0, et al. A com­munity trial of ivermectin in the onchocerciasis focus of Asu­bende, Ghana. I\. Adverse reactions . Tropical Medicine andParasitology, 40: 375-382, 1989

de Sole G, Dadzie KY, Giese J, Remme J. Lack of adverse re­actions in ivermectin treatment of onchocerciasis . Lancet 335:1106-1107, 1990

Devaney E, Howells RE. The microfilaricidal activity of iver­mectin in vitro and in vivo . Tropenrnedizin und Parasitologie35: 47-49, 1984

Diallo S, Aziz MA, Lariviere M, Diallo JS, Diop-Mar I, et al. Adouble-blind comparison of the efficacy and safety of iver­mectin and diethylcarbamazine in a placebo controlled studyof Senegalese patients with onchocerciasis. Transactions of theRoyal Society of Tropical Medicine and Hygiene 80: 927-934,1986

Diallo S, Aziz MA, Ndir 0 , Badiane S, Bah IB, et al. Dose-rangingstudy of ivermectin in treatment of filariasis due to Wucher­eria bancrofti . Lancet I: 1030-1031, 1987

Dickinson CM. Improved high-performance liquid chromato­graphic method for quantitation ofivermectin in whole blood,serum or muscle tissue. Journal of Chromatography 528: 250­257, 1990

Duke BOL. Human onchocerciasis - an overview of the disease.Acta Leidensia 59: 9-24, 1990

Duke BOL, Soula G, Zea-Flores G, Bratthauer GL, Doumbo O.Migration and death of skin-dwelling Onchocerca volvulus mi­crofilariae after treatment with ivermectin. Tropical Medicineand Parasitology 42: 25-30, 1991

Duke BOL, Zea-Flores G, Castro J, Cupp EW, Munoz B. Effectsof multiple monthly doses of ivermectin on adult Onchocercavolvulus. American Journal of Tropical Medicine and Hygiene43: 657·664, 1990

Duke BOL, Zea-Flores G, Gannon RT. On the reproductive ac­tivity of the female Onchocerca volvulus . Tropical Medicineand Parasitology 41: 387-402, 1990

Dukuly ZD, Pacque M, Nara A, Taylor HR, Williams PN, et al.A prospective study in high risk subjects of electrocardio­graphic changes with ivermectin. Tropical Medicine and Par­asitology 41: 73-74, 1990

Edwards G, Breckenridge AM. Clinical pharmacokinetics of an­thelmintic drugs. Clinical Pharmacokinetics 15: 67-93, 1988

Edwards G, Dingsdale A, Helsby N, Orme ML'E, BreckenridgeAM. The relative systemic availability of ivermectin afteradministration as capsule, tablet, and oral solution. EuropeanJournal of Clinical Pharmacology 35: 681-684,1988

Drugs 42 (4) 1991

Ette EI, Thomas WOA, Achumba J\. Ivermectin: a long-actingmicrofilaricidal agent. mcp, Annals of Pharmacotherapy 24:426-433, 1990

Fink DW, Porras AG. Pharmacokinetics of ivermectin in animalsand man. In Campbell WC (Ed.) Ivermectin and abamectin.Springer-Verlag, New York, pp. 113-130, 1989

Freedman DO, Zierdt WS, Lujan A, Nutman TB. The efficacyof ivermectin in the chemotherapy of gastrointestinal helmin­thiasis in humans. Journal of Infectious Diseases 159: 1151­1153, 1989

Greene BM, Dukuly ZD, Munoz B, White AT, Pacque M, et al.A comparison of 6-, 12-, and 24-monthly dosing with iver­mectin for treatment of onchocerciasis. Journal of InfectiousDiseases 163: 376-380, 1991

Greene BM, Taylor HR, Cupp EW, Murphy RP, White AT, etal. Comparison of ivermectin and diethylcarbamazine in thetreatment of onchocercias is. New England Journal of Medicine313: 133-138, 1985

Guderian RH, Anselmi M, Sempertegui R, Cooper PJ. Adversereactions to ivermectin in reactive onchodermatitis. Lancet 337:188, 1991

Helling G, Awissi D, Adjamgba C, Heuschkel C, Klager S, et al.Ivermectin: a safe drug in the treatment of onchocerc iasis ina phase-III-study in Togo. Tropical Medicine and Parasitology38: 348, 1987 \

Heuschkel C, Schulz-Key H, Bania M, Gergen H, Klager S, et al.Onchozerkosetherapie: eine Langzeitstudie mit Ivermectin inTogo. Mitteilungen der Osterreichischen Gesellschoft fur Tro­penmedizin und Parasitologie II : 81-88, 1989

Homeida MMA, Bagi lA, Galib HW, Sheikh HE, Yusif MA, etal. Prolongation of prothrombin time with ivermectin . LancetI: 1346-1347, 1988

Jurgens S, Schulz-Key H. Effect of ivermectin on the vertical dis­tribution of Onchocerca volvulus microfilariae in the skin.Tropical Medicine.and Parasitology 41: 165-168, 1990

Klotz U, Ogbuokiri JE, Okonkwo PO. Ivermectin binds avidlyto plasma proteins . European Journal of Clinical Pharmacol­ogy 39: 607-608, 1990

Kumaraswami V, Ottesen EA, Vijayasekaran V, Devi SU, Swa­minathan M, et al. Ivermectin for the treatment of Wuchereriabancrofii filarl'asis. Efficacy and adverse reactions . Journal ofthe American Medical Association 259: 3150-3153, 1988

Lariviere M, Beauvais B, Aziz M, Garin YJ-F, Abeloos J, et al.A study in the Ivory Coast (1985-1987) of the efficacy andtolerance of iverrnectin (Mectizan'P) in human onchocerciasis .\. A comparative double-blind study of 220 patients with onch­ocerciasis treated with a single oral dose of 100, 150 or 200meg/kg, Bulletin de la Societe du Pathologie Exotique et deses Filiales 82: 35-47, 1989a

Lariviere M, Beauvais B, Aziz M, Garin YJ-F, Abeloos J, et al.A study in the Ivory Coast (1985-1987) of the efficacy andtolerance of ivermectin (Mectizan'P) in human onchocerciasis .II. Evaluation in the light of mass campaigns on the effect ofyearly or half-yearly administration of single oral doses of 100,150 or 200 rngc/kg, Bulletin de la Societe du Pathologie Ex­otique et de ses Filiales 82: 48-57, 1989b

Lariviere M, Beauvais B, Aziz M, Garin YJ-F, Peignot C, et al.A study in the Ivory Coast (1985-1987) of the efficacy andtolerance of ivermectin (Mectizan) in human onchocerc iasis.II\. The tolerance and efficacy of a single oral dose of 150 meg/

Ivermectin in Onchocerciasis: A Review

kg in children. Bulletin de la Societe du Pathologie Exotiqueet de ses Filiales 82: 58-64, 1989c

Lariviere M, Vingtain P, Aziz M, Beauvais B, Weimann D, et al.Double-blind study of ivermectin and diethylcarbamazine inAfrican onchocerciasispatients with ocular involvement. LancetI: 174-177, 1985

Matsumoto K, Yamazaki J, Kasuya M, Fukuda H. The actionsof ivermectin on cultured chick spinal cord neurons. Neuro­science Letters 69: 279-284, 1986

Mossinger J, Schulz-Key H, Dietz K. Emergence of Onchocercavolvulus microfilariae from skin snips before and after treat­ment of patients with ivermectin . Tropical Medicine and Par­asitology 39: 313-316, 1988

Naquira C, Jimenez G, Guerra JG, Bernal R, Nalin DR, et al.Ivermectin for human strongyloidiasis and other intestinal hel­minths . American Journal of Tropical Medicine and Hygiene40: 304-309, 1989

Newland HS, White AT, Green BM, D'Anna SA, Keyvan-Lari­jani E, et al. Effect of single-dose ivermectin therapy on humanOnchocerca volvulus infection with onchocercal ocular in­volvement. British Journal of Ophthalmology 72: 561-569,1988

Ottesen EA, Vijayasekaran V, Kumaraswami V, Pillai SVP, Sa­danandam A, et al. A controlled trial of ivermectin and dieth­ylcarbamazine in lymphatic filariasis. New England Journal ofMedicine 322: 1113-1117, 1990

Pacque M, Munoz B, Greene BM, White AT, Dukuly Z, et al.Safety of and compliance with community-based ivermectintherapy. Lancet 335: 1377-1380, 1990a

Pacque M, Munoz B, Poetschke G, Foose J, Greene BM. Preg­nancy outcome after inadvertent ivermectin treatment duringcommunity-based distribution. Lancet 336: 1486-1489, 1990b

Pacque MC, Munoz B, White AT, Williams PN, Greene BM.Ivermectin and prothrombin time. Lancet I: 1140, 1989

Plorde JJ. Filariasis. In Braunwald et al. (Eds) Harrison's prin­ciples of internal medicine. I. 11th edition, pp. 808-809,McGraw-Hili Book Company, New York, 1987

Pong S-S, Wang CC, Fritz LC. Studies on the mechanism of ac­tion of avermectin Bja : stimulation of release of 'Y-aminobu­tyric acid from brain synaptosomes. Journal of Neurochem­istry 34: 351-358, 1980

Porras AG, Chiou R, Kubovetz W, Hall-Gregg M, Stubbs RJ, etal. Dose proportionality of the anthelmintic ivermectin in man.Pharmaceutical Research 4 (Suppl.): S95, 1987

Remme J, Baker RHA, de Sole G, Dadzie KY, Walsh JF, et al.A community trial of ivermectin in the onchocerciasis focusof Asubende, Ghana . I. Effect on the microfilarial reservoirand the transmission of Onchocerca volvulus. Tropical Med­icine and Parasitology 40: 367-374, 1989

Richard-Lenoble D, Kombila M, Rupp E, Pappayliou E, GaxotteP, et al. Ivermectin in loiasis and concomitant O. volvulus andM. perstans infections. American Journal of Tropical Medi­cine and Hygiene 36: 480-483, 1988

Richards Jr FO, Zea Flores R, Duke BOL. Dynamics of micro­filariae of Onchocerca volvulus over the first 72 hours aftertreatment with ivermectin . Tropical Medicine and Parasitol­ogy 40: 299-303, 1989a

Richards Jr FO, McNeeley MB, Bryan RT, Eberhard ML, McNeelyMF, et al. Ivermectin and prothrombin time. Lancet I: 1139­1140, 1989b

Rothova A, van der Lelij A, Stilma JS, Wilson WR, Barbe RF.

657

Side-effects of ivermectin in treatment of onchocerciasis. LancetI: 1439-1441, 1989

Rothova A, van der Lelij A, Stilma JS, Klaassen-Broekema N,Wilson WR, et al. Ocular involvement in patients with onch­ocerciasis after repeated treatment with ivermectin. AmericanJournal of Ophthalmology 110: 6-16, 1990

Roux J, Perolat Ph, Cartel J-L, Boutin J-P, Sechan Y, et al. Iver­mectin study for the treatment of Bancroftianfilariasisof FrenchPolynesia. Bulletin de la Societe de Pathologie Exotique et deses Filiales 82: 72-81, 1989

Satti MZ, VandeWaa EA, Bennett JL, Williams JF, Conder GA,et al. Comparative effects of anthelmintics on motility in vitroof Onchocerca gutturosa, Brugia pahangi and Acanthocheilo­nema vitcae. Tropical Medicine and Parasitology 39: 480-483,1988

Schulz-Key H. Observations on the reproductive biology ofOnchocerca volvulus. Acta Leidensia 59: 27-43, 1990

Schulz-Key H. The collagenase technique: how to isolate and ex­amine adult Onchocerca volvulus for the evaluation of drugeffects. Tropical Medicine and Parasitology 39: 423·440, 1988

Semba RD, Murphy RP, Newland HS, Awadzi K, Greene BM,et al. Longitudinal study of lesions of the posterior segment inonchocerciasis. Ophthalmology 97: 1334-1341, 1990

Soboslay PT, Newland HS, White AT, Erttmann KD, Albiez EJ,et al. Ivermectin effect on microfilariae of Onchocerca vol­vulus after a single oral dose in humans . Tropical Medicineand Parasitology 38: 8-10, 1987

Taylor HR, Murphy RP, Newland HS, White AT, D'Anna SA,et al. Treatment of onchocerciasis. The ocular effects of iver­mectin and diethylcarbamazine. Archives of Ophthalmology104: 863-870, 1986

Taylor HR, Semba RD, Newland HS, Keyvan-Larijani E, WhiteA, et al. Ivermectin treatment of patients with severe ocularonchocerciasis. American Journal of Tropical Medicine andHygiene 40 (5): 494-500, 1989

Taylor HR, Pacque M, Munoz B, Greene BM. Impact of masstreatment of onchocerciasis with ivermectin on the transmis­sion of infection. Science 250: 116-118, 1990

Townsend LB, Wise DS. Filariasis: river blindness, elephantiasisand other filarial infections. Pharmacy International 5: 70-74,1984

Townson S. The development of a laboratory model for oncho­cerciasis using Onchocerca gutturosa: in vitro culture, colla­genase effects, drug studies and cryopreservation . TropicalMedicine and Parasitology 39: 475-479, 1988

Townson S, Connelly C, Dobinson A, Muller R. Drug activityagainst Onchocerca gutturosa males in vitro: a model forchemotherapeutic research on onchocerciasis. Journal of Hel­minthology 61: 271-281, 1987

Townson S, Dobinson A, Connelly C, Muller R. Chemotherapyof Onchocerca lienalismicrofilariae in mice: a model for theevaluation of novel compounds for the treatment of oncho­cerciasis. Journal of Helminthology 62: 181-194, 1988

Townson S, Dobinson AR, Townsend J, Siemienska J, Zea-F1oresG. The effects of ivermectin used in combination with otherknown anti-parasitic drugs on adult Onchocerca guuurosa andO. volvulus in vitro. Transactions of the Royal Society of Trop­ical Medicine and Hygiene 84: 411-416, 1990

Townson S, Shay KE, Dobinson AR, Connelly C, Comley JCW,et al. Onchocerca gutturosa and O. volvulus: studies on the vi­ability and drug responses of cryopreserved adult worms in

658

vitro. Transactions of the Royal Society of Trop ical Medicineand Hygiene 83: 664-669, 1989

Townson S, Tagboto SK. The effects of ivermectin on the via­bility of Onchocerca Iienalis microfilariae in vitro and on theirsubsequent development in the blackfly vector, Simul ium or­natum . Tropical Medicine and Parasitology 42: 31-37, 1991

Trpis M, Childs JE, Fryauff DJ, Greene BM, Williams PN, et aI.Effect of mass treatm ent of a human populat ion with iver­mectin on transmission of Onchocerca volvulus by SimuliumYahense in Liberia, West Africa. American Journal of Trop icalMedicine and Hygiene 42: 148-156, 1990

Wann KT. The electrophysiology of the somat ic muscle cells ofAscaris suum and Ascaridia gal/i. Parasitology 94: 555-566, 1987

Whitworth JAG, Maude GH, Luty AJF. Expatriates treated withivermect in. Lancet 337: 625-626, 1991

Whitworth JAG, Morgan D, Maude GH , Downham MD, TaylorDW. A community trial of ivermectin for onchocercias is in

Drugs 42 (4) /99/

Sierra Leone: clinical and parasitology responses to the initialdose. Transactions of the Royal Society of Tropical Medicineand Hygiene 85: 92-96, 1991

Whitworth JAG, Morgan D, Maude GH, Taylor DW. Commun­ity-based treatment with ivermectin. Lancet 2: 97-98, 1988

WHO Expert Committee on Onchocerciasis. Third Report WHOTechnical report services 752, 1987

Yamazaki J, Matsumoto K, Ono H, Fukuda H. Macrolide com­pounds, ivermectin and milbemycin D, stimulate chloridechannel s sensitive to GABAergicdrugs in cultured chick spinalneurons. Comparative Biochemistry and Physiology 93C: 97­104, 1989

Correspondence: Karen L. Goa, Adis International Limited , 41

Centorian Drive , Private Bag, Mairangi Bay, Auckland 10, NewZealand .

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