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Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus


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To determine the distribution of ivermectin in plasma and tissues of onchocerciasis patients following a single oral dose of 150 micrograms kg-1. Medical Department at Soba University Hospital, Khartoum. Twenty five patients and fourteen healthy volunteers. Serial blood samples were obtained from both groups. Tissue samples were removed from various patients as full thickness skin punch biopsies or during nodulectomy. Ivermectin concentration was determined by radioimmunoassay. The plasma pharmacokinetic variables for patients were; maximum plasma concentration 52.0 ng ml-1; time to achieve maximum concentration, 5.2 h.; elimination half life, 35.0 h; and the area under the plasma concentration curve versus time, 2852 In healthy volunteers, the plasma ivermectin distribution was similar to that in patients, and both groups showed a tendency for a second rise in plasma concentration of the drug suggestive of enterohepatic recirculation. Ivermectin was detected in tissues obtained from patients. Fat showed the highest and most persistent levels, whilst values for skin, nodular tissues, and worms were comparable. Subcutaneous fascia contained the lowest concentrations. Infection with O. volvulus does not affect the pharmacokinetics of ivermectin, and filarial infected tissues and parasites themselves do take up the drug. There may be prolonged retention of ivermectin because of depot formation in fat tissue.
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Eur J Clin Pharmacol (1996) 50:407–410 © Springer-Verlag 1996
O. Z. Baraka · B. M. Mahmoud · C. K. Marschke
T. G. Geary · M. M. A. Homeida· J. F. Williams
Ivermectin distribution in the plasma and tissues of patients
infected with
Onchocerca volvulus
Received: 16 August 1995/Accepted in revised form: 8 December 1995
Abstract Objective: To determine the distribution of
ivermectin in plasma and tissues of onchocerciasis
patients following a single oral dose of 150µgkg
Setting: Medical Department at Soba University
Hospital, Khartoum.
Patients: Twenty ve patients and fourteen healthy
Methods:Serial blood samples were obtained from
both groups. Tissue samples were removed from vari-
ous patients as full thickness skin punch biopsies or
during nodulectomy. Ivermectin concentration was
determined by radioimmunoassay.
Results: The plasma pharmacokinetic variables for
patients were; maximum plasma concentration
; time to achieve maximum concentration,
5.2h.; elimination half life, 35.0h; and the area under
the plasma concentration curve versus time,
2852 ng·h ml¯
. In healthy volunteers, the plasma iver-
mectin distribution was similar to that in patients, and
both groups showed a tendency for a second rise in
plasma concentration of the drug suggestive of entero-
hepatic recirculation. Ivermectin was detected in tis-
sues obtained from patients. Fat showed the highest
and most persistent levels, whilst values for skin, nodu-
lar tissues, and worms were comparable. Subcutaneous
fascia contained the lowest concentrations.
Conclusion:Infection with O. volvulus does not aect
the pharmacokinetics of ivermectin, and larial
infected tissues and parasites themselves do take up the
drug. There may be prolonged retention of ivermectin
because of depot formation in fat tissue.
Key words Ivermectin, Onchocerciasis; pharmaco-
kinetics, tissue concentration, enterohepatic
Ivermectin is a macrocyclic lactone with potent
antiparasitic activity, widely used in veterinary medi-
cine (Campbell et al. 1983; Campbell 1985). Ivermectin
pharmacokinetics and tissue distribution, have been
extensively studied in animals (Chiu and Lu 1989).
Following successful clinical trials of ivermectin in
human onchocerciasis (Aziz et al. 1982; Taylor and
Greene 1989), it has become the drug of choice for
symptomatic treatment, with a potential for strategic
use in controlling the transmission of Onchocerca volvu-
lus infection (Greene 1992). However, despite its wide
popularity, knowledge of the pharmacokinetics of the
drug in man is rudimentary. There are only a few pub-
lished reports about oral bioavailability in healthy vol-
unteers (Edwards and Breckenridge 1988; Goa et al.
1991; Edwards et al. 1988), or in patients (Okonkwo
et al. 1993). Ivermectin concentration is determined by
HPLC (Downing 1989; Chiou et al. 1987). This method
although specic, generally requires large samples when
dealing with tissue samples, extensive instrumentation,
and sample preparation is time consuming.
The development of a radioimmunoassay (RIA) for
ivermectin by Marschke (1989), employing antibodies
with high avidity and specicity for the parent com-
pound, has made it possible to measure the drug in
very small volumes of plasma and tissue. The proce-
dure is sensitive down to 1 ng ml
, the antibodies
show only 19–23% cross reactivity with avermectin,
and the amount required for 50% displacement of the
label (ED50) is 3 ng ml
. This development has made
possible the study of ivermectin distribution in patients,
especially in organs with a high larial density, and the
O. Z. Baraka (*) ·M. A. Homeida
Department of Medicine, Faculty of Medicine, University of
Khartoum, Khartoum, P.O. Box 102, Sudan
B. M. Mahmoud
Department of Pharmacology, Faculty of Pharmacy, University
of Khartoum, Khartoum, Sudan
C. K. Marschke ·T. G. Geary
The UpJohn Company, Kalamazoo, MI, USA
J. F. Williams
Microbiology, Michigan State University, E. Lansing, MI, USA
results should shed light on some important issues in
drug/parasite/disease interactions.
In this study the distribution of ivermectin in
onchocerciasis patients was determined in samples of
plasma, skin, subcutaneous fascia, fat, onchocercal
nodules and worms, collected at various time points
after a single oral dose of 150µgkg
in patients and
in volunteers.
Materials and methods
Subjects and sampling procedure
Twenty ve patients with onchocerciasis and microlaria-positive
skin snip biopsies participated in the study. Microlarial loads
ranged from 1.2 to 164 mfmg
. All were admitted to hospital.
Fourteen healthy volunteers were recruited for the study of iver-
mectin plasma pharmacokinetics. Oral and written consent were
obtained from each subject. Ethical clearance for the study was
obtained from the University of Khartoum, Faculty of Medicine
Research Committee. All subjects were non smokers, did not con-
sume alcohol, and were not on medication. The females were non-
pregnant and not lactating. Each subject received a single oral dose
of ivermectin 150µgkg
body weight after an overnight fast.
Subjects were allowed only water for 2h following treatment.
Heparinised venous blood samples 5ml were taken from an
indwelling cannula in the antecubital fossa at 0, 1, 2, 3, 4, 6, 8, 12,
24, and 48h post treatment no blood samples were obtained at 48
h from the volunteers. The plasma was immediately separated and
stored at [20
C until the assay.
Tissue samples were obtained from the patients at various times
taking care not to subject any individual to more than one surgi-
cal intervention. Tissues were obtained either as full thickness 3 mm
skin punch biopsies or during surgical nodulectomy. Samples were
immediately frozen in liquid nitrogen and kept until assayed.
Analysis of plasma samples
Ivermectin concentrations in plasma samples were determined with-
out extraction by the RIA technique of Marschke (1989). One hun-
dred µl from each sample or standard (chromatographically puried
ivermectin), tritiated ivermectin (Amersham, 22.4 Ci/mmol
6000 dpmper assay-tube), and antiserum (diluted 1/1000) were
added to 12 ×75 mm glass tube and mixed. The tube was kept at
C for 16h. Stirred charcoal suspension, 0.7ml, (0.75% Sigma
activated C-4386) was added to all tubes except the Total Count
tube to which was added 0.7ml RIA buer. The tube contents were
mixed immediately and at 7.5 and 15min. Following centrifuga-
tion, the supernatant decanted into 10ml scintillation cocktail.
Tritium was determined with a liquid scintillation counter.
Ivermectin extraction from tissues
The tissue samples were dissected into their dierent components
to obtain skin, fascia, subcutaneous fat and nodules. Worm frag-
ments were obtained from onchocercal nodules by the collagenase
technique (Schultz-Key et al. 1980). Individual tissue samples were
weighed and assayed in duplicate. The tissue fragments were repeat-
edly homogenised in acetone using an electrical homogeniser with
vortex mixing. After centrifugation, the acetone layer was trans-
ferred to a new tube and evaporated. Acetonitrile was added to the
residue, which was repeatedly extracted into hexane. The acetoni-
trile layer was collected in 75 ×15 mm glass tubes and evaporated
to dryness. The residue was dissolved in 100µl of RIA buer. The
amount of ivermectin extracted from each tissue sample was then
determined by RIA.
To assess the ecacy of extraction, lean beef muscle and fat
samples were spiked with known amounts of ivermectin. About an
85% extraction rate was obtained.
Pharmacokinetic analysis
Pharmacokinetic parameters were calculated using GraphPAD
GPIP Inplot and the Medusa software package. The following were
determined; maximum plasma concentration (C
); the time to the
maximum concentration of the drug (t
); elimination half life (t
and the area under the plasma concentration curve time (AUC).
Statistical analysis
The unpaired t-test was applied. P <0.05 was considered signicant.
Plasma ivermectin concentrations
No signicant dierences were observed between phar-
macokinetic parameters in patients with onchocerciasis
and healthy volunteers (Table 1). Ivermectin appeared
in plasma within 1h after the oral dose (5.7 to
38.8 ngml
), and was detected for up to 48 h
(10.8–62.6 ngml
). Some of the individual plasma
concentration proles (6 patients and 5 volunteers)
showed a second rise in plasma concentration follow-
ing an initial decrease. The secondary peak mostly
occurred between 6 and 12h after the dose. The curves
of the mean plasma concentrations of the patients and
the volunteers showed that the elimination phase was
similar and slow, and that it exhibits linear decay
Tissue ivermectin concentrations
Ivermectin concentrations in dierent tissues of
patients with onchocerciasis are shown in Table 2. The
drug was detected in all tissue sampled. Fat showed the
highest concentrations. Values for the skin, nodules,
and worms from the same patient were comparable.
The lowest concentrations were consistently seen in
subcutaneous fasciae.
Table 1 Ivermectin pharmacokinetics mean (SD) in 14 healthy vol-
unteers, and 14 patients infected with O. volvulus following oral
administration of 150µg·kg
)(h) (h) (µg·hml
Healthy 54.4 (12.2) 4.9 (1.5) 36.6 (10.2) 3.18 (1.39)
Patients 52.0 (12.0) 5.2 (1.9) 35.0 (9.2) 2.850 (0.841)
Ivermectin administration to healthy volunteers did
not cause any post-treatment reactions. All the patien-
t’s skin snips obtained on D7 were negative for
Our results show that infection with O. volvulus does
not aect the distribution of ivermectin in plasma of
patients compared to healthy volunteers. In both
groups there was a common tendency for a secondary
peak to appear, suggestive of enterohepatic circulation.
Accumulation of the parent drug in fat probably con-
tributes to prolonged retention of ivermectin in the
The ivermectin plasma half-life in healthy volunteers
was reported to be 12, 22, and 28h (Fink and Porras
1989; Edwards 1987; Edwards and Breckenridge 1988),
and 56h in onchocercal patients (Okonkwo et al. 1993).
In comparison our results were 36.6, and 35h, respec-
tively. The AUC we obtained was higher than the
reported values of 885 (389) and 1545.3 (190.5)
ng·h ml
, (Edwards 1987; Edwards and Breckenridge
1988; Okonkwo et al. 1993). The dierence in the sys-
temic availability of ivermectin can be attributed to sev-
eral factors. In previous reports it was not stated if
subjects had taken food during the 2hours immedi-
ately after dosing and we now know that food intake
can result in a signicant reduction in the amount of
ivermectin absorbed (submitted). Ivermectin consist of
a mixture of 80% dihydroavermectin B
) and
20% dihydroavermectin B
). The HPLC
method used measured only the H
fraction of the
compound. Details of the specic recovery rates were
not given and values as low as 60% by extraction from
plasma have generally been accepted (Downing 1989).
The sensitivity of the RIA we used may have been supe-
rior, since the antibody is expected to react with the
whole compound and no extraction procedure was
applied during analysis of plasma samples. However,
we are aware of the fact that cross reactivity of the anti-
body with ivermectin metabolites could be an added
factor. The sensitivity of the RIA was demonstrated by
its ability to show secondary peaks similar to those
observed in a study of ivermectin disposition in four
healthy volunteers given the tritium-labelled drug (Fink
and Porras, 1989).
Ivermectin is mainly excreted in bile (Fink and
Porras 1989) and is undetectable in urine (Okonkwo
et al. 1993). The excretion of ivermectin in bile was
expected since it has a high molecular weight and is
very lipid soluble (Fisher and Morzik 1989). Hence,
enterohepatic circulation of the drug is to be expected.
Similar secondary peaks are frequently seen with com-
pounds that undergo hepatic recycling (Miller 1984;
Terhaag and Hermann 1986).
Ivermectin depletion appears very slow in most tis-
sues. The pattern of dierential distribution of iver-
mectin concentrations obtained in our human tissue
samples was comparable to that seen in animals (Chiu
and Lu 1989). The high concentration of ivermectin in
fat is a function of the lipid solubility of the drug, and
fat acts as a reservoir for ivermectin. This could explain
previous observations that ivermectin was detected in
human milk for 12 days following a single oral dose
(Chiou et al. 1987). Ivermectin concentrations in areas
of high larial density, the nodule, worm and skin were
comparable. This supports our previous observation
Fig. 1 Plasma Ivermectin concentrations [Mean (SEM)] in healthy
volunteers (n=14) and onchocerciasis patients (n=14) after
150µg/kg single oral dose
Table 2 Ivermectin concentration in tissues (ngg
of tissue) of 10
patients with onchocerciasis, after a single oral dose of 150 µg kg
NA sample not available; NB repetition of time points represents
analysis of tissues from dierent patients.
Time (h) Skin Fascia Fat Nodule Worm
90.9 NA 141 62.4 NA
670.5 31.8 NA 70.8 79.4
NA 26.2 NA 31.6 NA
30 71.7 38.2 NA 54.7 NA
66.6 NA NA 101.5 NA
72 NA 42.5 NA 56.4 NA
72 64.9 NA NA NA 44.2
72 41.4 18.5 NA 37.1 59.5
4 Days NA 58.9 117.6 NA NA
5 Days 15.6 NA 94.1 NA NA
Corresponding plasma values for these tissue samples were 46,
28.8 and 24 ngml
, respectively
that, O. volvulus is accessible to blood-borne agents
(Mahmoud et al. 1991).
The sustained reduction of O. volvulus microlariae
in skin tissues has been explained by the eect of the
drug on the gravid uterus of the female worm (Albiez
et al. 1988). The sustainability of the eect may also
be attributable in part to prolonged retention of the
drug in the body. However, even allowing for prolonged
persistence of the drug, the relation between ivermectin
pharmacokinetics and its antiparasitic eect is still far
from being understood. Since ivermectin does not
directly aect target organisms (microlariae) invitro,
nor is there evidence of bioconversion invivo to metabo-
lites with direct activity (Soboslay et al. 1987). The like-
lihood is that suitable host responses act in concert
with ivermectin to bring about the antiparasitic effects
(Baraka et al. 1995). Dening these eector mecha-
nisms awaits further studies.
Acknowledgements We thank Dr. M. M. Ali for his assistance in
the parasitological aspect of this study. This work was supported
by MSU/NIH/SUDAN Medical Parasitology Grant No: A1-16312.
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... Its excretion is mainly by the fecal route, and only 1% is excreted in the urine [49]. In healthy individuals and patients infected with onchocerciasis treated with a dose of 0.150 mg /Kg of Ivermectin, significant variability in pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion is not observed [49]. ...
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... These results indicate that infection could influence the PK of moxidectin, resulting in a decrease in total moxidectin exposure. This finding is in line with what has been observed in veterinary studies [30], but is in contrast to findings for ivermectin, a related macrocyclic lactone, where infection with Onchocerca volvulus did not influence the PK [31]. Unfortunately, we could not relate the baseline infection intensity to any PPK parameter. ...
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Background Moxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies.MethodsA PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy).ResultsA two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63–5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60–70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively.Conclusion We describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs.Trial RegistrationRegistered at (NCT04056325).
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Despite the urgent need for effective antivirals against SARS-CoV-2 to mitigate the catastrophic impact of the COVID-19 pandemic, there are still no proven effective and widely available antivirals for COVID-19 treatment. Favipiravir and Ivermectin are among common repurposed drugs, which have been provisionally used in some countries. There have been clinical trials with mixed results, and therefore, it is still inconclusive whether they are effective or should be dismissed. It is plausible that the lack of clear-cut clinical benefits was due to the finding of only marginal levels of in vivo antiviral activity. An obvious way to improve the activity of antivirals is to use them in synergistic combinations. Here we show that Favipiravir and Ivermectin had the synergistic effects against SARS-CoV-2 in Vero cells. The combination may provide better efficacy in COVID-19 treatment. In addition, we found that Favipiravir had an additive effect with Niclosamide, another repurposed anti-parasitic drug with anti-SARS-CoV-2 activity. However, the anti-SARS-CoV-2 activity of Favipiravir was drastically reduced when tested in Calu-3 cells. This suggested that this cell type might not be able to metabolize Favipiravir into its active form, and that this deficiency in some cell types may affect in vivo efficacy of this drug.
Background Ivermectin is a potent semi-synthetic antiparasitic drug used in veterinary medicine. It is widely used for the treatment of parasites. Objective This study aimed to develop a stability-indicating reversed-phase HPLC (RP-HPLC) method for assay and identification of ivermectin including identification and estimation of its related substances in bulk drug substance batches of ivermectin. Method Ivermectin and its related substances were separated on an Ascentis Express C18 column (100 mm × 4.6 mm id, 2.7 µm particle size) maintained at 45°C (column temperature) on an HPLC system with gradient elution. The mobile phase was composed of water − acetonitrile (ACN; 50 + 50, v/v) as mobile phase A, and isopropanol − ACN (15 + 85, v/v) as mobile phase B. Analytes were detected with a detection wavelength of 252 nm and quantitated against an external reference standard of ivermectin with a quantitation limit of 0.1% of the target (analytical) concentration. Results The HPLC method was able to separate all analytes of interest by gradient elution within 25 min. The method was validated according to the guidelines described in the International Conference on Harmonization guideline Q2(R1). Conclusions The HPLC method for assay of ivermectin and estimation of its related substances was successfully developed, validated, and demonstrated to be accurate, robust, specific, and stability indicating. Highlights The performance of the HPLC method is significantly faster and possesses a higher degree of selectivity. Implementation of this method for routine analysis in QC laboratories would save significant time, resources and solvents.
Ivermectin is used widely as an antiparasitic agent in food-producing animals. As in the case of any such drug, the residual tissue concentration of the therapeutic agent, or tissue residue, is a safety concern to the meat-consuming public. To evaluate the toxic potential of the residual tissue concentration of ivermectin and its metabolites, metabolism studies have been carried out in target species (cattle, sheep, swine) using the radiolabeled drug. Comparative metabolic studies were done in a laboratory animal, the rat, and in liver microsomes from various species.
We measured ivermectin in plasma, urine, and saliva of nine patients with onchocerciasis. The aim was to establish pharmacokinetic parameters and to assess the most facile medium for use in monitoring compliance. Binding of ivermectin to plasma proteins in vitro was also investigated. The mean ( SEM) plasma values for the nine subjects were as follows: weight, 66.3 2.8 kg; dose, 11.11 0.4 mg; half-life, 56.50 7.01 hours; clearance, 142.5 22.6 L/kg; volume of distribution, 9.91 2.67 L/kg; area under the plasma concentration—time curve, 1545.3 190.5 ng/ml hr; time to reach maximum concentration, 4.7 0.5 hours; and maximum concentration, 38.2 5.8 ng/ml. Ivermectin was not detected in the urine of any of the nine subjects. Low levels were found in saliva. Blood specimens remain the only reliable biologic fluid for assessment of compliance after ivermectin oral administration. Ivermectin binds specifically to human serum albumin.
A sensitive and specific radioimmunoassay for oxytocin has been developed. The sensitivity of the assay was in the order of 0.2 to 0.25 μu./ml. plasma. Vasopressin reacted with antiserum only in concentrations of 10,000 times that of oxytocin. The correlation between the bioassay and immunoassay was found to be highly significant (P<0.001).
Control of human onchocerciasis has been problematic. Vector control is practical and effective in only a circumscribed region of West Africa. Even in this area, control depends on meticulous monitoring of the vector and associated parasite species and precise application of requisite larvicide on a regular basis. As an alternative to vector control, chemotherapy-based control has been revolutionized by the finding that ivermectin, a novel semisynthetic macrocyclic lactone, is acceptable for mass distribution at the community level and that it represents an effective means of disease control when given once yearly. Efforts are underway to develop a vaccine to prevent infection.
Ivermectin, a derivative of avermectin B, is an orally effective microfilaricidal agent. It is the current drug of choice for treating patients infected with the nematode Onchocerca volvulus, which is a major cause of blindness in inhabitants of some tropical areas. Ivermectin is administered orally as a single dose of 150 micrograms/kg given annually. Skin and ocular microfilarial counts are dramatically reduced after the first dose, with some evidence for a resulting decrease in transmission of infection by the blackfly vector. With the exception of rare serious reactions such as severe systemic postural hypotension, ivermectin is generally well tolerated. The drug has the clear advantages of ease of administration and better tolerability compared with diethylcarbamazine and suramin, agents previously used to treat onchocerciasis. Thus, ivermectin is suitable for inclusion in mass treatment programmes and is the best therapeutic option presently available to combat onchocerciasis. As such it provides hope for many thousands of people at risk of becoming blind, and represents a major contribution to tropical medicine.
Patients infected with Onchocerca volvulus in the Cayapa River focus in north-east Ecuador were given 500 mg chloroquine diphosphate (CQ) orally prior to nodulectomy. The concentrations of CQ were determined in parasite fragments and host tissue dissected from the nodules, in skin overlying the nodules, and in plasma at 3, 4, 7, and 24 hours after dosing. Onchocerca volvulus took up CQ rapidly, in some cases accumulating the drug to concentrations of over 600 pmol mg-1 worm tissue by three hours, and maintaining similar concentrations through 24 hours. These amounts were markedly higher than peak concentrations in plasma (3.16 pmol microliters-1) and in host tissues (78 pmol mgm-1) and skin (up to 93 pmol mg-1). In vitro uptake of CQ by females of O. volvulus was greater under alkaline conditions (pH 8.4) than at pH 6.8 and 7.4. Uptake reached equilibrium after one to two hours, with final concentrations being approximately 10 times lower than those reached in vivo. Inhibitory effects of chloroquine and its major metabolite desethylchloroquine on the motility of O. volvulus and other filariae have been observed previously in vitro; whether or not the drug had adverse effects on adult parasites in vivo was not determined in these experiments. However, the results illustrate the accessibility of O. volvulus to blood borne agents in vivo, and the potential importance of pharmacodynamic characteristics in the search for new macrofilaricidal agents.
Ivermectin is a macrocyclic lactone that has widespread antiparasitic activity. Numerous clinical trials have shown that ivermectin is safe and effective in the treatment of human infection with Onchocerca volvulus. Although it is rapidly microfilaricidal, it does not cause a severe reaction, as is seen with diethylcarbamazine treatment. The drug temporarily interrupts production of microfilaria but has not known long-lasting effects on the adult worms. In patients with onchocerciasis, a single oral dose of ivermectin (150 micrograms/kg) repeated once a year leads to a marked reduction in skin microfilaria counts and ocular involvement. At this dose, ivermectin causes minimal side effects and is sufficiently free of severe reactions to be used on a mass scale. It promises to revolutionize the treatment of onchocerciasis.
A rational strategy for chemotherapy demands that dosage schedules be based on an adequate knowledge of clinical and biochemical pharmacology. Many anthelmintic drugs (e.g. suramin, diethylcarbamazine, hycanthone) were introduced before modern techniques for drug evaluation (controlled clinical trials) and before the development of specific and sensitive analytical methods for the assay of drugs and metabolites in biological fluids. Thus, many of the regimens used today for the treatment of parasitic diseases are largely empirically derived. By means of specific analytical methodology (high performance liquid chromatography, gas chromatography and mass-spectrometry) introduced in the 1960s, it is now possible to measure drugs and their metabolites with specificity and sensitivity. Much of this review deals with compounds which are active against the major systemic helminths, i.e., filariae (diethylcarbamazine, ivermectin and suramin) and schistosomes (niridazole, metrifonate, oxamniquine and praziquantel), but recent advances in the treatment of hydatid disease involving the benzimidazole carbamates albendazole and mebendazole are also discussed. Among the imidazole derivatives, mebendazole, a broad-spectrum anthelmintic, is poorly absorbed from the gastrointestinal tract after a therapeutic dose, but that fraction which is absorbed and escapes hepatic first-pass extraction is pharmacologically active against systemic helminths. Albendazole is more completely absorbed, but is almost undetectable in plasma due to its rapid conversion to an active sulphoxide metabolite. This compound may well become the drug of choice for the chemotherapy of echinococcosis. Levamisole, the 1-isomer of tetramisole, is rapidly and completely absorbed, but has not been widely used in systemic helminthiases because of severe side effects associated with prolonged dosage. Diethylcarbamazine is microfilaricidal against Onchocerca volvulus, but its use has been associated with major adverse effects resulting from its action on the microfilariae. These effects are related to the concentration of the drug in the plasma which, in turn, is influenced by urinary pH. The elimination half-life of diethylcarbamazine is prolonged and renal clearance reduced in alkaline urine. Under these conditions the microfilaricidal effect is enhanced, but the adverse reactions to treatment are more severe. Suramin is the only available antifilarial agent with macrofilaricidal activity. It has a long elimination half-life (36 to 54 days), and is highly (99.7%) bound to plasma protein which limits its removal from the blood. Ivermectin is a macrocyclic lactone with microfilarial activity which persists long after the drug has been eliminated from the plasma, suggesting that its mode of action is not related directly to its concentration in the systemic circulation. Metrifonate is an organophosphate, active against Schistosoma haematobium without major side effects. It is also microfilaricidal against Onchocerca volvulus but produces a greater degree of systemic side effects than diethylcarbamazine. The drug is well absorbed but is transformed into an active compound, dichlorvos, by a non-enzymic process. Both metrifonate and dichlorvos are eliminated rapidly by the kidneys. The schistosomicides niridazole, oxamniquine and praziquantel are all extensively metabolised. Niridazole and praziquantel are highly extracted on the first-pass through the liver. Oxamniquine is metabolised by the enzymes in the gut wall, but is relatively poorly cleared by the liver. All 3 compounds are rapidly eliminated. The presence of intra- and extrahepatic shunts in patients with hepatosplenic schistosomiasis might lead to reduced clearance and increased bioavailability of niridazole and praziquantel, necessitating dosage reductions in these subjects.
During chemotherapy trials in hyperendemic onchocerciasis areas in West Africa 15 adult nodule carriers in Liberia and 24 patients in Mali received single doses of ivermectin (150 or 200 micrograms/kg). Nodules were extirpated two, six and ten months after therapy and examined histologically. No macrofilaricidal effect of ivermectin was observed. Two months after therapy, in 93% of all female worms with intrauterine stretched microfilariae nearly all microfilariae were degenerated. The percentage was lower after ten months but still significantly higher than in untreated control groups. Ivermectin did not cause degeneration of the intrauterine coiled microfilariae. But the percentage of the female worms with coiled microfilariae was significantly lower two and ten months after therapy than that in the placebo or untreated control groups. Correspondingly, the percentage of nodules with intact microfilariae in the nodule tissue was also significantly lower throughout the examination period than that of the untreated control groups. There was not observed any effect on the spermatogenesis and spermatozoa were found frequently in the uteri of female worms. Using the method of histology, the long lasting inhibitory effect of a single dose of ivermectin on the intrauterine production of microfilariae could clearly be demonstrated. This proves the value of histology for the assessment of drug effects on adult O. volvulus.