Naunyn-Schmied Arch Pharmacol (2010) 381:147–152

DOI 10.1007/s00210-009-0483-z

ORIGINAL ARTICLE

Ivermectin is a nonselective inhibitor of mammalian

P-type ATPases
Paulo Henrique Cotrim Pimenta &
Claudia Lucia Martins Silva & François Noël

Received: 14 September 2009 / Accepted: 1 December 2009 / Published online: 30 December 2009
# Springer-Verlag 2009

Abstract Ivermectin is a large spectrum antiparasitic drug
that is very safe at the doses actually used. However, as it is
being studied for new applications that would require higher
doses, we should pay attention to its effects at high
concentrations. As micromolar concentrations of ivermectin
have been reported to inhibit the sarco-endoplasmic reticulum
Ca2+-ATPase (SERCA), we decided to investigate its
putative inhibitory effect on other two important P-type
ATPases, namely the Na+, K+-ATPase and H+/K+-ATPase.
We first extended the data on SERCA, using preparations
from rat enriched in SERCA1a (extensor digitorum longus)
and 1b (heart) isoforms. Secondly, we tested the effect of
ivermectin in two preparations of rat Na+, K+-ATPase
in order to appreciate its putative selectivity towards the
α1 isoform (kidney) and the α2/α3 isoforms (brain), and in
an H+/K+-ATPase preparation from rat stomach. Ivermectin
inhibited all these ATPases with similar IC 50 values
(6–17 µM). With respect to the inhibition of the Na+,
K+-ATPase, ivermectin acts by a mechanism different from
the classical cardiac glycosides, based on selectivity towards
the isoforms, sensibility to the antagonistic effect of K+ and
to ionic conditions favoring different conformations of the
enzyme. We conclude that ivermectin is a nonselective
inhibitor of three important mammalian P-type ATPases,
which is indicative of putative important adverse effects if
this drug were used at high doses. As a consequence,
we propose that novel analogs of ivermectin should be
P. H. C. Pimenta : C. L. M. Silva : F. Noël (*)
Laboratório de Farmacologia Bioquímica e Molecular,
Instituto de Ciências Biomédicas,
Bloco J do Centro de Ciências da Saúde, sala 17,
Universidade Federal do Rio de Janeiro, Cidade Universitária,
Av. Carlos Chagas Filho, 373,
CEP: 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil
e-mail: fnoel@pharma.ufrj.br
developed and tested both for their parasitic activity and in
vitro effects on P-type ATPases.
Keywords Ivermectin . ATPase . SERCA . ATPase, Na-K .
H/K-ATPase . Adverse effect
Abbreviations
DMSO dimethyl sulfoxide
EDTA ethylenediaminetetraacetic acid
HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
PMSF phenylmethylsulfonyl fluoride
POPOP 1,4-bis-[2-(5-phenyloxazolyl)]-benzene
PPO 2,5-diphenyloxazole
Tris tris(hydroxymethyl)aminomethane
Introduction
Discovering alternative uses for known compounds, the
so-called “repositioning/repurposing” is a widespread strategy
of small pharma companies (Bradley 2005). As emphasized
by Aronson (2007), we should look hard at old drugs for
new indications since many successful examples of this
strategy have been reported. Such phenomenon is occurring
with ivermectin, a macrocyclic lactone endectocide intro-
duced in 1981 for nematode worm control in veterinary
medicine and later (1987) in humans, initially for the control
of onchocerciasis (Geary 2005). Ivermectin was then
progressively used against other filarial parasites, such as
Wuchereria bancrofti, Brugia malayi, Brugia timori and,
more recently, it was registered for the treatment of
strongyloidiasis and also of human ectoparasites (apud;
Prichard 2007). After more than 20 years success due to
high potency, large spectrum, and very good safety, this
“wonder drug” (Geary 2005) is yet being studied for new
148
applications. Recently, ivermectin has been showed to be
active against axenic promastigote and intracellular amastigote
forms of Leishmania amazonensis (Santos et al. 2009).
However, this in vitro leishmanicidal activity occurred at
relatively high concentrations (IC50 ≈5–7 µM) when compared
to the nanomolar concentrations effective against many
nematode species (Geary 2005) and to the therapeutic peak
plasma concentrations (about 40 nM) measured in humans
treated for onchocerciasis control (Shu et al. 2000). As a
consequence, attention has to be drawn to the safety of such
higher doses that would be necessary for treating human
leishmaniasis and other parasitic infections requiring high
doses of ivermectin. As ivermectin has been reported to inhibit
the skeletal muscle sarcoplasmic reticulum Ca2+-ATPase
(SERCA1a) of rabbit and the porcine brain endoplasmic
reticulum Ca2+-ATPase (SERCA2b) in the micromolar
range of concentrations (Bilmen et al. 2002), we decided to
investigate its putative inhibitory effect on other two types of
P-ATPases, namely the Na+, K+-ATPase and H+/K+-ATPase.
Firstly, we confirmed and extended the data on SERCA,
using preparations from rat enriched in SERCA1a (extensor
digitorum longus, EDL) and 1b (heart) isoforms. Secondly,
we tested the effect of ivermectin in two preparations of rat
Na+, K+-ATPase in order to appreciate its putative selectivity
towards the α1 isoform (kidney) and the α2/α3 isoforms
(predominant in brain). We also give some insight into its
mechanism of action by comparing its effect to the ones of
ouabain, a classical cardiac glycoside. Finally, we look at the
H+/K+-ATPase prepared from the rat stomach. Our results
show that ivermectin inhibits the three main P-types ATPases
of mammals, in the micromolar range of concentrations, so
that there is concern for its use in higher than usual doses.
Materials and methods
Tissue preparation
Adult male Wistar rats (250 g) were anesthetized and killed by
decapitation (in accordance to the Institutional Ethical
Committee for use of experimental animals—CEUA, process
number DFBCICB011) and their brains, hearts, EDL muscles,
and kidneys were rapidly excised and stored at −80°C. The
stomachs were immediately removed, opened, and washed for
the scrap of mucous membrane. Preparation from the scrap
was done at the same day (Pôças et al. 2008).
ATPases preparations
Preparations enriched in Na+, K+-ATPase from brain and
kidney and H+, K+-ATPase preparation from stomach were
obtained as earlier described (Poças et al. 2003, 2008).
(Ca2++Mg2+)-ATPase preparations from heart and EDL
Naunyn-Schmied Arch Pharmacol (2010) 381:147–152
were prepared as described previously for the gastrocnemius
muscle (Pôças et al. 2008). The protein concentration was
measured according to the method of Lowry et al. (1951)
using bovine serum albumin as the standard.
Measurement of ATPase activity
The ATPasic activity was determined by measuring the Pi
liberated according to the Fiske and Subbarow (1925)
colorimetric method with slight modifications, as described
earlier (Noël and Souto-Pardon 1989): the reaction was
stopped by adding 1 ml of a chilled fresh mixture of
2.19 mM sodium sulfite, 1.45 mM sodium bisulfite,
0.19 mM aminonaphthosulfonic acid, 3 mM ammonium
molybdate, and 0.75 N sulfuric acid. The amount of protein
was adjusted to a value which ensured that less than 20% of
the initial ATP present was hydrolyzed during the incubation
period. The specific conditions for measuring the three
different ATPases, already validated and published elsewhere
(Pôças et al. 2008), are briefly described below.
Inhibition of Na+, K+-ATPase activity
The specific Na+, K+-ATPase activity of the enzyme (116
and 175 µmol Pi mg−1 protein h−1, for kidney and brain
preparations, respectively) corresponds to the difference
between the total ATPase activity and the activity measured
in the presence of 1 mM ouabain and absence of KCl (basal
activity). The preparation was incubated at 37°C for 2 h, in
a total volume of 0.5 mL. Unless otherwise stated, the
incubation was performed in the presence of 87.6 mM
NaCl, 3 mM KCl, 3 mM MgCl2, 1.2 mM ATPNa2, 1 mM
EGTA, 10 mM sodium azide and 20 mM maleic acid
buffered to pH 7.4 with Tris in the absence or presence of
ivermectin (see details in the figures).
Inhibition of (Ca2++Mg2+)-ATPase activity
Enzyme incubation was performed for 1 h at 37°C in a
medium containing 5 mM ATPNa2, 4 mM MgCl2, 100 mM
KCl, 0.3 mM EGTA, 10 mM sodium azide, 50 mM HEPES
pH 7.4, A23187 1 µM, and 10 µM free Ca2+ in the absence
or presence of ivermectin. The specific activity of the
enzyme (7 and 60 µmol Pi mg−1 protein h−1, for heart and
extensor EDL preparations, respectively) corresponds to
the difference between the total ATPase activity and the
activity measured in the absence of Ca2+.
Inhibition of H+, K+-ATPase activity
The preparation was incubated for 1 h at 37°C in a total volume
of 0.5 mL of incubation medium containing 2 mM ATPNa2,
2 mM MgCl2, 10 mM KCl, 10 mM NH4Cl, 5 µg/mL
Naunyn-Schmied Arch Pharmacol (2010) 381:147–152
nigericin, 10 mM sodium azide, and 40 mM Tris–HCl buffered
to pH 7.4. The specific activity of the enzyme (3 µmol Pi mg−1
protein h−1) corresponds to the difference between the total
ATPase activity and the activity measured in the absence of
KCl and NH4Cl in the absence or presence of ivermectin.
Analysis of the results
The parameters IC50 (mean inhibitory concentration) and Imax
(maximal inhibition) were calculated using a computerized
non-linear regression analysis of the data (Prism®, GraphPad
Software Inc., version 4.00), assuming a sigmoidal dose–
response curve model with variable slope (Hill coefficient
not fixed to 1).
Drugs and reagents
The commercial Ivermectin used throughout this work was
a mixture of 22,23-dihydroavermectin B1a and B1b, in a
ratio greater than 97:3 as determined by HPLC analysis
(Santos et al. 2005). Ivermectin was dissolved in 100%
DMSO to obtain a 10 mM stock solution. The final
concentration of DMSO in the assay never exceeded 1%
(v/v) and had no significant effect by its own. Ouabain was
obtained from Sigma–Aldrich, Inc. (St. Louis, MO, USA).
All other reagents were of analytical grade.
Results
Inhibition of (Ca2++Mg2+)-ATPase
In these experiments we used preparations from EDL and
heart since they contain predominantly the isoforms
SERCA1a and SERCA2a, respectively (Wuytack et al.
2002). Note that the Mg2+-dependent Ca2+-stimulated ATPase
activity of our preparations was totally inhibited by 1 µM
thapsigargin (data not shown) indicating that it represents a
SERCA and not a plasma membrane Ca2+-ATPase (PMCA)
or a secretory pathway Ca2+-ATPase activity (Wuytack et al.
2002). Figure 1 shows that ivermectin (1–70 µM) inhibited
the SERCA activity of both preparations in a concentration-
dependent manner and with a similar potency. Note that the
inhibition was not maximal (Table 1), as already reported by
Bilmen et al. (2002) for the SERCA1a. The slope was also
steeper than normally for a bimolecular reaction, as shown by
Hill coefficients higher than 1 (Table 1).
Inhibition of Na+, K+-ATPase
As rodent isoforms of the Na+, K+-ATPase have different
sensibilities to their selective inhibitors (cardiac glycosides),
we decided to test the effect of ivermectin on our previously
149
100
Heart
EDL
75
Inhibition (%)
50
25
0
10 -6 10 -5 10 -4
Ivermectin (M)
Fig. 1 Concentration–effect curves for inhibition of (Ca2++Mg2+)-
ATPase from rat EDL (mostly SERCA1a) and heart (mostly
SERCA2a) by ivermectin. Results are expressed as percent of
inhibition and represent the mean±SEM from five experiments
performed in triplicate. Curves were drawn using the parameters
fitted by non-linear regression analysis with the model of sigmoidal
dose–response curve with variable slope (see the values of the
parameters in Table 1)
described preparations of kidney and brain (Poças et al. 2003):
the full inhibition of kidney Na+, K+-ATPase by ouabain was
compatible with the presence of only the low-affinity
isoform α1 in this tissue, whereas the nearly full inhibition
of brain Na+, K+-ATPase at low ouabain concentrations
indicated that our brain preparation contains mainly the high
affinity isoforms (i.e., α2/α3). Figure 2 shows that the two
inhibition curves obtained with ivermectin (1–70 µM) are
nearly superimposed, with an IC50 around 10 µM, a maximal
effect around 70% and a Hill coefficient higher than 1
(Table 1), as reported for the SERCA.
In order to give some insight into the mechanism of action
of ivermectin, we tested the effect of K+, a classical antagonist
of the cardiac glycosides, on the inhibition of the α1 isoform
(kidney preparation) produced by ivermectin. As shown in
Fig. 3, increasing the concentrations of K+ from 1 to 3 mM
did not affect the inhibition promoted by ivermectin, as
evidenced by the overlap of the inhibition curves (mean IC50
8 and 10 µM, respectively, n=3). On the other hand, a
further increase of the K+ concentration (from 3 to 10 mM)
produced a threefold shift of the curve to the right, increasing
the IC50 value from 10 µM to 31 µM (n=3).
In another experiment we used two ionic conditions in
order to favor different conformations of the enzyme, an
experimental approach previously used to differentiate the
effect of a coumestan from that of vanadate, a classical
inhibitor of P-type ATPases that is more potent to inhibit the
Na+, K+-ATPase when in an E2 conformation, favored by a
medium containing a low concentration of Na+ along with
high concentrations of K+ and Mg2+ (Pôças et al. 2008).
Figure 4 shows that the inhibition curves of ivermectin were
identical in both ionic conditions whereas ouabain was five
times more potent in the high Na+/low K+/low Mg2+ medium
(IC50 =19 µM) than in the low Na+/high K+/high Mg2+
150 Naunyn-Schmied Arch Pharmacol (2010) 381:147–152

Table 1 Parameters for ivermectin inhibition of different rat P-type ATPases

SERCA Na+, K+-ATPase H+, K+-ATPase

EDL (1a; n=5) Heart (2a; n=5) Kidney (α1; n=3) Brain (α2/α3; n=3) Stomach (n=5)

IC50 (µM) 16.9 (14.0–20.3) 6.72 (5.22–8.65) 8.23 (6.15–11.0) 6.48 (5.12–8.21) 7.59 (6.15–9.36)
Imax (% inhibition) 75.2±3.1 55.4±2.2 69.5±4.1 68.9±3.1 100 (fixed)
nH 1.87±0.03 2.16±0.39 1.61±0.29 1.45±0.21 2.17±0.44

IC50 values are expressed as mean with the 95% confidence interval (in parenthesis). The other values are expressed as mean±SEM. Three to five
experiments were performed in triplicate. In the case of H+ , K+ -ATPase the Imax was fixed at 100% (see “Results”). nH =Hill coefficient

medium (IC50 =96 µM) that has been shown to favor the
inhibition by vanadate.
Inhibition of H+, K+-ATPase
As concentrations of ivermectin above 10 µM interfered
with the assay in the experimental conditions used for
measuring the H+, K+-ATPase, we were not able to
construct a full concentration–effect curve (Fig. 5). As an
alternative, we estimated the IC50 of ivermectin by fixing
the Imax value to 100% and by considering only four
concentrations of the drug that produced at most 50%
inhibition (between 1 and 10 µM). Even with these
technical limitations, the IC50 and Hill coefficient were
estimated with a satisfactory precision and were similar to
the ones found for the other P-type ATPases (Table 1).
Discussion
The inhibition of SERCAs by ivermectin has already been
reported for different mammals. Ahern et al. (1999) were the
first to suggest that micromolar concentrations of ivermectin
(10 µM) reduced the Ca2+ uptake by the rabbit sarcoplasmic
reticulum Ca2+-ATPase. A more direct and quantitative
analysis was then reported by Bilmen et al. (2002) who
demonstrated that ivermectin inhibited the Ca2+-ATPase
activity of rabbit skeletal muscle sarcoplasmic reticulum
(containing mainly the SERCA1a isoform) and of porcine
brain microsomes (containing mainly the SERCA2b isoform).
In present work, we first confirmed that ivermectin inhibits
the SERCA1a activity with an IC50 value of 17 µM, just as
reported by Bilmen et al. (IC50 =15 µM), using a preparation
from rat EDL. We also extended this observation to the
SERCA2a isoform, by using a rat heart preparation. In both
cases, the inhibition was not maximal and the Hill coefficient
was higher than 1, as already reported by Bilmen et al. (2002)
for the SERCA1a. Although occurring at a relatively high
concentration (micromolar range, about 100 times higher than
the therapeutic peak plasma concentrations measured in
humans treated for onchocerciasis control (Shu et al. 2000)),
such inhibition of the SERCA1a could explain some side
effects of ivermectin, that has been reported to affect muscular
activity in animals when given at high doses to treat parasite
infestations (Lovell 1990).
The exact mechanism of this action is unknown albeit
ivermectin stabilizes the SERCA in a Ca2+-bound, E1
conformational state (Bilmen et al. 2002) which differs

100
Brain 100
kidney 1 mM KCl
75
Inhibition (%)

3 mM KCl
75
Inhibition (%)

10 mM KCl
50
50

25
25

0
10 -6 10 -5 10 -4
Ivermectin (M)
Fig. 2 Concentration–effect curves for inhibition of Na+/K+-ATPase
from brain (mostly α2/α3 isoforms) and kidney (only α1 isoform) by
ivermectin. Results are expressed as percent of inhibition (mean±SEM)
and were obtained from three experiments performed in triplicate.
Curves were drawn using the parameters fitted by non-linear regression
analysis with the model of sigmoidal dose–response curve with variable
slope (see the values of the parameters in Table 1)
0
10 -6 10 -5 10 -4
Ivermectin (M)
Fig. 3 Effect of potassium on ivermectin inhibition of rat kidney
Na+/K+-ATPase. The effect of ivermectin was measured at three different
concentrations of KCl. Results are expressed as percent of inhibition
(mean±SEM) and were obtained from three experiments performed in
triplicate. The fitted curves were obtained by non-linear regression using
the model of sigmoidal dose–response curve with variable slope
Naunyn-Schmied Arch Pharmacol (2010) 381:147–152 151

100 high Na +/low K+/low Mg 2+ Therefore, it is possible that the ivermectin effect could be
low Na + /high K+/high Mg 2+ relatively unspecific so that inhibition of other P-type
75
ATPases was hypothesized. As the homology between
Inhibition (%)

SERCA and Na+, K+-ATPase is more extensive than with

50
any other ATPase, even the PMCA (Sweadner and Donnet
2001), we decided to firstly investigate the effect of
25
ivermectin on the activity of rat kidney and brain preparations
a of this enzyme. Note that the full inhibition of kidney Na+,
0
10 -6 10 -5 10 -4 K+-ATPase by ouabain is compatible with the presence of
Ivermectin (M) only the low-affinity isoform α1 in this tissue, whereas the
nearly full inhibition of brain Na+, K+-ATPase at low
100 high Na + /low K+ /low Mg 2+ ouabain concentrations indicates that our brain preparation
low Na +/high K+ /high Mg 2+ contains mainly the high affinity isoforms α2/α3 (Poças
75 et al. 2003). Ivermectin inhibited both the kidney and brain
Inhibition (%)

isoforms of Na+, K+-ATPase with identical IC50 values and

50
25
0
10 -6 10 -5 10 -4
Ouabain (M)
Fig. 4 Influence of the ionic conditions on the inhibitory effect of
ivermectin (a) and ouabain (b) on rat kidney Na+/K+-ATPase. Two
different ionic conditions were used in order to favor different conforma-
tions of the enzyme: 100 mM NaCl, 3 mM MgCl2, and 3 mM KCl (high
Na+/low K+/low Mg2+); 30 mM NaCl, 15 mM MgCl2, and 20 mM KCl
(low Na+/high K+/high Mg2+). In both ionic conditions 3 mM ATP-Na2
and 10 mM sodium azide were used. Each point represents the mean
inhibition (%) ±SEM of three (ouabain) or four (ivermectin) experiments
performed in triplicate. Curves were fitted by non-linear regression
analysis using the model of sigmoidal dose–response with variable slope
from selective inhibitors of SERCA (thapsigargin, cyclo-
piazonic acid, and BHQ) that bind to the enzyme in a
Ca2+-free state (referred to as E2.Pi or E2) and prevent
the binding of Ca2+ (reviewed in Yatime et al. 2009).
100
75
Inhibition (%)
very similar to the ones observed for the two SERCAs. This
is very different from ouabain, and other cardiac glycosides,
that is much more potent for inhibiting the brain isoforms of
b Na+, K+-ATPase (IC50 =0.09 µM) than the α1 isoform
10 -3
present in the kidneys (IC50 =70 µM; Poças et al. 2003).
Another evidence that ivermectin could inhibit the Na+,
K+-ATPase by a mechanism different from the cardiac
glycosides was the lack of effect of K+ when increasing its
concentration from 1 to 3 mM, although a shift to the right of
the inhibition curve was observed at higher concentrations.
This is qualitatively different from what was observed with
ouabain in the same conditions (Poças et al. 2003) and
classically referred to the K+-cardiac glycosides antagonism,
a characteristic feature of these drugs (Noël and Cumps
1989), which has clinical consequences. As this K+-shift
assay was not totally conclusive, we also used another
approach to compare the inhibitory effect of ivermectin and
ouabain. The concentrations of Na+, Mg2+, and K+ in the
incubation medium can favor one or another conformation of
the enzyme and thus the inhibitory effect of drugs that bind
preferentially to a specific conformation during the catalytic
cycle. Using two different compositions of the medium that
had been previously used for favoring or not the inhibitory
effect of vanadate, a classical nonselective P-type inhibitor

with higher affinity for the E2 conformation (Cantley et al.

50
25
0 of high Na+/low K+/low Mg2+ concentrations than in the
10 -6 10 -5
Ivermectin (M)
Fig. 5 Concentration–effect curve for inhibition of H+, K+-ATPase
from rat stomach by ivermectin. Results are expressed as percent of
inhibition and represent the mean±SEM from five experiments
performed in triplicate. The curve was drawn using the parameters
fitted by non-linear regression analysis with the model of sigmoidal
dose–response curve with variable slope and Imax fixed at 100% (see
the values of the parameters in Table 1)
1978; Noël and Souto-Pardon 1989; Poças et al. 2003), we
were able to show that ivermectin has a different mechanism
of action than ouabain. Indeed, ouabain (but not ivermectin)
had a higher potency (five times lower IC50) in the presence
10 -4 presence of low Na+/high K+/high Mg2+ concentrations.
We previously reported that a coumestan inhibited the rat
kidney Na+, K+-ATPase with equal potencies in both ionic
conditions and was a nonselective inhibitor of P-type
ATPases, like ivermectin, since it inhibited the rat SERCA
and H+/K+-ATPase with similar potencies as for the Na+,
K+-ATPase (Pôças et al. 2008) and was nearly equipotent for
inhibiting the rat kidney and brain enzymes. This coumestan
152
inhibited the Na+, K+-ATPase by oxidation of essential
sulfydryl groups of the enzyme, as it decreased the number
of free sulfydryls and its effect was blocked by the
antioxidant dithiothreitol. Such mechanism of action was
here discarded since the antioxidant dithiothreitol did not
block the inhibitory effect of ivermectin (data not shown).
We can also discard the possibility of a vanadate-like effect
since in this case the inhibition of Na+, K+-ATPase is increased
when the incubation medium (low Na+/high K+/high Mg2+)
favors the “E2” conformation (Poças et al. 2003). On the
other hand, although only speculative, we cannot discard the
hypothesis of an inhibitory effect through nonspecific
interaction with plasma membrane phospholipids, as reported
for epigallocatechin-3-gallate, an agent that is equally potent
for inhibiting the three P-type ATPases considered in our
experiments (Ochiai et al. 2009), as ivermectin did.
As it is well known that the H+, K+-ATPase is also a P-type
ATPase and has a great homology (65%) with the Na+,
K+-ATPase (Sachs et al. 2000; Yatime et al. 2009), we also
extended our investigation by studying the effect of ivermectin
on the H+, K+-ATPase activity of a rat stomach preparation.
Although we had some technical limitations due to the low
specific activity of the preparation, our results clearly indicate
that ivermectin also inhibits this P-type ATPase in the
same range of concentrations that inhibits SERCA and Na+,
K+-ATPase, further indicating that ivermectin has a mechanism
of action different from the cardiac glycosides that inhibit
selectively the Na+, K+-ATPase.
As a conclusion, these series of experiments indicate that
ivermectin is a nonselective inhibitor of three important
mammalian P-type ATPases. As a final consideration, we
propose that the newly discovered effects of ivermectin reported
here are probably indicative of putative important adverse
effects if this drug were used in such high doses reported to be
active in vitro against L. amazonensis for instance, although
a final conclusion should be based on in vivo animal studies
and clinical studies. As a consequence, we propose that novel
analogs of ivermectin should be developed and tested both
for their parasitic activity and in vitro effects on P-type
ATPases since they are indicative of serious adverse effects.
Acknowledgments Financial support was provided by Fundação
Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de
Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), Brazil. F. Noël and PHC Pimenta
were fellows of CNPq.
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