Theriogenology 85 (2016) 555566

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Theriogenology
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Review

Aglepristone: A review on its clinical use in animals

Anne Gogny a, *, Francis Fini b
a
Small Animal Reproduction Unit, University Veterinary Hospital, Nantes-Atlantic National College of Veterinary Medicine, Food
Science and Engineering-Oniris, Nantes, France
b
Laboratory of Biotechnology and Pathology of Reproduction, Nantes-Atlantic National College of Veterinary Medicine, Food Science
and Engineering-Oniris, Nantes, France

a r t i c l e i n f o a b s t r a c t

Article history: Aglepristone (RU 46534) is a competitive progesterone antagonist that is indicated for the
Received 9 July 2015 treatment of various progesterone-dependent physiological or pathologic conditions. Agle-
Received in revised form 6 October 2015 pristone has proven to be an effective means of terminating pregnancy in most species. When
Accepted 7 October 2015
used to induce parturition, aglepristone was effective in all cases in the bitch, cow, and goat,
with no apparent adverse effects on neonatal health or milk production. When used to
Keywords:
schedule an elective cesarean section, aglepristone treatment was deemed safe for dams and
Aglepristone
puppies, providing that the ovulation date had been accurately assessed at the time of
Progesterone antagonist
Pregnancy termination breeding. Irrespective of the stage of pregnancy at injection, treatment with aglepristone has
Pyometra no apparent negative effects on subsequent fertility. Aglepristone is also a safe and relatively
Mammary broadenomatosis effective means of treating pyometra. However, given the high level of septic risk and the
likelihood of rapid deterioration, such therapy is not recommended in emergency situations.
Treatment of feline broadenomatosis using aglepristone has given promising results, but
repeat treatment may be necessary in cats previously treated with long-acting progestagens.
The use of aglepristone in other progesterone-dependent diseases has yet to be fully evaluated
but may prove valuable, especially in the treatment of insulin-resistant diabetes mellitus,
acromegaly, and the treatment of some vaginal tumors in the bitch.
2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction This article reviews the clinical use of aglepristone in

Aglepristone (RU 46534) is a competitive progesterone
antagonist; it binds to progesterone receptors (PRs)
without inducing the molecular cascade associated with
progesterone. Its afnity to PRs is higher than progesterone
(3.12, 3.8, and 9.26 times greater in the bitch, doe rabbit,
and queen, respectively) [1]. Aglepristone can therefore be
used in various progesterone-dependent physiological or
pathologic conditions, with the aim of blocking the action
of progesterone.
domestic animals.
2. Clinical use of aglepristone during pregnancy
Progesterone plays a critical role in the establishment
and maintenance of pregnancy. Thus, progesterone antag-
onists have been considered in the termination of preg-
nancy or to induce parturition.
2.1. In the bitch

In the bitch, pregnancy termination may be deemed

* Corresponding author. Tel.: 33 (0)2 40 68 77 13; fax: 33 (0)2 40 68 necessary in the event of accidental mating or for thera-
77 48. peutic reasons, at various stages of gestation. According to
E-mail address: anne.gogny@oniris-nantes.fr (A. Gogny). the data sheet, aglepristone can be used to terminate

0093-691X/ 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.theriogenology.2015.10.010
556 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
Fig. 1. Recommended protocol for the management of termination of pregnancy with aglepristone.
pregnancy from Day 0 to Day 45 after mating in the bitch.
The recommended protocol is two subcutaneous (SC) in-
jections of 10 mg/kg of body weight 24 hours apart (Fig.1). In
this species, pregnancy termination results from prevention
of implantation before Days 22 to 24 after mating, from
embryonic resorption from Day 25 to Days 30 to 35, and
from expulsion of ossied fetuses after Days 30 to 35 [2].
2.1.1. Early-stage pregnancy termination
Within 25 days of ovulation, aglepristone used at rec-
ommended doses prevents implantation in nearly 100% of
bitches (n 268, all studies combined) [38]. When used
below the recommended dose, the efcacy of aglepristone
remains high, with 91.6% and 100% pregnancy prevention
in bitches treated with two doses of 5 mg and 7.5 mg,
respectively, injected SC 24 hours apart (n 24) [8].
When performed after implantation and before Days 30
to 35, aglepristone treatment results in embryonic resorp-
tion [4,5,7,911]. Induced embryonic deaths are asynchro-
nous, ranging from 1 to 7 per day [9]. The total duration of
pregnancy termination may be lengthy: after aglepristone
injections on Days 24 and 25 after ovulation, the rst em-
bryonic death was observed 2 to 4 days after the rst in-
jection and termination was completed at 15 to 17 days [9].
During the early stages of pregnancy, adverse effects of
the treatment are usually limited to local pain or itching at
the injection site [4,5,7,11]. However, mucoid vulvar
discharge (6 of 6 [9], 7 of 35 [4], and 18 of 93 bitches [7]), slight
depression, and transient anorexia (26 of 93 bitches [7]) or
conversely increased appetite (2 of 93 bitches [7]) were re-
ported within 2 weeks of the rst injection of aglepristone in
some bitches [4,7,9]. Other adverse effects are uncommon at
this stage of pregnancy, although 5.7% of bitches developed
endometritis (5 of 88 bitches) after treatment [4].
Treatment failure is rare but still possible (1 of 93
bitches [7] and 1 of 36 bitches [8]). Therefore,
ultrasonographic control, performed at least 20 days after
ovulation, is recommended to assess treatment outcome
[2,4,68]. In case of failure, a repeat treatment is often
successful [6].
Long-term surveys conducted in a large number of
bitches (n 148 in all combined studies) revealed no
negative consequences for subsequent fertility [4,7,8].
Pregnancy rate was 90% at rst estrus after treatment [8].
However, when the treatment was performed within
the rst 10 days of the luteal phase, the interestrus interval
was reduced by 13 to 15 days [8].
2.1.2. Midterm pregnancy termination
When performed 25 to 45 days after ovulation (i.e., after
pregnancy diagnosis), aglepristone terminates pregnancy
in around 95% of cases (n 228 bitches in all combined
studies) [36,11,12]. Embryonic or fetal death usually be-
gins within 1 day and is completed within 4 to 7 days
(range: 3.614 days) of the rst injection (14 of 15 [3], 66 of
69 [4], 5 of 5 [5], 117 of 124 [6], 21 of 22 [11], 6 of 6 [12], 5 of
5 [13], and 7 of 7 [14] pregnancies). The more advanced is
the pregnancy, the faster is the termination [4].
At this stage, pregnancy termination is usually associated
with several clinical signs. A brown hemorrhagic vaginal
discharge (17 of 22 [11] and 22 of 69 [4] bitches), with oc-
casional fetal parts, is the main reported symptom [4,11].
This vaginal discharge usually starts within 2 days of treat-
ment and lasts 1 to 2 weeks [4,11]. Signs of parturition
including panting, shivering, hyperactivity, and nesting
behavior may be observed as well (9 of 22 [11] and 17 of 69
[4] bitches) [4,11]. They begin 1 to 2 days after treatment and
generally last 1 to 2 days, although they may continue for as
long as 7 days [4,11]. Anorexia and/or depression (8 of 22 [11]
and 14 of 69 [4] bitches) possibly leading to dramatic weight
loss (1 of 22 bitches [11]), gastrointestinal disturbances (9 of
69 bitches [4]), and polydipsia (1 of 22 bitches [11]) may be
 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
observed within 2 weeks after treatment [4,11]. Mammary
gland congestion may also be noticed [6]. In addition, rectal
temperature is reduced by about 1.5  C within 24 hours of
the start of the medication (n 14 bitches) [3].
In the days after pregnancy termination, short-term
adverse effects of the treatment are uncommon. Endome-
tritis requiring additional treatment (metergoline or clo-
prostenol) was diagnosed in a small number of bitches, all
of whom recovered uneventfully [4]. Cystic endometrial
hyperplasia was also identied 4 weeks after treatment in a
5-year-old bitch, without subsequent complications [12].
Treatment failures are possible, with partial abortion
resulting in the subsequent birth of viable puppies (2 of 69
bitches) [4]. Ultrasonographic control with repeat treat-
ment, where necessary, is therefore recommended about
10 days after the start of the medication. This second
treatment should also be monitored; one case of fetal
retention and mummication has been reported after
repeat treatment. In the latter case, ovariohysterectomy
revealed delayed involution of placental sites [15]. This
underlines the importance of close monitoring of treated
females, despite the generally good results of the
treatment.
None of the protocols tested with the aim of increasing
the success rate of aglepristone treatment during midg-
estation resulted in any signicant improvement
[13,14,16,17]. A combination of cabergoline and aglepri-
stone reduced the duration of abortion, but these results
were not conrmed in a second study using a combination
of aglepristone with cabergoline and misoprostol [13,16].
Similarly, a combination of aglepristone and misoprostol
reduced the time needed for completion of abortion,
although the difference with aglepristone treatment alone
was not signicant and these results were not conrmed in
another study using an identical protocol [16,17]. Likewise,
aglepristonecloprostenol or aglepristonecabergoline
misoprostol combinations did not reduce the time to the
Table 1
Induction of parturition with aglepristone in the bitch: time span before the rst pup expulsion, mean fetal expulsion length, and mean interpup interval (in
hours).
Protocol for induction of parturition Number of
treated bitches
Aglepristone (15 mg/kg SC) at Days 58 and 5 32.6  3.7
59 (Day 0: ovulation) alfaprostol
(0.08 mg/kg SC) every 2 h from Day 59
until the end of delivering
Aglepristone (15 mg/kg SC) at Days 58 and 5 31.6  3.6
59 (Day 0: ovulation) oxytocin (0.15
IU/kg SC) every 2 h from Day 59 until
the end of delivering
Aglepristone (15 mg/kg SC) twice at 9-h 6 41.0  3.7 (range: 3256 h)
interval on Day 58 (Day 0: mating)
oxytocin (2 IU/kg SC) only in case of
delayed fetal expulsion
Aglepristone (15 mg/kg SC) on Days 60 and 22
61 (Day 0: LH surge) oxytocin (0.15
IU/kg SC) every hour from Day 61 until
the end of delivering
Aglepristone (15 mg/kg SC) between Days 7 25.9  3.29 (range: 2130 h)
59 and 61 (Day 0: ovulation) oxytocin
(0.15 IU/kg SC) 24 h later, every 2 h until
the end of delivering
Abbreviation: SC, subcutaneous.
557
start of abortion or the duration of fetal expulsion in bitches
treated during midpregnancy [14,16].
Long-term follow-up, over several years after treatment,
did not reveal any negative adverse effects of aglepristone
treatment on subsequent estrous cycles, fertility, or the
genital tract [4,11,12,18]. However, as observed after early-
stage pregnancy termination, in some bitches (2 of 22
[11], 6 of 6 [12], and 5 of 5 [5] bitches), the rst interestrus
interval after pregnancy termination was shortened by 1 to
4 months [4,5,11,12].
2.1.3. Induction of parturition
Induction of parturition may be considered for conve-
nience or medical reasons. However, in the bitch, an ac-
curate assessment of the expected date of birth is essential
before initiating treatment to avoid prematurity [19].
Used near term, aglepristone induces effective labor in
100% of bitches [2023] (Table 1).
In the majority of published studies, expulsion phase
length and interpup interval were comparable to those of
spontaneous parturitions [21,22]. However, Fontbonne
et al. [23] reported conicting results regarding the
interpup interval, which was longer in induced parturition
than in spontaneous whelping. Although no clear expla-
nation supported this observation, large and giant breeds
seemed to be slower to respond to treatment, with a longer
expulsion phase length due to prolonged interpup intervals
[23].
Although the studies are hardly comparable, the com-
bination of uterokinetics with aglepristone seems to reduce
the delay to the expulsion of the rst pup [20,22,23].
Similarly, a combination of aglepristone and oxytocin
shortened the interpup interval compared to treatment
with aglepristone alone [2022]. However, this observation
could not be reproduced in a study conducted on a small
number of bitches from different breeds [23]. Administra-
tion of oxytocin every hour versus every 2 hours did not
Time between rst injection Mean fetal expulsion Mean interpup Reference
and rst pup expulsion (h) length (h) interval (h)
9.1  2 1.7  0.5 [20]
4.5  1.8 0.8  0.2 [20]
10.6  2.2 1.7  0.3 [21]
29.7  5.6 (range: 1540.5 h) 5.9  1.9 1.1  0.4 [22]
9.6  5.4 1.92  1.38 [23]
(range: 3.717.5 h)
558 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
affect the pattern of the induced parturition or improve
delivery time [20,22].
Litter size was similar in treated bitches and in spon-
taneous whelping bitches, as well as the survival rates at
birth and 48 hours after birth [2123]. However, a case of
fetal prematurity was reported in a Yorkshire terrier, in
which parturition had been induced at Day 59 after
ovulation, highlighting the need for accurate determination
of the parturition date before medical induction [23].
Surprisingly, despite the reduced gestation length in
treated dams, the birth weight of the puppies was similar to
litters born at term [21,23]. The mean growth rate of the
puppies during the rst month of life was not different to
spontaneously born puppies, suggesting that aglepristone
does not interfere with lactation [21,23]. The effects of
aglepristone-induced parturition on subsequent cycle
length and fertility have yet to be assessed.
2.1.4. Scheduling an elective cesarean section
When performed as an emergency, C-section is associ-
ated with lower newborn survival rates than scheduled
hysterotomy [24]. However, the scheduled C-section is
risky in the dog because of the high risk of prematurity in
this species. Thus, Levy et al. [25] hypothesized that agle-
pristone, by inducing the initiation of parturition, might
limit the risks associated with prematurity in newborn
puppies at the time of the C-section.
Aglepristone (15 mg/kg SC) injected on Day 59 or 60
after ovulation followed 20 to 24 hours later by a planned
C-section resulted in the birth of 188 vigorous mature
puppies (n 37 bitches). After 2 weeks, the survival rate of
the puppies was 97.4%. No postoperative complications
were reported in the dams; 89.1% had a normal lactation,
but the remaining 9.9% had no milk secretion for the rst
24 hours after surgery [25]. The exact gestation length
beyond which puppies can be considered as mature is not
clearly dened in the dog. This study did not have a control
group; thus, aglepristone cannot be credited with
enhancing the outcome of the C-section. However, this
single study indicates that a C-section performed 1 to
2 days before the due date, after aglepristone treatment, is
safe for dams and puppies, provided that the ovulation date
had been accurately determined at the time of mating.
2.2. In the queen
Aglepristone is not licensed for use in the cat. However,
this drug has been evaluated off-label for feline pregnancy
termination at various stages of gestation [2632]. In this
species, termination of pregnancy results from preventing
implantation before Day 13 after mating, embryonic
resorption from Days 13 to 28, and expulsion of ossied
fetuses after Day 28.
2.2.1. Early-stage pregnancy termination
Outdoor cats run a high risk of unwanted pregnancy.
Aglepristone can prevent implantation when administered
as early as 5 days after mismating. In the only study con-
ducted at this stage of pregnancy, treatment was successful
in 100% of cases (n 11) after two injections of 10 mg/kg of
aglepristone on Days 5 and 6 after mating [26] (Fig. 1).
The treatment was well tolerated; the only adverse ef-
fect observed was scratching at the injection site in 2 of 11
cats. Subsequent long-term fertility was not impaired, as all
the treated queens conceived during one of the four es-
truses after treatment, with similar pregnancy rates in the
treatment and control groups [26].
The mean interestrus interval after treatment was
18.5  5.2 days after the rst injection of aglepristone, but
64% of the queens came into estrus 5 to 8 days after the
start of the medication. As in the dog, this could be linked to
a shortened interestrus interval [26].
2.2.2. Midterm and late-term pregnancy termination
When performed after Day 21 after mating, aglepristone
(1015 mg/kg SC 24 hours apart) induced termination of
pregnancy with a rate of success ranging from 66.7% to
100% of the queens (Fig. 1) [2830,32,33].
On Days 21 to 22 of gestation, conrmed by ultrasound,
aglepristone treatment (10 mg/kg SC 24 hours apart)
resulted in pregnancy termination in 100% of treated
queens (n 6) [29]. On Days 25 to 26 after mating, an
identical protocol resulted in abortion in 87% of the females
(n 23) [30]. When the same protocol was applied be-
tween Days 35 and 38 of pregnancy, the success rate was
100% (n 6) [29].
A higher dose of aglepristone does not seem to alter the
outcome of treatment; in 61 pregnant queens treated with
15 mg/kg SC 24 hours apart at midgestation (33.3 
4.2 days after mating), the termination rate was 88.5% [28].
Similarly, in 30 queens treated at various stages of preg-
nancy (31.37  8.23 days, range: Days 2150) with agle-
pristone (15 mg/kg SC 24 hours apart), pregnancy
termination occurred in 90% of the cases [33].
Compared to midterm aglepristone administration, late-
term treatment seems to be less efcient. When aglepri-
stone was injected (10 mg/kg SC 24 hours apart) to pregnant
queens on Days 45 and 46 after mating, pregnancy termi-
nation occurred in 66.7% of cases (n 6) [32]. The authors
suggested that this lower success rate might be related to
the specic physiology of pregnancy in the queen: a luteo-
tropic action of prolactin or placental progesterone pro-
duction might interfere with the action of aglepristone
during late pregnancy [32]. Conversely, Fini et al. [33]
recorded a higher success rate (90%) for all combined
stages of pregnancy in a study conducted in 30 queens
treated between Days 21 and 50, although the exact timing
of treatment in each queen and the corresponding results
are lacking. Further studies are therefore needed to draw a
denitive conclusion regarding the efcacy of aglepristone
in late-term pregnancy termination in the queen.
Clinical signs associated with pregnancy termination
were mainly brown vulvar discharge; hemorrhagic or pu-
rulent discharge was also observed immediately before or
during abortion [28,30,32,33]. The interval from the rst
injection to observation of vulvar discharge was a few days
(Days 2122 of pregnancy: 3.6  0.9 days [29]; Days 2526
after mating: 5  1 days [30]; Days 3538 of pregnancy:
3.1  0.7 days [29]). Vulvar discharge usually lasted a few
days (range: 16 days) [29,32]. For most of the females,
vulvar discharge resolved spontaneously within 15 days
with no sequelae [28].
 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
Transient depression and anorexia were observed in a
small number of queens (9.3% of 61 queens) immediately
before fetal expulsion [28].
Ultrasound examination revealed that gestational sac
diameters and fetal measurements (crownrump length,
biparietal diameter, and thoracic diameter) ceased to in-
crease within 24 hours of the start of the treatment [29].
Increased fetal movements were detected in several dams
24 hours before fetal expulsion [30,32]. At the time of
abortion, ultrasound revealed both live and dead fetuses in
the uterine horns of some cats, suggesting that the process
of placental detachment occurs suddenly [30]. Uterine
contractions were observed during abortion. Focal zones of
uid accumulation were observed in the uterus of some
cases [30]. Compared to nontreated pregnant queens,
placental sites remained enlarged and uid lled for 1 day
after abortion [32].
Fetal expulsion generally occurs within 10 days of the
rst injection of aglepristone. In 95% of the queens (i.e., 19/
20 of 23 treated queens) that aborted after injections of
aglepristone performed on Days 25 to 26 after mating, fetal
expulsion occurred within 5 to 9 days of the rst injection
[30]. In all the queens treated around Day 33 (33.3 
4.2 days) after mating, pregnancy termination was com-
plete within 8 days. In half of them, fetal expulsion was
complete within 3 days of treatment [28]. Similarly, when
aglepristone treatment (10 mg/kg SC on two consecutive
days) began between Days 35 and 38 of pregnancy, preg-
nancy termination occurred 4.4  4.6 days after the rst
injection [29]. In queens treated between Days 21 and 50,
fetal expulsion occurred within 5 days on average [33].
When aglepristone was injected on Days 45 and 46 after
mating (late term), abortion was completed 5.8  1.3 days
after the rst injection [32].
The duration of abortion dened as expulsion of all fe-
tuses is short. When aglepristone was injected on Days 25 to
26 after mating, abortion lasted less than 2 days, with most
queens aborting in 24 hours [30]. Fetuses may be expelled
within intact fetal membranes [30]. In a few cases, aborted
fetuses were eaten by the dams, hindering the clinical
monitoring of the abortion process [32]. This highlights the
importance of ultrasonographic monitoring of pregnancy
termination to differentiate treatment failures from con-
sumption of the expelled products by the female.
A histologic study conducted in the queen found that
treatment with aglepristone leads to massive damage of
maternal venules, resulting in blood extravasation into the
endometrial and cervical interstitium and uterine lumen.
This process leads to uteroplacental detachment and would
also explain the hemorrhagic vaginal discharge observed in
queens after abortion [31]. This was not reported in bitches
treated with a similar protocol, suggesting that aglepristone
has a different mechanism of action in the two species [10].
Mild anemia and leukocytosis were present in queens
treated on Days 45 to 46 after mating [32]. As suggested by
the authors of the study, this could be linked to local
inammation resulting from the abortion process or to
stress related to fetal expulsion [32]. However, aglepristone
might limit pregnancy-induced late-term anemia; the
packed-cell volume, hemoglobin, and hematocrit were
signicantly higher in queens treated on Days 45 to 46 after
559
mating than in nontreated queens [32]. This effect might
result from the termination of pregnancy itself: the abor-
tion would end the processes involved in late-term gesta-
tional modications [34].
Treatment failure may occur and be partial or complete.
The remaining fetuses may stay alive or die. Therefore,
treatment failure may result in the subsequent birth of
normal viable kittens or fetal maceration [30]. In the latter
case, macerated fetal parts may be expelled over the
following days, but fetal maceration without expulsion or
vaginal discharge has also been described [30].
Moreover, aglepristone might interfere with maternal
behavior; one study reported a case of cannibalism in a
queen after the birth of two viable kittens at Day 67 after a
treatment performed at Days 45 and 46 after mating [32].
Careful monitoring of the abortion is therefore essential.
Treatment failure can be identied on ultrasound around
10 days after aglepristone injection. In such cases, repeat
treatment was reported to be effective (n 2 queens) [28].
Pregnancy termination with aglepristone is considered
safe for the females. Adverse effects are mild or nonex-
istent, with the exception of pain on injection or a
moderate local reaction, which affected less than 10% of
the females [29,30,33].
When the treatment was administered on Days 45 and
46 of pregnancy, mammary enlargement and lactation
were observed 2 to 5 days after the rst injection of agle-
pristone (5 of 6 queens) [32]. Although prolactin concen-
trations were not evaluated in this study, mammary
hypertrophy and milk secretion were attributed to the
hormonal status of the females at this stage of pregnancy
and were deemed to be consistent with late term [32].
Although retention of fetal membranes was reported in
4 out of 61 queens treated at midpregnancy, uterine
adverse effects of aglepristone are generally moderate and
resolve spontaneously in most cases [28]. However, endo-
metritis was described in two cats that had aborted after
aglepristone treatment [35].
Aglepristone seems to have limited consequences on
subsequent fertility. The treatment does not seem to alter
the estrous cycle. Estrus occurred normally after preg-
nancy termination [28,32]. The interestrus interval
ranged from 40 to 77 days [28,32]. Contrary to early
pregnancy termination, shortening of the interestrus in-
terval was not reported in cats treated in the second half
of pregnancy [27,29,32].
There was no negative impact on subsequent fertility of
treated queens, with a conception rate of 77% at the rst
cycle (47 of 61 females) and a further 10% (6 of 61 females)
identied as pregnant at the second estrus after pregnancy
termination [28]. In another study, all of the queens became
pregnant after treatment (n 6) [32]. There were no re-
ported differences in litter size or kitten viability [28,32].
2.3. In lagomorphs and rodents
2.3.1. In rabbits
In the doe rabbit, pregnancy usually lasts between 30
and 32 days. Blastocyst implantation occurs on Day 7 after
mating [36]. Aglepristone can be used successfully as an
abortifacient in this species [3739].
560 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
Aglepristone (10 mg/kg SC) injected 24 hours apart on
Days 6 and 7 after mating prevented implantation in 100%
of does (n 13) [38]. In the uterus, implantation sites began
to regress from Day 9 and were no longer detectable on Day
11 after mating. Vaginal bleeding and discharge were ab-
sent, and body temperature remained unchanged. No other
adverse effects were observed in the treated females [38].
Subsequent fertility was unaffected, with 5 of 5 does
becoming pregnant. However, the females expressed
irregular mating behavior for 17.8 days (range: 1521 days).
These females subsequently whelped normally, delivering
live kittens [38].
Injected on Days 15 and 16 after mating and after ul-
trasonographic diagnosis of gestation, aglepristone (10 mg/
kg SC 24 hours apart) terminated pregnancy in 100% of
females (n 10) [37,39].
At midpregnancy, pregnancy termination resulted in
fetal expulsion. Vaginal bleeding and discharge were
recorded in all does, starting 32.4  5.6 hours after the
initial injection (range: 19 hours to 3 days) [37,39]. The time
lapse between the rst vaginal discharge and the end of
fetal expulsion was reported to be 70.2  12 hours (range:
21130 hours) [36]. The mean interval between the
expulsion of the rst and last fetus expulsion was 1.3 days
(range: 15 days) [36]. Fetal expulsion was complete within
3  0.7 days (range: 24 days) [39].
Twice-daily ultrasound monitoring during the abortion
revealed decreasing fetal uid on consecutive examina-
tions [39]. Fetal heartbeats were detected throughout the
process [39]. Fetuses were expelled with or separately from
their fetal membranes [39].
After the initial injection and for at least 17 days, the
appetite of treated does was reduced compared to the
control group [37]. Another study reported diarrhea but no
loss of appetite [39]. Some of the does exhibited maternal
behavior during the abortion, and none showed canni-
balism [39]. No difference in body temperature was re-
ported between treated and control females [37,39].
Hematologic parameters were comparable in the treatment
and control groups, with the exception of neutrophil
counts, which were increased in treated does on Days 19,
21, and 23 after treatment, although within the reference
ranges [39]. The white blood count also tended to increase,
but the difference was not signicant [39].
Midterm pregnancy termination with aglepristone did
not alter subsequent fertility, with 80% of the does (8 of 10
does) becoming pregnant, whelping normally, and deliv-
ering live kittens [37]. However, as with early termination,
mating behavior was irregular for 52.3  2 days (range: 46
63 days) after the rst injection of aglepristone [37]. This
resulted in a relatively long period before pregnancy.
Aglepristone can be used to prevent implantation and
induce abortion in the rabbit. This treatment appears to be
safe and reliable for this indication. However, although
treatment failure has yet to be reported, ultrasonographic
monitoring is recommended in this species as for dogs and
cats.
2.3.2. In rats
Although there are few published reports in this spe-
cies, aglepristone is an effective means of terminating
midterm pregnancy in rats [40,41]. When aglepristone
was injected (10 mg/kg SC 24 hours apart) on Days 11 and
12 after mating (i.e., at midpregnancy), pregnancy termi-
nation was recorded in 100% of females [40,41]. A bloody
vulvar discharge was seen around 24 hours after the rst
injection of aglepristone (24.7  3.8 hours [40] and 24.2 
3.3 hours [41]). Vaginal discharge continued for around
2 days (47  5.7 hours [40] and 51.3  8.6 hours [41]).
Abortion was accompanied by reduced appetite, resulting
in a lower body weight in treated females compared to
controls, from Day 16 to the end of the experiment on Day
20 [40].
Long-term fertility was not impaired, with all the rats
becoming pregnant. There were no reported differences in
gestation length, litter size, litter weight, fetal weight, and
percentage of live fetuses between the treatment and
control groups. However, subsequent pregnancy was
delayed in aglepristone-treated females when introduced
to male rats 4 days after pregnancy termination (23.7  6.6
vs. 12.5  2.7 days in the control group) [41]. As with rab-
bits, this delay was linked to a prolonged period of reduced
sexual receptivity in treated females [37,41]. These behav-
ioral changes were not observed at subsequent pregnancies
in these same rats, suggesting a direct connection with
aglepristone treatment.
2.4. In ruminants
In the goat, aglepristone has been used to induce
parturition. Injected SC once at Day 145 of pregnancy, the
treatment was successful in 100% of the cases (n 48) [42].
Several doses ranging from 1.5 to 5 mg/kg were tested, and
all demonstrated the same efcacy. Parturition occurred
within 30 to 32 hours of the initial injection at dose rates
higher than 1.5 mg/kg. At 1.5 mg/kg, parturition occurred
signicantly later (46.8  3.5 hours). This suggests that
lower doses of aglepristone are as effective as standard
doses. A single injection appears sufcient for induction of
parturition.
The incidence of dystocia, retained fetal membranes,
and neonatal mortality were similar to the control group
[42]. All kids were alive at birth.
In cattle, aglepristone has been used for pregnancy
termination and induction of parturition.
For pregnancy termination, aglepristone (5 mg/kg SC
once at Day 47 of gestation or twice at Days 47 and 48 of
gestation) induced fetal death in all heifers (n 5) [43]. In
this study, aglepristone was used to create a model of fetal
death, with the aim of nding possible diagnostic methods
for predicting pregnancy loss after the use of articial
reproduction techniques, such as in vitro embryo produc-
tion and cloning. Fetal death occurred on average 58 hours
(range: 4880 hours) after the rst injection of aglepri-
stone. In accordance with reports in other species, in which
pregnancy termination appears to be a sudden event, fetal
bradycardia was recorded only 8 hours before the diagnosis
of fetal death. Fetal death was preceded by a visible
reduction in the volume of allantoic uid and by separation
of the allantochorionic membrane from the endometrium.
The level of uterine tone increased between the initial in-
jection of aglepristone and fetal death, likely reecting
 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
myometrial contractions. As in other species, fetal expul-
sion was accompanied by vaginal discharge [43].
To induce parturition, aglepristone was administered
(5 mg/kg SC) at Days 270 and 271 of pregnancy [44]. The
treatment resulted in the expulsion of live calves within
48.5  7.3 hours of the initial injection.
However, dystocia due to insufcient myometrial activ-
ity, retained fetal membranes, and impaired neonatal vi-
tality were recorded in all cases (n 3) [44]. These effects
might be linked to early calving, although they were not
observed in goats treated with a similar protocol [42].
Despite the low number of animals treated with this pro-
tocol and hence unreliable conclusions, these complications
should be considered before clinical use. Furthermore, large
volumes are required making the treatment expensive;
aglepristone treatment is therefore unsuitable for preg-
nancy induction in cattle in routine practice.
3. Clinical use of aglepristone for the treatment of
progesterone-dependent diseases
In domestic species, aglepristone is routinely used for
the treatment of pyometra and feline mammary broade-
nomatous hyperplasia, both of which are progesterone
dependent. There are also anecdotal reports of its use for
other indications in the bitch.
3.1. Conservative treatment of pyometra
Pyometra is a life-threatening disease, dened as the
accumulation of pus within the uterus. It is described in
numerous domestic species [4548].
Pyometra is linked to hormonal imbalance or an
abnormal response to estrogens and progesterone or de-
rivatives of progesterone, and it is mainly identied during
the luteal phase [45,49,50]. In most species, ovariohyster-
ectomy combined with appropriate intensive care is the
reference treatment for pyometra. However, removal of the
genital tract is not desirable in breeding females, and
anesthesia is sometimes formally contraindicated because
of concurrent chronic disease. A conservative treatment,
whose aim is to promote uterine emptying, is a viable
alternative in such cases, according that the condition of
the female is not critical: these treatments need several
hours or days before being efcient and should therefore be
restricted to stable animals only. Thus, conservative treat-
ment is not recommended in life-threatening situations
needing emergency procedures, such as peritonitis due to
uterine rupture, serious renal insufciency, or severe elec-
trolytes/acidbase imbalance.
Moreover, additional therapeutic measures (anti-
biotherapy, uid therapy, correction of digestive troubles,
and so forth) have to be implemented according to the
condition of the female [51].
Therapeutic protocols based on aglepristone, alone or
combined with cloprostenol, a PGF2a analogue, have been
described in various species. In parallel, an in vitro study
conducted on canine myometrial bers reported promising
results with a combination of aglepristone and oxytocin;
however, these results have yet to be conrmed clinically
[52]. Aglepristone treatment is intended to block the effects
561
of progesterone and, in cases of closed-cervix pyometra, to
promote cervical relaxation and opening. The addition of
prostaglandins is intended to induce uterine contractions
and promote uterine emptying.
3.1.1. In bitches
When used alone, aglepristone (10 mg/kg SC) injected
24 hours apart, followed by weekly injections at the same
dose until complete recovery, absence of vaginal discharge,
and absence of uterine lumen enlargement on ultrasound,
is effective with a success rate of 46% to 100% [5356]
(Table 2). A protocol using aglepristone at Days 1, 3, 6,
and 9 (Day 1: day of diagnosis) without subsequent in-
jections showed a success rate of 100% [62]. When agle-
pristone was combined with cloprostenol, the treatment
was successful in 84.4% to 100% of cases [53,55,58]. When
aglepristone was combined with intrauterine antibiotics,
the success rate was reported to be 81% [54].
With all protocols, vaginal discharge occurred (closed-
cervix pyometra) or increased (open-cervix pyometra)
within 4 to 38 hours of the rst injection [53,54,57,60,62].
In cases of closed-cervix pyometra, the treatment induced
cervical relaxation in all dogs [53]. However, one study
described delayed cervix opening, beginning 38 
6.92 hours after the rst injection (n 12) [59].
The physical condition of the animal usually improved
after uterine emptying [53,5557,62]. Ultrasonography
revealed reduced uterine lumen diameter from the seventh
day after the rst injection [53,57,58,62]. Complete recov-
ery was recorded within 14 to 90 days [5362].
Recurrence of pyometra is common within 24 months of
treatment [53,56,58,6062]. However, a modied protocol,
using aglepristone at Days 0, 2, 5, and 8 (Day 0: day of
diagnosis) was not associated with any relapses within
24 months of treatment, suggesting a higher long-term
efcacy [62].
Bitches under 5 years of age carry a lower risk of relapse,
as reported by Jurka et al. [60] (n 24 bitches, followed up
to 54 months after treatment) and Ros et al. [61] (n 28
bitches, followed up to 6 years after treatment). Conversely,
older bitches showed a relapse rate of 85% [60,61]. The
presence of ovarian cysts and cystic endometrial hyper-
plasia tended to increase the recurrence rate, although
these observations were not reported in all studies [60,61].
Medical treatment of pyometra does not appear to affect
subsequent fertility. Several long-term follow-ups reported
pregnancy rates of 69% to 85%, followed by the whelping of
normal litters [61,62]. Most of the bitches become pregnant
as soon as the rst estrus after aglepristone administration
[53,5658,61,62]. However, age seems to inuence the suc-
cess of mating after medical treatment of pyometra, preg-
nancy rates being higher in bitches under 5 years of age [60].
As observed with other indications of aglepristone in
the bitch, aglepristone tends to inuence the interestrus
interval: shortening was observed in 19% to 43% of bitches
[56,60,62], whereas 20% of cases had prolonged interestrus
intervals [56].
3.1.2. In queens
Subcutaneous injections of aglepristone (10 mg/kg SC)
can be used to treat pyometra in queens. The success rate,
 562
Table 2
Medical treatment of pyometra in the bitch: results of various protocols based on aglepristone.

Protocol Number of treated bitches Success rate, Time for recovery Recurrence of pyometra (number of Fertility after treatment (number Reference
n/N (%) (days) bitches followed after treatment) of bitches mated after treatment)
Aglepristone 5 or 6 mg/kg SC on Day 7 (2 With open-cervix pyometra 7/7 (100) 828 0% (n 4) Whelping rate: 100% (n 2) [57]
1, then 3 mg/kg SC on Days 2, 3, 4, and 5 with closed-cervix
8, 12, and 16 pyometra)
Aglepristone 10 mg/kg SC on Days 1, 8 8/8 (100) 1529 20% (n 15) (All recurrences in Pregnancy rate: 100% (n 1 bitch [58]
3, and 8  15 cloprostenol 1 bitches aged >7 y) aged 2 y)
mg/kg at Days 3 and 8
Aglepristone 10 mg/kg SC on Days 1, 7 7/7 (100) 1529 [58]
3, and 8  15 cloprostenol 1
mg/kg at Days 3, 5, 8, 10, 12  15
Aglepristone 10 mg/kg SC on Days 1, 52 48/52 (92.3) Within 21 days 18.9% (n 37) Whelping rate: 83.4% (n 6) [56]
2, and 7
Aglepristone 10 mg/kg SC on Days 1, 13 (7 With open-cervix pyometra 6/13 (46.1) Within 15 days No case reported in the study 2 Pregnant bitches (n unknown) [54]

A. Gogny, F. Fini / Theriogenology 85 (2016) 555566

2, 7, and 14 and 6 with closed-cervix
pyometra)
Aglepristone 10 mg/kg SC on Days 1, 11 (6 With open-cervix pyometra 9/11 (81.8) within 15 days 3 Pregnant bitches (n unknown) [54]
2, 7, and 14 intrauterine and 5 with closed-cervix
antibiotic based on the pyometra)
antibiogram results on Days 1, 2,
4, 6, and 8
Aglepristone 10 mg/kg SC on Days 1, 20 12/20 (60) 1490 19% (n 21) Pregnancy rate: 80% (n 5) [53]
2, and 8  14  28
Aglepristone 10 mg/kg SC on Days 1, 32 27/32 (84.4) 1490
2, and 8  14  28 cloprostenol
1 mg/kg at Days 3, 4, 5, 6, and 7
Aglepristone 10 mg/kg SC on Days 1, 12 (Closed-cervix pyometra) 12/12 (100) 714 Not evaluated Not evaluated [59]
2, 8, and 15
Aglepristone 10 mg/kg SC on Days 1, 24 24/24 (100) Within 14 days Bitches aged <5 y: 0% (n 14) Whelping rate: [60]
2, 7, and 14 Bitches aged >5 y: 30% (n 9) Bitches aged <5 y: 57.1% (n 14)
Bitches aged >5 y: 0% (n 9)
Aglepristone 10 mg/kg SC on Days 1, 6 6/6 (100) 821 Not evaluated Not evaluated [55]
2, 7  14
Aglepristone 10 mg/kg SC on Days 1, 6 6/6 (100) 821 Not evaluated Not evaluated [55]
2, 7  14 cloprostenol 1 mg/kg on
Days 1, 2, 7  14 cloprostenol
2 mg/kg on Days 3, 4, 5, 6
Aglepristone 10 mg/kg SC on Days 1, 28 21/28 (75) 149 48% (n 21) Whelping rate: 69% (n 13) [61]
2, 7 or 8, 14 or 15 and every 7th to
8th day until the end of treatment
Aglepristone 10 mg/kg SC on Days 1, 26 (12 With open-cervix pyometra 23/26 (88.5%) Within 14 days 17.4% (n 23) Whelping rate: 85.7% (n 7) [62]
2, and 7 and 14 with closed-cervix
pyometra)
Aglepristone 10 mg/kg SC on Days 1, 47 (20 With open-cervix pyometra 47/47 (100) Within 14 days 0% (n 47) Whelping rate: 78.3% (n 23) [62]
3, 6, and 9 and 27 with closed-cervix
pyometra)

Abbreviation: SC, subcutaneous.

 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
according to clinical, laboratory, and ultrasound ndings,
was reported to be 90% at Day 21 after four injections at
Days 1, 2, 7, and 14 (9 of 10 queens [63]) and 100% after
three injections at Days 1, 2, and 7 (4 of 4 queens [64])
[63,64]. No adverse effects were observed during or after
the treatment, and no relapses were reported within a
follow-up period of 2 years [63]. Two queens bred after
aglepristone treatment became pregnant and delivered
normal and healthy kittens [63].
3.1.3. In Guinea pigs and hamsters
Unlike bitches and queens, in rodents, the role of pro-
gesterone in the etiopathogenesis of pyometra is not
known. However, two clinical reports concerning the use of
aglepristone in a hamster and a Guinea pig with pyometra
indicated that the treatment can be curative [65,66].
In the hamster, aglepristone was injected at a dose of
20 mg/kg twice, 24 hours apart, on Days 1 and 2, then again
on Days 8 and 15 (Day 1: day of diagnosis). On Day 8, the
female was clinically recovered, and 2 months after the last
injection, her health status was optimal. She showed
several estrous cycles after the treatment, and no re-
currences were reported on long-term follow-up [66].
In the Guinea pig, aglepristone was injected at a dose of
10 mg/kg on Days 1, 2, and 8 (Day 1: day of diagnosis). Two
hours after the rst injection, vulvar discharge was
observed. The next day, the animal had recovered, and on
Day 8, all signs of pyometra had resolved [65].
However, neither of the reports gave any clear evidence
of progesterone involvement in pathogenesis of the dis-
ease. Furthermore, in the hamster case, recovery might be
attributed to the antibiotics administered in parallel with
aglepristone treatment. Therefore, although these results
Table 3
Results of aglepristone treatment in cats with mammary broepithelial hyperplasia.
Dose of aglepristone and therapeutic protocol Number of treated cats
10 mg/kg SC for 45 consecutive days 6 Queens
10 mg/kg SC for 45 consecutive days 1 Tomcat (aged 13 y, had
received depot progestins) Recurrence 13 days after
20 mg/kg SC once a week 7 Cats
10 mg/kg SC two consecutive days once a week 15 Cats
10 mg/kg SC at 24 h interval 2 Queens and 1 tomcat
10 mg/kg SC on Days 1, 2, and 7 1 Queen
10 mg/kg SC every 34 days 1 Cat
5 mg/kg SC for 5 consecutive days 1 Cat
5 mg/kg SC once a week for 3 wk 1 Cat
10 mg/kg SC on Days 1, 2 and Days 7, 14, and 21 1 Queen
10 mg/kg SC for 5 consecutive days 1 Tomcat
10 mg/kg SC on Days 1, 2, then once a week 14 Queens
until complete regression of the lesions
10 mg/kg SC on Days 1 and 2 1 Queen
Abbreviation: SC, subcutaneous.
563
are promising, further studies are needed to conrm the
role of aglepristone for treating pyometra in these species.
3.2. Treatment of feline mammary broepithelial hyperplasia
Feline mammary hyperplasia is a nonneoplastic disease,
characterized by rapid hypertrophy of one or several
mammary glands. Progesterone and estrogen receptors
have been identied in the mammary lesions, suggesting
that both hormones are involved [6770].
Feline mammary hyperplasia is usually identied in
young queens within a few days of ovulation [35,7173].
The disease may also affect spayed/neutered or intact
queens or tomcats after progestagen administration
[67,70,71,7376].
Feline broadenomatosis may regress spontaneously.
Given the hormonal dependence of the disease, ovariec-
tomy was initially recommended as the treatment of choice
[73]. However, broadenomatosis does not always respond
to ovariectomy, and in some cases, the growth of the
mammary lesions may continue after removal of the
ovaries [35,77]. According to Grlinger et al. [35], this might
result from the action of local steroid-independent mech-
anisms, supported by insulin-like growth factors (IGFs),
growth hormone (GH), or both.
Conversely, aglepristone (10 mg/kg SC), injected at Days
1 and 2, then once weekly until complete regression of
mammary lesions, is successful in nearly 100% of cases
(Table 3). Complete resolution of mammary lesions is
generally observed within 4 weeks (range: 111 weeks)
[35,71,72,74,7780]. Resolution may take longer in cats
treated with long-acting progestagens before the onset of
broadenomatosis [72]. In some of the cases that did not
Evolution of the lesions Reference
Regression starting on Day 5 and complete regression 34 wk [80]
after initial injection
Regression starting on Day 3 [80]
Complete regression within 14 wk after initial injection in [35]
all cats but 1 (2 queens that were pregnant at presentation [35]
aborted then developed endometritis)
Complete regression within 511 wk [71]
Complete regression of the lesions within 3 wk [81]
Complete regression within 3 wk after initial injection [79]
Partial regression after 5 days and complete regression after [78]
6 wk
Regression starting on Day 2 and complete regression 4 wk [74]
after initial injection
Regression starting during the second week of treatment and [72]
complete regression 4 wk after initial injection
Longer treatment needed in some cats previously treated
with long-acting progestagens
Recurrences within 12 mo after treatment in 5 queens (one of
them that had received long-acting medroxyprogesterone
acetate before aglepristone treatment, another one treated
with medroxyprogesterone acetate a few months after
aglepristone treatment)
Complete regression 3 wk after initial injection [77]
564 A. Gogny, F. Fini / Theriogenology 85 (2016) 555566
respond rapidly to aglepristone treatment, mastectomy
was performed at the owners request [80]. However,
prolongation of the treatment in other cases resulted in
complete regression of the lesions [72].
A relapse of broadenomatosis may occur, especially in
cats treated previously with long-acting progestagens and
in intact queens during subsequent estrous cycles [72,80].
Ovariectomy is therefore recommended in nonbreeding
females once the lesions have regressed [72].
3.3. Promising use of aglepristone
3.3.1. Treatment of insulin-resistant diabetes mellitus in bitches
Diabetes mellitus is a common metabolic disorder in
dogs. Affected animals are usually more than 5 years of age,
and females are affected more often than males. Treatment
of diabetes mellitus revolves around insulin administration
[82]. However, endogenous progesterone secretion during
diestrus or pregnancy or administration of exogenous
progesterone derivatives for contraception can stimulate
hypersecretion of mammary GH, which can secondarily
lead to insulin resistance [8284]. Ovariectomy limits
progesterone-induced insulin resistance and is therefore
strongly recommended especially if diabetic ketoacidosis is
present [82,85].
The administration of aglepristone (10 mg/kg SC at Days
1, 2, 9, and 17) during the luteal phase may help to control
hyperglycemia in diabetic bitches with diestrus-induced
insulin resistance (n 8 bitches). The effects of the treat-
ment were signicant from Day 12, with reductions in the
dose of insulin needed to control glycemia [86]. Aglepri-
stone might therefore be useful as an adjuvant treatment
for insulin-resistant diabetes mellitus, particularly in
bitches in which ovariectomy is not an option.
3.3.2. Treatment of acromegaly in bitches
Acromegaly is a chronic endocrine disease caused by the
hypersecretion of GH and IGF-1; characteristic symptoms
include soft tissue overgrowth and bony proliferation.
Progesterone-induced acromegaly is the most common
form of acromegaly in dogs and usually appears after pro-
longed administration of progestagens or during the luteal
phase in older intact females. Treatment involves ovariec-
tomy or withdrawal of exogenous progestagens [82].
Complete recovery may also require the removal of mam-
mary tumors in affected bitches because of a local secretion
of GH within mammary gland tumors [87,88]. Once the
source of progesterone has been eliminated, the prognosis
is good [82].
Given its antiprogesterone properties, aglepristone may
be considered as an alternative therapeutic option for the
treatment of progesterone-induced acromegaly. Treatment
with aglepristone (10 mg/kg of body weight injected SC at
Days 1, 8, 15, and 22) resulted in a reduction in mean
plasma concentrations of GH and IGF-1 in affected Beagle
bitches (n 5) [89].
3.3.3. Treatment of canine benign vaginal tumors
In the bitch, vaginal tumors are mainly benign smooth
muscle tumors [90]. The tumors can grow quite large,
making surgical removal difcult, locally destructive, and
painful [90,91]. Reduction in tumor size would likely
improve the comfort of the bitch by reducing local com-
pressions of the digestive tract and facilitate the surgical
removal of poorly accessible tumors or vaginal tumors
localized near the urethral opening.
Given the presence of PRs in such tumors, aglepristone
has been suggested as a therapeutic option and was used in
a 12-year-old intact bitch with a vaginal broma [92].
Aglepristone was administered on Days 1, 2, 8, 15, 28, and
35 (Day 1: day of diagnosis). On Day 45, the size of the
tumor had noticeably reduced, decreasing from
9.1  5.4 cm to 6.4  4.7 cm [93]. Although isolated, this
case report suggests that progesterone antagonists might
be of interest in the treatment of progesterone-dependent
tumors in the bitch.
4. Conclusions
Although some of the results have yet to be conrmed,
many of the clinical effects of aglepristone have now been
clearly reported. This substance has proven to be an
effective and safe means of inducing pregnancy termina-
tion or parturition in a large number of domestic species.
Aglepristone has also proved to be a promising medical
therapeutic option in some progesterone-dependent dis-
eases, with the main benet of replacing and sometimes
even surpassing surgical options.
Acknowledgments
The authors deeply thank Dr Josephine Billet for assis-
tance with English translation. The authors would also like
to show their gratitude to Pr Marc Gogny and Pr Jean-
Franois Bruyas for comments that greatly improved the
article.
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