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Aglepristone for Managing a Closed-Cervix Pyometra

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    October 5, 2017 10:49 AM EDT

    In our Specialty Update on Canine Pyometra - Why Some Dogs Don't Get Better With Medical Treatment or Experience Relapses, Dr. Marco Coutinho da Silva mentions use of the drug aglepristone (Alizine) - a progesterone antagonist - for managing dogs with a closed-cervix pyometra. 

    An article titled Aglepristone: A review on its clinical use in animals,authored by Anne Gogny and Francis Fiéni, was published in Theriogenology, Vol 85(4), 2016, pp 555-566 and provides a comprehensive review on this drug and its clinical uses in a variety of species including cats, dogs, guinea pigs, and hamsters.

    Here are some select excerpts from this open access article for your reference (published with permission under Creative Commons License):


    Abstract


    Aglepristone (RU 46534) is a competitive progesterone antagonist that is indicated for the treatment of various progesterone-dependent physiological or pathologic conditions. Aglepristone has proven to be an effective means of terminating pregnancy in most species. When 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 schedule an elective cesarean section, aglepristone treatment was deemed safe for dams and puppies, providing that the ovulation date had been accurately assessed at the time of breeding. Irrespective of the stage of pregnancy at injection, treatment with aglepristone has no apparent negative effects on subsequent fertility. Aglepristone is also a safe and relatively 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 fibroadenomatosis 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.


    1. Introduction

    Aglepristone (RU 46534) is a competitive progesterone antagonist; it binds to progesterone receptors (PRs) without inducing the molecular cascade associated with progesterone. Its affinity 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.

    2. Clinical use of aglepristone during pregnancy

    Progesterone plays a critical role in the establishment and maintenance of pregnancy. Thus, progesterone antagonists have been considered in the termination of pregnancy or to induce parturition.

    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 fibroadenomatous 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, defined as the accumulation of pus within the uterus. It is described in numerous domestic species [45–48].

    Pyometra is linked to hormonal imbalance or an abnormal response to estrogens and progesterone or derivatives of progesterone, and it is mainly identified during the luteal phase [45,49,50]. In most species, ovariohysterectomy 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 efficient and should therefore be restricted to stable animals only. Thus, conservative treatment is not recommended in life-threatening situations needing emergency procedures, such as peritonitis due to uterine rupture, serious renal insufficiency, or severe electrolytes/acid–base imbalance.

    Moreover, additional therapeutic measures (antibiotherapy, fluid 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 PGF2α analogue, have been described in various species. In parallel, an in vitro study conducted on canine myometrial fibers reported promising results with a combination of aglepristone and oxytocin; however, these results have yet to be confirmed clinically [52]. Aglepristone treatment is intended to block the effects 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% [53–56] (Table 2). A protocol using aglepristone at Days 1, 3, 6, and 9 (Day 1: day of diagnosis) without subsequent injections showed a success rate of 100% [62]. When aglepristone 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 first 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 first injection (n=12) [59].

    The physical condition of the animal usually improved after uterine emptying [53,55–57,62]. Ultrasonography revealed reduced uterine lumen diameter from the seventh day after the first injection [53,57,58,62]. Complete recovery was recorded within 14 to 90 days [53–62].

    Recurrence of pyometra is common within 24 months of treatment [53,56,58,60–62]. However, a modified 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 efficacy [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 hyperplasia 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 first estrus after aglepristone administration [53,56–58,61,62]. However, age seems to influence the success of mating after medical treatment of pyometra, pregnancy rates being higher in bitches under 5 years of age [60].

    As observed with other indications of aglepristone in the bitch, aglepristone tends to influence the interestrus interval: shortening was observed in 19% to 43% of bitches [56,60,62], whereas 20% of cases had prolonged interestrus intervals [56].


    References - Refer to the original article


    Read More
    about Aglepristone and its use in cats, guinea pigs, and hamsters as well as promising uses of aglepristone for treating insulin-dependent diabetes mellitus, acromegaly, and benign vaginal tumors in bitches.