Analgesic and anti-inflammatory properties of losmapimod, an oral p38 MAPK inhibitor, on acute pain components in male rat

Les traitements antalgiques actuels se sont révélés être insuffisants dans de nombreuses situations cliniques et le développement de nouvelles molécules semble essentiel. La protéine p38 MAPK est une protéine impliquée dans de nombreuses voies de signalisation intra- cellulaire dont celles constituant la réponse à un stimulus douloureux et l’inflammation. Plusieurs inhibiteurs ont déjà été testés comme antalgiques. Nous avons souhaité tester l’un d’entre eux, le losmapimod qui est disponible par voie orale et bénéficie d’un important recul en matière de sécurité d’emploi en clinique humaine, mais dans des domaines différents de celui de la douleur. Ainsi, nos travaux ont pour but d’évaluer les propriétés antalgiques du losmapimod sur les différentes composantes de la douleur aigue. L’inflammation prenant une part importante dans l’entretien du signal douloureux, nous avons également évalué ses caractéristiques anti-inflammatoires. Tous les tests ont été réalisés chez le rat mâle en utilisant plusieurs modèles douloureux : injection de carragénine (ayant une forte composante inflammatoire), incision plantaire (permettant de simuler une douleur postopératoire pariétale) et ligature sciatique (équivalent de douleur neuropathique). Ces expérimentations étant les premières réalisées avec le losmapimod dans la douleur aigue. Nos travaux avaient également comme objectifs de déterminer les courbes dose- réponse du losmapimod et les ED50 pour les actions antalgiques et anti- inflammatoires après injection de carragénine. Le losmapimod a également été comparé à plusieurs médicaments usuels en clinique humaine (paracétamol, kétamine, kétoprofène et morphine). Dans le cadre de la douleur neuropathique, nous avons également réalisé une étude d’interaction avec la gabapentine, actuellement recommandée en première intention pour le traitement de ces douleurs. Enfin, une étude immunohistochimique a été réalisée pour évaluer les effets du losmapimod sur les neurones afférents ainsi que sur les cellules médullaires microgliales et astrocytaires afin de mieux comprendre les voies d’activation/inhibition mises en jeu. Un effet antalgique marqué a été retouvé sur l’ensemble des composantes de la douleur aigue. Après injection de carragénine, les effets antalgiques du losmapimod étaient proches de ceux de la morphine et les effets anti- inflammatoires similaires à ceux du kétoprofène. Les courbes dose-réponse ont mis en évidence que la seule dose décrite dans la littérature chez le rat et hors du contexte douloureux (12mg/kg), correspondait à une ED70 antalgique et une ED26 anti-inflammatoire. Les effets antalgiques puissants obtenus après injection de carragénine ont été confirmés après incision plantaire et ligature sciatique. Dans le cadre de la ligature sciatique, l’étude d’interaction avec la gabapentine réalisée par méthode isobolographique a permis de mettre en évidence des effets additifs des deux molécules. Concernant la tolérance, nous n’avons pas mis en évidence d’effet indésirable grave chez les animaux. Enfin, d’un point de vue mécanistique, le losmapimod permet une inhibition de l’activation des neurones afférents et de la microglie médullaire. Nous n’avons pas mis en évidence d’inhibition de l’activation astrocytaire. Ces différents résultats permettent de confirmer l’intérêt potentiel des inhibiteurs de la p38 MAPK et du losmapimod en particulier pour la prise en charge de la douleur aigue. Ce dernier semble particulièrement prometteur car nous avons mis en évidence une combinaison d’effets antalgiques et anti-inflammatoires et pas d’effets secondaires graves, confirmant les données cliniques. Même si aucune de celles-ci n’a étudié le losmapimod dans la douleur aigue, nos résultats ainsi que les nombreuses données de tolérance dont nous disposons maintenant chez l’homme appuient l’intérêt potentiel de relancer son évaluation chez l’homme.Current analgesic treatments remain not potent enough in many clinical situations and the development of new molecules seems essential. The p38 MAPK protein is involved in many intracellular signaling pathways including those constituting the response to a painful stimulus and inflammation. Several inhibitors have already been tested as analgesic drugs. We wished to test one of them, losmapimod, which is available orally and benefits from a significant safety record in human studies, but in areas different from pain. Thus, the aim of our work is to evaluate the analgesic properties of losmapimod on the various components of acute pain. As inflammation plays an important role in the the pain signal, we also evaluated its anti-inflammatory characteristics. All the tests were carried out in male rats using several pain models: injection of carrageenan (having a strong inflammatory component), plantar incision (allowing to simulate a postoperative parietal pain) and sciatic nerve ligation (equivalent of neuropathic pain). These experiments are the first ones carried out with losmapimod in acute pain. Our work also had as objectives to determine the dose-response curves of losmapimod and the ED50 for the analgesic and anti- inflammatory actions after carrageenan injection. Losmapimod was also compared to several drugs commonly used in humans (paracetamol, ketamine, ketoprofen and morphine). In the context of neuropathic pain, we also performed an interaction study with gabapentin, currently recommended as first-line treatment for such pain. Finally, an immunohistochemical study was performed to evaluate the effects of losmapimod on afferent neurons as well as on spinal microglial and astrocytic cells in order to better understand the activation/inhibition pathways involved. A marked analgesic effect was found on all components of acute pain tested. After injection of carrageenan, the analgesic effects of losmapimod were close to those of morphine and the anti- inflammatory effects similar to those of ketoprofen. Dose-response curves showed that the only dose described in the literature in rats outside the context of pain (12mg/kg) corresponds to an analgesic ED70 and an anti-inflammatory ED26. The strong analgesic effect obtained after carrageenan injection was confirmed after plantar incision and sciatic nerve ligation. In the context of sciatic nerve ligation, the study of interaction with gabapentin carried out by isobolographic method allowed to highlight additive effects of the two molecules. Concerning tolerance, we did not find any serious adverse effect in animals. Finally, from a mechanistic point of view, losmapimod was shown to inhibit the activation of afferent neurons and spinal microglia. We did not show any inhibition of astrocytic activation. These different results confirm the potential efficacy of p38 MAPK inhibitors and more specifically losmapimod for the management of acute pain. This latter drug seems particularly promising because we demonstrated a combination of analgesic and anti-inflammatory effects without serious side effects, therefore confirming clinical data. Although no study has evaluated losmapimod in acute pain, our results and numerous safety data now available in humans support the potential value of reviving its evaluation in humans

Efficacy of Intra-Uterine Tamponade Balloon in Post-Partum Hemorrhage after Cesarean Delivery: An Impact Study

Invasive therapies (surgery or radiological embolization) are used to control severe post-partum hemorrhage. The intra-uterine tamponade balloon is a potential alternative, well documented after vaginal delivery. However, available data on its use after cesarean delivery remain scarce. This study assessed the efficacy of the intra-uterine tamponade balloon during post-partum hemorrhage in a cesarean delivery setting. Using a retrospective impact design, post-partum hemorrhage-related outcomes before (“pre-balloon” period) versus after implementation of intra-uterine tamponade balloon (“post-balloon” period) were compared. All women with post-partum hemorrhage requiring potent uterotonic treatment with prostaglandins after cesarean delivery over a 9-year period were eligible. The primary outcome was the rate of invasive procedure (conservative surgery, radiological embolization and/or hysterectomy). p < 0.05 was considered statistically significant. A total of 279 patients were included (140 vs. 139). Most baseline characteristics were comparable between the two studied periods. The success rate of the intra-uterine tamponade balloon was 82%, and no related complications occurred. Rates of invasive procedures and transfusion were significantly reduced (28.6% vs. 11.5%, p < 0.001 and 44.3% vs. 28.1%, p = 0.006 respectively) during the “post-balloon” period, and length of hospital stay was shorter (p < 0.001). Implementation of intra-uterine tamponade balloon during post-partum hemorrhage after cesarean delivery appears to be safe and effective, with a decrease in both invasive procedures and transfusion rates

Management practices for postdural puncture headache in obstetrics: a prospective, international, cohort study

© 2020 British Journal of AnaesthesiaBackground: Accidental dural puncture is an uncommon complication of epidural analgesia and can cause postdural puncture headache (PDPH). We aimed to describe management practices and outcomes after PDPH treated by epidural blood patch (EBP) or no EBP. Methods: Following ethics committee approval, patients who developed PDPH after accidental dural puncture were recruited from participating countries and divided into two groups, those receiving EBP or no EBP. Data registered included patient and procedure characteristics, headache symptoms and intensity, management practices, and complications. Follow-up was at 3 months. Results: A total of 1001 patients from 24 countries were included, of which 647 (64.6%) received an EBP and 354 (35.4%) did not receive an EBP (no-EBP). Higher initial headache intensity was associated with greater use of EBP, odds ratio 1.29 (95% confidence interval 1.19–1.41) per pain intensity unit increase. Headache intensity declined sharply at 4 h after EBP and 127 (19.3%) patients received a second EBP. On average, no or mild headache (numeric rating score≤3) was observed 7 days after diagnosis. Intracranial bleeding was diagnosed in three patients (0.46%), and backache, headache, and analgesic use were more common at 3 months in the EBP group. Conclusions: Management practices vary between countries, but EBP was more often used in patients with greater initial headache intensity. EBP reduced headache intensity quickly, but about 20% of patients needed a second EBP. After 7 days, most patients had no or mild headache. Backache, headache, and analgesic use were more common at 3 months in patients receiving an EBP

Management practices for postdural puncture headache in obstetrics : a prospective, international, cohort study

Background: Accidental dural puncture is an uncommon complication of epidural analgesia and can cause postdural puncture headache (PDPH). We aimed to describe management practices and outcomes after PDPH treated by epidural blood patch (EBP) or no EBP. Methods: Following ethics committee approval, patients who developed PDPH after accidental dural puncture were recruited from participating countries and divided into two groups, those receiving EBP or no EBP. Data registered included patient and procedure characteristics, headache symptoms and intensity, management practices, and complications. Follow-up was at 3 months. Results: A total of 1001 patients from 24 countries were included, of which 647 (64.6%) received an EBP and 354 (35.4%) did not receive an EBP (no-EBP). Higher initial headache intensity was associated with greater use of EBP, odds ratio 1.29 (95% confidence interval 1.19-1.41) per pain intensity unit increase. Headache intensity declined sharply at 4 h after EBP and 127 (19.3%) patients received a second EBP. On average, no or mild headache (numeric rating score <= 3) was observed 7 days after diagnosis. Intracranial bleeding was diagnosed in three patients (0.46%), and backache, headache, and analgesic use were more common at 3 months in the EBP group. Conclusions: Management practices vary between countries, but EBP was more often used in patients with greater initial headache intensity. EBP reduced headache intensity quickly, but about 20% of patients needed a second EBP. After 7 days, most patients had no or mild headache. Backache, headache, and analgesic use were more common at 3 months in patients receiving an EBP