Miguel Laurin’s research while affiliated with University of Paris-Saclay and other places

Objectives Our overall aim was to provide experimental pharmacological evidence for the use of intracavernosal (ic) onabotulinumtoxinA alone or in combination with phosphodiesterase type 5 inhibitors for difficult-to-treat erectile dysfunction. We thus compared the effects of botulinum toxin A alone and botulinum toxin A combined with phosphodiesterase type 5 inhibitor, and a placebo treatment. Methods Erectile function was evaluated following cavernous nerve electrical stimulation at different frequencies in 4 groups (n = 8 / group) of anesthetized, spontaneously hypertensive rats. Rats were treated by onabotulinumtoxinA 10U or saline ic 1 week prior to erectile function testing and sildenafil (0.3 mg/kg) or saline iv 4 minutes prior to testing. Frequency-response curves were compared with a two-way ANOVA. Results Intracavernosal pressure/mean arterial pressure ratios were significantly increased by sildenafil and onabotulinumtoxinA ic versus the control condition. OnabotulinumtoxinA 10U ic combined with sildenafil significantly potentiated erectile responses. Area under the curve/mean arterial pressure ratio increased by 19% with sildenafil, by 15% with onabotulinumtoxinA ic and by 58% with the combined treatment. Conclusions Both onabotulinumtoxinA ic, and sildenafil, significantly improved erectile responses in spontaneously hypertensive rats, however the effect was greatly amplified when the treatments were combined. These results support further studies into the mechanisms behind the pro-erectile effect of BTX-A ic, as well as multicenter randomized control trials to evaluate the safety and efficacy of BTX-A combined with sildenafil for difficult-to-treat ED. Conflicts of Interest No conflict of interest

Objectives Proof of concept study to investigate the effect of lib-01 on erection in anesthetized rats. The active substance lib-01 is a semi-synthetic molecule, originating from neobeguea mahafalensis roots with a long tradition in madagascar of ethnopharmacological use for the treatment of sexual disability. Methods Adult Wistar rats (n=12 /group) were administered LIB-01 at 4 or 15 mg/kg by subcutaneous injection once daily for 3 consecutive days. Erection was assessed 1, 2 or 7 days after the last treatment by electrical stimulation of the cavernous nerve (ES CN) at different frequencies under isoflurane anaesthesia. LIB-01 treatment was compared to a single dose of sildenafil 0.3 mg/kg iv dispensed 4 minutes prior penile erection testing. Results There was no safety signal post LIB-01 treatment. Ratios of intracavernous pressure (ICP) and area under the curve (AUC)/mean arterial pressure (MAP) were increased in rats treated with LIB-01 sc 15 mg/kg/day for 3 days when erection was tested 1 day post last administration vs vehicle-treated rats (at 10 Hz, ICP/MAP: + 11 %) compared to a 19 % increase in sildenafil-treated group. The proerectile facilitator effects of LIB-01 at 15 mg/kg were improved when erection was tested 2 days compared to 1 day post-treatment, and further increased when evaluated 7 days post treatment (at 10 Hz, ICP/MAP increased by 36 % and 48 % 2 and 7 days post-LIB-01 treatment respectively). Conclusions LIB-01 significantly improved erection following subcutaneous administration for 3 days. This effect lasted at least 7 days post-treatment and interestingly increased overtime. The mechanism of action supporting the beneficial impact of increasing delay post-treatment remains to be investigated. Conflicts of Interest Study supported by a restricted grant from Dicot

Background Botulinum toxin A (BTX-A) has a variety of uses in medicine. Some evidence suggests that intracavernosal (ic) BTX-A injection administered in addition to phosphodiesterase type 5 inhibitors (PDE5-Is) could effectively treat erectile dysfunction (ED) in insufficient responders to PDE5-Is. Aim To provide experimental pharmacological evidence for the use of onabotulinumtoxinA ic alone or in combination with PDE5-Is for difficult-to-treat ED. We thus compared the effects of BTX-A ic alone and BTX-A ic combined with PDE5-I iv, and a placebo treatment ic or iv. Methods Erectile function was evaluated following cavernous nerve electrical stimulation (6 V, 1-millisecond pulse, 45-second duration) at different frequencies (0, 2, 3, 4, 5, 7.5, and 10 Hz) in 4 groups (n = 8 / group) of anesthetized, spontaneously hypertensive rats, a robust animal model of ED of vascular origin. Rats were treated by onabotulinumtoxinA 10U or saline ic 1 week prior to erectile function testing and sildenafil (0.3 mg/kg) or saline iv 4 minutes prior to testing. Frequency-response curves were compared with a 2 way ANOVA. Outcomes Both onabotulinumtoxinA ic, and sildenafil iv significantly improved erectile responses in spontaneously hypertensive rats, however the effect was greatly amplified when the treatments were combined. Results Intracavernosal pressure and/or mean arterial pressure ratios were significantly increased by sildenafil and onabotulinumtoxinA ic versus the control condition. OnabotulinumtoxinA 10U ic combined with sildenafil iv significantly potentiated erectile responses. Area under the curve and/or mean arterial pressure ratio increased by 19% with sildenafil iv, by 15% with onabotulinumtoxinA ic and by 58% with the combined treatment following cavernous nerve electrical stimulation at 6V, 1 ms, 10 Hz: these stimulation parameters elicited the maximal erectile response. Clinical Translation These data provide a pharmacological rationale for the combined administration of onabotulinumtoxinA ic and sildenafil iv since the effects of both treatments were potentiated when their administration was combined. Strengths & Limitations First evidence of a synergistic pro-erectile effect of BTX-A combined with PDE5-I, however the mechanism behind the pro-erectile effect of BTX-A ic remains hypothetical. Conclusions These results support further studies into the mechanisms behind the pro-erectile effect of BTX-A ic, as well as multicenter randomized control trials to evaluate the safety and efficacy of BTX-A ic combined with sildenafil for difficult-to-treat ED. Giuliano F., Joussain C., Denys P., et al. Intracavernosal OnabotulinumtoxinA Exerts a Synergistic Pro-Erectile Effect When Combined With Sildenafil in Spontaneously Hypertensive Rats. J Sex Med 2021;XX:XXX–XXX.

Background: The main purpose of this study is to investigate the effect of silodosin on the urodynamic consequences in a previously established model of lower urinary tract symptoms associated with benign prostate hyperplasia, the spontaneously hypertensive rats (SHR) supplemented with testosterone. Methods: Three groups of animals (8-week-old; n = 10/group) were considered: Wistar Kyoto (control) rats (WKY), SHR supplemented with testosterone at 3 mg/kg/day and treated with either vehicle (SHR-T, n = 10) or silodosin at 0.1 mg/kg/day (SHR-T + silodosin, n = 10) by oral gavage for 6 weeks. Cystometry experiments were performed. The bladder was harvested, weighed and paraffin-embedded for morphometric analysis. The prostate was also harvested and weighed. Results: The number of animals included in the analysis were n = 10/10 for WKY and n = 7-8/10 for each SHR rats supplemented with testosterone group. SHR-T displayed a significant decrease in the intercontraction interval, infused volume and mean flow rate whereas the frequency of non-voiding contractions was increased. Silodosin improved the voiding behavior of SHR-T by significantly increasing the intercontraction interval, the infused volume and the mean flow rate and decreasing the number of non-voiding contractions. SHR-T displayed a significant increase in prostate and bladder weights and a 15% increase in the detrusor wall area compared to WKY. Conclusions: Chronic silodosin treatment relieved storage symptoms in SHR supplemented with testosterone and decreased the frequency of non-voiding detrusor contractions during the filling phase.

Background: Low-intensity extracorporeal shock wave therapy (Li-ESWT) has been reported to improve erectile function in patients with moderate-to-severe erectile dysfunction (ED) or even convert phosphodiesterase type 5 inhibitors nonresponders to responders. ED is highly prevalent in hypertensive patients. The effect of Li-ESWT on an animal model of hypertension-associated ED has not been reported. Aim: To investigate the effect of Li-ESWT on hypertension-associated ED and provide plausible mechanisms of action of Li-ESWT on local mechanisms of penile erection. Methods: Spontaneously hypertensive rats (SHRs) in the active group (n = 13) received Li-ESWT at energy flux density 0.06 mJ/mm2 (Aries; Dornier MedTech, Wessling, Germany) twice weekly for 6 weeks. The emitter was set to zero for SHRs in the sham group (n = 12). Erectile function was assessed 4 weeks post-treatment by monitoring intracavernosal pressure (ICP) in response to electrical stimulation of cavernous nerve before and after single dose of 0.3 mg/kg intravenous sildenafil. Cavernosal tissue was then evaluated for collagen/smooth muscle content, neuronal nitric oxide synthase (nNOS), and vascular endothelial factor (CD31) expression. Outcomes: Erectile function was assessed with ICP, erectile tissue remodeling was studied by smooth muscle/collagen ratio, nNOS and CD31 were semiquantitatively evaluated on cavernosal sections. Results: The improvement of ICP parameters was greater in Li-ESWT-treated rats compared with controls with and without sildenafil. Sildenafil led to 20% increase in area under the intracavernosal pressure curve measured during the entire response/mean arterial pressure at 10 Hz in ESWT_SHR + sildenafil compared with ESWT_SHR. The smooth muscle/collagen ratio increased 2.5-fold in Li-ESWT compared with sham. Expression of CD31 tended to be increased whereas nNOS was unchanged. Conclusions: Li-ESWT by Aries may represent an effective noninvasive therapeutic alternative and a relevant add-on therapy to phosphodiesterase type 5 inhibitors for ED in hypertensive patients, and it is suggested that it acts via remodeling of the penile tissue and promoting cavernosal vascularization. Assaly R, Giuliano F, Clement P, et al. Extracorporeal Shock Waves Therapy Delivered by Aries Improves Erectile Dysfunction in Spontaneously Hypertensive Rats Through Penile Tissue Remodeling and Neovascularization. Sex Med 2019;XX:XXX-XXX.

Purpose: Erectile dysfunction (ED) is highly prevalent in type II diabetes mellitus (T2DM). Li-ESWT improves erectile function in patients with ED from vasculogenic origin including diabetes, although its mode of action remains unknown. The effects of Li-ESWT on ED in a T2DM model compared or combined to sildenafil were investigated the hypothesis of a mode of action targeting the cavernosal NO/cGMP pathway tested. Materials and methods: Goto-Kakizaki (GK), a validated model of T2DM, and age-matched Wistar rats were treated by Li-ESWT twice weekly for 3 weeks, repeated after a 3-week no-treatment interval. The rat penis was stretched and dipped into a specifically designed water-filled cage. Shockwaves were delivered by a calibrated probe yielding a controlled energy flux density (0.09mJ/mm(2)) attached to an electrohydraulic unit with a focused shockwave source allowing an accurate extrapolation to humans. Following a 4-week wash-out period, erectile function, endothelium-dependent, -independent and nitrergic relaxations of corpus cavernosum of GK rats were assessed. Results: Li-ESWT significantly improved erectile function in GK rats to the same extent as sildenafil. Li-ESWT's effects were potentiated when combined with sildenafil. Li-ESWT's effects were not associated to improved cavernosal endothelium-dependent, -independent or nitrergic reactivity. Conclusions: Li-ESWT improves erectile function in GK rats. Unexpectedly, this was not mediated by a NO/cGMP-dependent mechanism. Sildenafil increases Li-ESWT's efficacy. This preclinical paradigm for delivering Li-ESWT to the rat's penis should help further exploration of Li-ESWT mode of action on the erectile tissue.

Objectifs Des études cliniques rapportent l’utilisation d’ondes de choc de faible intensité (Li-ESWT) appliquées sur la verge pour traiter la dysfonction érectile (DE). Le mécanisme d’action de cette thérapeutique innovante reste inconnu. Nous avons évalué l’efficacité des Li-ESWT dans le contexte expérimental de la DE associée au diabète utilisant le rat diabétique Goto-Kakizaki (GK) et son contrôle normoglycémique Wistar pour préciser le mécanisme d’action des Li-ESWT. Méthodes Certains rats GK (n = 24) ont reçu 2 séries de traitements bi-hebdomadaires par Li-ESWT (Omnispec ED1000, Medispec), séparées de 3 semaines sans traitement. Ce protocole de traitement par Li-ESWT reproduisait exactement le protocole humain. Parmi ces rats GK, certains ont également reçu 0,3 mg/kg iv de sildénafil au moment de l’évaluation de la fonction érectile, 4 semaines après la dernière séance par Li-ESWT, en mesurant la pression intracaverneuse lors de stimulations électriques du nerf caverneux. La réactivité en bain d’organes isolés des corps caverneux (CC) issus des mêmes rats a été également mesurée afin d’explorer le rôle éventuel de la voie NO/cGMP. Résultats La fonction érectile des rats diabétiques GK est significativement diminuée en comparaison des rats contrôles Wistar et associée à une diminution des relaxations endothélium-dépendantes, -indépendantes et nitrergiques des corps caverneux. Les Li-ESWT ont significativement amélioré la fonction érectile des rats diabétiques GK. De plus, le sildénafil a augmenté significativement l’effet pro-érectile du traitement par Li-ESWT. Cependant, la relaxation des CC n’a pas été améliorée par Li-ESWT, qu’elle soit endothélium-dépendante, -indépendante ou nitrergique. Conclusion Li-ESWT améliore la fonction érectile des rats diabétiques de type II GK. Le sildénafil associé aux Li-ESWT améliore encore ces réponses. L’effet thérapeutique des Li-ESWT est indépendant de la voie du NO/cGMP. D’autres études sont nécessaires pour comprendre le mécanisme d’action des Li-ESWT.