Phosphodiesterase Inhibitor Research Articles

Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease

Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the ATP2A2 gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms.

Exploring the Influence of Cold Plasma on Epidermal Melanogenesis In Situ and In Vitro

Epidermal melanin synthesis determines an individual’s skin color. In humans, melanin is formed by melanocytes within the epidermis. The process of melanin synthesis strongly depends on a range of cellular factors, including the fine-tuned interplay with reactive oxygen species (ROS). In this context, a role of cold atmospheric plasma (CAP) on melanin synthesis was proposed due to its tunable ROS generation. Herein, the argon-driven plasma jet kINPen® MED was employed, and its impact on melanin synthesis was evaluated by comparison with known stimulants such as the phosphodiesterase inhibitor IBMX and UV radiation. Different available model systems were employed, and the melanin content of both cultured human melanocytes (in vitro) and full-thickness human skin biopsies (in situ) were analyzed. A histochemical method detected melanin in skin tissue. Cellular melanin was measured by NIR autofluorescence using flow cytometry, and a highly sensitive HPLC-MS method was applied, which enabled the differentiation of eu- and pheomelanin by their degradation products. The melanin content in full-thickness human skin biopsies increased after repeated CAP exposure, while there were only minor effects in cultured melanocytes compared to UV radiation and IBMX treatment. Based on these findings, CAP does not appear to be a useful option for treating skin pigmentation disorders. On the other hand, the risk of hyperpigmentation as an adverse effect of CAP application for wound healing or other dermatological diseases seems to be neglectable.

What Every Clinician Should Know About Inflammation in COPD

Inflammation drives chronic obstructive pulmonary disease (COPD) pathogenesis and exacerbations. Although the conceptual framework and major players in the inflammatory milieu of COPD have been long established, the nuances of cellular interactions and the etiologic differences that create heterogeneity in inflammatory profiles and treatment response continue to be revealed. This wealth of data and understanding is not only a boon to the researcher but also provides guidance to the clinician, moving the field closer to precision medicine. It is through this lens that this review seeks to describe the inflammatory processes at play in COPD, relating inflammation to pathologic and functional changes, identifying patient-specific and disease-related factors that may influence clinical observations, and providing current insights on existing and emerging anti-inflammatory treatments and treatment targets, including biologic therapies and phosphodiesterase inhibitors.

Pentoxifylline as a Novel Add-on Therapy for Major Depressive Disorder in Adult Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

Evidence indicates an association between immune dysregulation and major depressive disorder (MDD). Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to reduce pro-inflammatory activities. The aim of this study was to evaluate changes in depressive symptoms and pro-inflammatory markers after administration of PTX as an adjunctive agent to citalopram in patients with MDD. One hundred patients were randomly assigned to either citalopram (20 mg/day) plus placebo (twice daily) (n=50) or citalopram (20 mg/day) plus PTX (400 mg) (twice daily) (n=50). The Hamilton Depression Rating Scale-17 (HAM-D-17) scores at baseline, weeks 2, 4, 6, 8, 10, and 12 and serum levels of interleukin1-β (IL-1-β), tumor necrosis factor-α, C-reactive protein, IL-6, serotonin, IL-10, and brain-derived neurotrophic factor (BDNF) at baseline and week 12 were evaluated. HAM-D-17 score in the PTX group significantly reduced in comparison to the control group after weeks 4, 6, 8,10, and 12 ((LSMD): - 2.193, p=0.021; - 2.597, p=0.036; - 2.916, p=0.019; - 4.336, p=0.005; and - 4.087, p=0.008, respectively). Patients who received PTX had a better response (83%) and remission rate (79%) compared to the placebo group (49% and 40%, p=0.006 and p=0.01, respectively). Moreover, the reduction in serum concentrations of pro-inflammatory factors and increase in serotonin and BDNF in the PTX group was significantly greater than in the placebo group (p<0.001). These findings support the safety and efficacy of PTX as an adjunctive antidepressant agent with anti-inflammatory effects in patients with MDD.

Fetal sex and the relative reactivity of human umbilical vein and arteries are key determinants in potential beneficial effects of phosphodiesterase inhibitors.

Intrauterine growth restriction (IUGR) is a common complication of pregnancy. We previously demonstrated that IUGR is associated with an impaired nitric oxide (NO)-induced relaxation in the human umbilical vein (HUV) of growth-restricted females compared to appropriate for gestational age (AGA) newborns. We found that phosphodiesterase (PDE) inhibition improved NO-induced relaxation in HUV, suggesting that PDEs could represent promising targets for therapeutic intervention. This study aimed to investigate the effects of PDE inhibition on human umbilical arteries (HUAs) compared to HUV. Umbilical vessels were collected in IUGR and AGA term newborns. NO-induced relaxation was studied using isolated vessel tension experiments, in the presence or absence of the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). PDE1B, PDE1C, PDE3A, PDE4B and PDE5A were investigated by Western blot. NO-induced vasodilation was similar between IUGR and AGA HUAs. In HUAs precontracted with serotonin, IBMX enhanced NO-induced relaxation only in IUGR females, whereas in HUV IBMX increased NO-induced relaxation in all groups except IUGR males. In umbilical vessels pre-constricted with the thromboxane A2 analog U46619, IBMX improved NO-induced relaxation in all groups, in a greater extent in HUV than HUAs. However, the PDEs protein content was higher in HUAs than HUV, in all study groups. Therefore, the effects of PDE inhibition depend on the presence of IUGR, fetal sex, vessel type and vasoconstrictors implicated. Despite a higher PDEs protein content, HUAs are less sensitive to IBMX than HUV, which could lead to adverse effects of PDE inhibition in vivo, by impairment of the fetoplacental hemodynamics.

The phosphodiesterase inhibitor, ibudilast ameliorates Huntington's disease pathology by modulating neuroinflammation and signaling pathway in a rat model

The phosphodiesterase inhibitor, ibudilast ameliorates Huntington's disease pathology by modulating neuroinflammation and signaling pathway in a rat model

Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases.

Flavonoid aglycones are secondary plant metabolites that exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and antiplatelet effects. However, the precise molecular mechanisms underlying their inhibitory effect on platelet activation remain poorly understood. In this study, we applied flow cytometry to analyze the effects of six flavonoid aglycones (luteolin, myricetin, quercetin, eriodictyol, kaempferol, and apigenin) on platelet activation, phosphatidylserine externalization, formation of reactive oxygen species, and intracellular esterase activity. We found that these compounds significantly inhibit thrombin-induced platelet activation and decrease formation of reactive oxygen species in activated platelets. The tested aglycones did not affect platelet viability, apoptosis induction, or procoagulant platelet formation. Notably, luteolin, myricetin, quercetin, and apigenin increased thrombin-induced thromboxane synthase activity, which was analyzed by a spectrofluorimetric method. Our results obtained from Western blot analysis and liquid chromatography-tandem mass spectrometry demonstrated that the antiplatelet properties of the studied phytochemicals are mediated by activation of cyclic nucleotide-dependent signaling pathways. Specifically, we established by using Förster resonance energy transfer that the molecular mechanisms are, at least partly, associated with the inhibition of phosphodiesterases 2 and/or 5. These findings underscore the therapeutic potential of flavonoid aglycones for clinical application as antiplatelet agents.

How to Recognize and Overcome Pulmonary Hypertension Crisis During Patent Ductus Arteriosus Closure by Device in Adult

Background: Managing a patent ductus arteriosus (PDA) with severe pulmonary hypertension (PH) is challenging since closing the PDA can result in reduced cardiac output and right ventricular (RV) failure. The latest guideline for Adult Congenital Heart Disease (ACHD) stated it is harmful to close the defect in patients with pulmonary vascular resistance (PVR) ≤5 WU and flow ratio (FR) &lt;1.5. Case presentation: A 37-year-old female was referred with cough, fever, low saturation, and murmur findings. After serial examination, she was diagnosed with large PDA and severe PH her peripheral saturation (SaO2) was 88%-89% and non-responder to acute vasoreactivity test. After a year of PH therapy, vasoreactivity showed a response to the vasoreactivity test and improved on clinical presentation with SaO2 91%-92%. Patient fell in to PH crisis condition during the procedure of device closure, prostacyclin analogue intravenous (IV) and phosphodiesterase inhibitors inhalation was administered, and the procedure was carried on. The device was successfully implanted, and the patient had SaO2 97% in all four extremities before discharge. Conclusion: With established PH therapy, PDA with severe PH can underwent PDA closure by device with satisfying outcome. Keyword: Case Report, Congenital Heart Disease Intervention, Patent Ductus Arteriosus, Pulmonary Hypertension Crisis.

Management of Refractory Chronic Obstructive Pulmonary Disease: A Review

Chronic obstructive pulmonary disease (COPD) is a common condition with an estimated prevalence of 12% in adults over the age of 30 years worldwide. COPD is a leading cause of morbidity and mortality globally, with a substantial economic and social burden. There are an estimated 3 million deaths annually due to COPD. However, most of the patients with COPD respond to routine interventions like bronchodilator therapy, assessing supplemental oxygen needs, smoking cessation, vaccinations, and pulmonary rehabilitation. There is a significant number of patients who unfortunately progress to have persistent symptoms despite these interventions. Refractory COPD is not yet formally defined. Patients with severe persistent symptoms or exacerbations despite appropriate care can be considered to have refractory COPD. Managing refractory COPD needs a multidimensional approach. In this review article, we will discuss essential interventions like ensuring adequate inhaler techniques, exploring the need for non-invasive ventilatory support, use of chronic antibiotics and phosphodiesterase inhibitors to advanced therapies like bronchoscopic lung volume reduction surgery, and the upcoming role of anti-IL5 agents in managing patients with refractory COPD. We will also discuss non-pharmacologic interventions like psycho-social support and nutritional support. We will conclude by discussing the palliative care aspect of managing patients with refractory COPD. Through this review article, we aim to better the approach to managing patients with refractory COPD and discuss new upcoming therapies.

Efficacy of cilostazol in promoting the maturation of newly created arteriovenous fistula in patients with end-stage renal disease: a systematic review and meta-analysis

BACKGROUND Arteriovenous fistula (AVF) is considered the gold standard for vascular access in hemodialysis. However, achieving the successful maturation of AVF remains a challenge. Cilostazol, a phosphodiesterase-3 inhibitor, has shown promise in enhancing AVF maturation. This study aimed to assess the clinical efficacy of cilostazol in promoting AVF maturation.&#x0D; METHODS This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive systematic literature search was performed using PubMed, ScienceDirect, Cochrane Library, ProQuest, and Google Scholar to identify studies investigating the efficacy of cilostazol on the maturation of newly created AVF in patients with end-stage renal disease and published up to August 2023. The intervention group received perioperative cilostazol therapy, while the control group did not receive cilostazol. The outcomes were the maturation rate of AVF and AVF-related complications. Meta-analysis was conducted using Review Manager software version 5.3.&#x0D; RESULTS 5 studies involving 549 patients were included. The intervention group comprised 228 patients, while the control group comprised 321 patients. In the pooled analysis, patients in the intervention group had a significantly higher rate of AVF maturation (odds ratio [OR] = 2.18, 95% confidence interval [CI]: 1.29–3.68, p = 0.003, I2 = 47%) and a lower rate of AVF-related complications (OR = 0.46, 95% CI: 0.28–0.77, p = 0.003, I2 = 27%) compared to the control.&#x0D; CONCLUSIONS Cilostazol was associated with a higher rate of AVF maturation and a lower rate of AVF-related complications.

Possible retinotoxicity of long-term vardenafil treatment

Phosphodiesterase (PDE) inhibitors – such as vardenafil – are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform. A sustained rise in cGMP in photoreceptors is known to be toxic; therefore, we hypothesized that long-term vardenafil treatment might result in retinotoxicity. The hypothesis was tested in a clinically relevant animal model of type 2 diabetes mellitus. Histological experiments were performed on lean and diabetic Zucker Diabetic Fatty rats. Half of the animals were treated with vardenafil for six months, and the retinal effects were evaluated. Vardenafil treatment alleviated rod outer segment degeneration but decreased rod numbers in some positions and induced changes in the interphotoreceptor matrix, even in control animals. Vardenafil treatment decreased total retinal thickness in the control and diabetic groups and reduced the number of nuclei in the outer nuclear layer. Müller cell activation was detectable even in the vardenafil-treated control animals, and vardenafil did not improve gliosis in the diabetic group. Vardenafil-treated animals showed complex retinal alterations with improvements in some parameters while deterioration in others. Our results point towards the retinotoxicity of vardenafil, even without diabetes, which raises doubts about the retinal safety of long-term continuous vardenafil administration. This effect needs to be considered when approving PDE inhibitors for alternative indications.

Novel Topical Treatments for Itch.

The experience of itch often poses a burden on patient quality of life and has the capacity to inflict significant suffering. Topical therapies are a mainstay of treatment for many cutaneous and systemic diseases and afford patients the opportunity to manage their conditions without many of the systemic side effects of non-topical therapies. We review a multitude of new topical medications targeting the skin, immune system, and neural receptors. The list includes Janus kinase inhibitors, tyrosine kinase inhibitors, phosphodiesterase inhibitors, transient receptor vanilloid inhibitors, topical cannabinoids, and topical acetaminophen. Many of the topical therapies reviewed show promising data in phase2-3 clinical trials, but further research is needed to compare therapies head-to-head and test their efficacy on a broader range of conditions.

Beyond traditional pharmacology: evaluating phosphodiesterase inhibitors in autism spectrum disorder.

Beyond traditional pharmacology: evaluating phosphodiesterase inhibitors in autism spectrum disorder.

Topical Treatments in Atopic Dermatitis: An Expansive Review.

Atopic dermatitis (AD) is a common inflammatory skin condition found worldwide. It impacts patient quality of life (QoL) and is thought to arise as an inflammatory response to epidermal barrier dysfunction and hypersensitivity. AD can lead to large out-of-pocket costs and increased healthcare expenses over a lifetime. An analysis of all randomized control trials conducted since 1990 on topical therapies for AD were reviewed, including 207 trials in the final analysis. It was found that an average of 226 patients were enrolled over 2.43 arms. Common topical treatments included corticosteroids, calcineurin inhibitors, JAK inhibitors, and phosphodiesterase inhibitors. The most utilized tools to identify treatment efficacy were the EASI, IGA, SCORAD, and PGA. There was a paucity of data on trials that evaluated efficacy, QoL, and cost of treatment simultaneously. This review highlights the need for comprehensive trials that evaluate multiple aspects of treatment, including financial cost and QoL impact, to ensure each patient has the best treatment modality for the management of their AD.

Intracellular pathways of calcitonin gene-related peptide-induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP-induced relaxation of human isolated coronary arteries (HCA). HCA were obtained from heart valve donors (27 M, 25 F, age 54 ±2years). Concentration-response curves to human α-CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation. Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL-12330A, and PKA inhibitors Rp-8-Br-cAMPs and H89, did not inhibit CGRP-induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM-34 + apamin, iberiotoxin or glibenclamide, or the Gαq inhibitor YM-254890. Phosphodiesterase inhibitors induced a concentration-dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries. While CGRP signalling is generally assumed to act via cAMP, the CGRP-induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP-induced relaxation than generally believed.

Management of Pulmonary Hypertension in the Context of Heart Failure with Preserved Ejection Fraction.

To review the current evidence and modalities for treating pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF). In recent years, several therapies have been developed that improve morbidity in HFpEF, though these studies have not specifically studied patients with PF-HFpEF. Multiple trials of therapies specifically targeting the pulmonary vasculature such as phosphodiesterase (PDE) inhibitors, prostacyclin analogs, endothelin receptor antagonists (ERA), and soluble guanylate cyclase stimulators have also been conducted. However, these therapies demonstrated lack of consistency in improving hemodynamics or functional outcomes in PH-HFpEF. There is limited evidence to support the use of pulmonary vasculature-targeting therapies in PH-HFpEF. The mainstay of therapy remains the treatment of the underlying HFpEF condition. There is emerging evidence that newer HF therapies such as sodium-glucose transporter 2 inhibitors and angiotensin-receptor-neprilysin inhibitors are associated with improved hemodynamics and quality of life of patients with PH-HFpEF. There is also a growing realization that more robust phenotyping PH and right ventricular (RV) function may hold promise for therapeutic strategies for patients with PH-HFpEF.

Phosphodiesterase Inhibitors of Natural Origin

Abstract: Phosphodiesterases (PDEs) function to hydrolyze intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), regulating a variety of intracellular signal transduction and physiological activities. PDEs can be divided into 11 families (PDE1~11) and the diversity and complex expression of PDE family genes suggest that different subtypes may have different mechanisms. PDEs are involved in various disease pathologies such as inflammation, asthma, depression, and erectile dysfunction and are thus targets of interest for several drug discovery campaigns. Natural products have always been an important source of bioactive compounds for drug discovery, over the years several natural compounds have shown potential as inhibitors of PDEs. In this article, phosphodiesterase inhibitors of natural origin have been reviewed with emphasis on their chemistry and biological activities.

Natural and Synthetic Phosphodiesterase Inhibitors in 2023: an Update on the Impact on Neurological and Psychiatric Conditions.

This Perspective provides an updated overview on the involvement of phosphodiesterase (PDE) isoforms and of the corresponding inhibitors in neurological disorders, including dementia, Parkinson's disease, multiple sclerosis, neuropsychiatric conditions and cerebral ischemia. Particular attention has been dedicated to natural and semi-synthetic compounds. Translation into the clinic of preclinical results, toxicity profile and bioavailability represent the challenging aspects in the development of PDE inhibitors. With the aim of providing the latest updates to the reader, the 2023 contributions in the field were considered for the preparation of this Perspective.

Placenta-anchored tadalafil liposomes rescues intrauterine growth restriction through continuous placental blood perfusion improvement

Physiological or pathological hypoperfusion of the placenta is one of the main causes of intrauterine growth restriction (IUGR) which poses a significant risk to the health of the fetus and newborn. Tadalafil, a 5-type phosphodiesterase inhibitor, has previously been found to improve the symptoms of IUGR in various clinical studies. Unfortunately, its clinical utility is hindered by its limited water solubility, rapid metabolism, and lack of specific distribution in target tissues rendering tadalafil unable to maintain long-term placental perfusion. In this study, iRGD-modified tadalafil-loaded liposomes (iRGD-lipo@Tad) featuring a size of approximately 480 nm were designed to rectify the shortcomings of tadalafil. The prepared iRGD-lipo@Tad exhibited superior stability, sustained drug release capacity, and low cytotoxicity. The fluorescence study, tissue slice study, and drug biodistribution study together demonstrated the placenta-anchored ability of iRGD-modified liposomes. This was achieved by a dual approach consisting of the iRGD-mediated placenta-targeting effect and special particle size-mediated placenta resident effect. The pharmacokinetic study revealed a significant improvement in the in vivo process of tadalafil encapsulated by the iRGD-modified liposomes. In comparison to the tadalafil solution, the peak plasma concentration of iRGD-lipo@Tad was significantly increased, and the area under the curve was increased by about 7.88 times. In the pharmacodynamic study, iRGD-lipo@Tad achieved a continuous and efficient improvement of placental blood perfusion. This was achieved by decreasing the ratio of plasma soluble fms-like tyrosine kinase to placental growth factor and increasing the levels of cyclic guanosine monophosphate and nitric oxide. Consequently, iRGD-lipo@Tad resulted in a significant increase in embryo weight and a reduction in the miscarriage rate of N-Nitro-L-arginine methyl ester-induced IUGR pregnant mice without detectable toxicity. In summary, the nanotechnology-assisted therapy strategy presented here not only overcomes the limitations of tadalafil in the clinical treatment of IUGR but also offers new avenues to address the treatment of other placenta-originated diseases.

(029) Safety and Efficacy of Botulinum Neurotoxin in the Treatment of Erectile Dysfunction Refractory to Phosphodiesterase Inhibitors: Results of a Randomized Controlled Trial

Abstract Introduction There has been recent interest in the use of botulinum neurotoxin (BoNT) in the field of Andrology, whereby it has been investigated in the treatment of penile retraction and premature ejaculation. Objective To evaluate the safety and efficacy of intracavernosal BoNT-A injection in the treatment of patients with erectile dysfunction (ED) refractory to oral phosphodiesterase inhibitors (PDE5Is). Methods A double-blind randomized placebo-controlled prospective comparative study conducted at one center and involved 70 patients with ED refractory to PDE5Is. At baseline, the following data were collected: erection hardness score (EHS), peak systolic velocity (PSV), end diastolic velocity (EDV), sexual health inventory for men (SHIM), and the sexual encounter profile 2&amp;3 (SEP-2&amp;3) questionnaires. Treatment group (n = 35) received a single ICI of 100 units of BoNT-A in 2 ml of saline and control group (n = 35) received a single ICI of 2 ml of saline. EHS, PSV, and EDV were assessed at 2 weeks post treatment. SHIM, SEP-2, SEP-3, and global assessment questionnaire (GAQ-Q1&amp;Q2) were completed at 2-, 6-, and 12-weeks post treatment. Results Two weeks post treatment, the treatment group showed a statistically significant improvement in the mean EHS, PSV, EDV, and GAQ-Q1 positive responders (p &amp;lt; 0.001) compared to the control group. At 6- and 12-weeks post treatment, the treatment group showed a statistically significant improvement in the SHIM scores, SEP-2, and GAQ-Q1&amp;Q2 positive responders compared to the control group. At 6 weeks, where there was a 5-point improvement in the mean SHIM score of the treatment group (10±5.9 from 5.4±1.7 at baseline) versus no improvement in the placebo group, 18 patients in the treatment group (53%) were able to have an erection hard enough for vaginal penetration versus only one patient in the control group. Conclusions BoNT-A is safe and effective as a potential treatment for ED refractory to PDE5I therapy. Disclosure No.