madman
Super Moderator
Abstract
Background: Erectile dysfunction (ED) is a socio-economic problem.There are several options for its management including intra-cavernosal injection (ICI).
Objective: To compare the safety, efficacy, and durability of ICI of onabotulinum toxin-A (BTX) in different doses (50 and 100 U) against placebo (saline) in the management of vasculogenic ED non-responding to pharmacological therapy (phosphodiesterase type 5 inhibitors or/and ICI of trimix).
Materials and Methods: A prospective randomized double-blind placebo-controlled trial was conducted between July 2016 and February 2019. A total of 176 patients were randomly assigned (1:1:1) to one of the treatment sequences: Botox 100 U group (BTX-100; 62 patients), Botox 50 U group (BTX-50; 59 patients), or placebo group (55 patients). All patients were followed up for 6 months.
Results: Significant improvement in all parameters, that is, SHIM score & Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), Global Assessment Score (GAS), and Doppler parameters (p < 0.001) was observed in patients of BTX-100 and BTX-50 groups with maximum improvement at the 3rd month of treatment. Around 40% of patients were responders and were able to engage in sexual intercourse. Patients in placebo group did not experience significant improvement (p = 0.264). It was noted that at the 2nd week and 3rd months after treatment, there was no statistically significant difference in the improvement of these parameters in BTX-100 and BTX-50 groups (p > 0.05). In the 6th month, there was a statistically significant difference between the aforementioned groups in favor of BTX-100 (p < 0.01).
Conclusions: Only one-time ICI of BTX (50 U and 100 U) is effective and safe for the treatment of refractory ED. This agent has a considerably long duration of action, particularly BTX-100U seems to be more durable.
1 | INTRODUCTION
Erectile dysfunction (ED), which is defined as a persistent inability to achieve or maintain a penile erection sufficient to permit satisfactory sexual performance, represents a significant medical challenge with an immense sociomedical and economical burden.1
The prevalence of ED is usually associated with other medical comorbidities such as cardiometabolic syndrome, neuropsychological disorders, and depression. The prevalence of ED is anticipated to affect about 1/3 billion patients by the year 20252 with an actual increase in its incidence among juniors.3
Several treatment modalities for ED are available including penile prosthesis, intra-cavernous injection (ICI), intra-urethral therapy, and oral phosphodiesterase type 5 inhibitors (PDE5Is). Despite the advances in oral and intra-urethral treatments, ICI remains a viable and effective second-line therapy for many patients.4-7 Recently, the application of stem cells and gene therapy for ED treatment has shown some early promise but disappointing clinical outcomes.8
Although the current modalities for ED treatment demonstrate some degree of clinical success, many of these modalities suffer from inherent disadvantages such as modest efficacy, lack of durability, and short-term efficacy, and sometimes debilitating side effects.8 Thus, the development of effective, safe, and durable treatment of ED, particularly the refractory vasculogenic erectile dysfunction, is a pressing and unmet medical need.
Approximately four out of five patients with ED are attributed to organic etiologies with multiple signal transduction pathways converge to endothelial dysfunction.9 Thus, effective therapy of vasculogenic ED should be directed toward this factor.
Onabotulinum toxin-A (BTX) is widely used for the treatment of various medical conditions.8,10 BTX exerts multiple pharmacological effects, which may qualify BTX as a therapeutic candidate for the treatment of ED. For instance, it blocks the release of acetylcholine and norepinephrine-mediated sympathetic pathway and increases the expression of vascular endothelial growth factor and CD31.11 The expression of these factors and the activation of its downstream signaling cascades enhance vasodilation and endothelial cell proliferation and thus are involved in the pathophysiology of ED. These findings represent the theoretical and molecular rationale for the potential effects of BTX in the treatment of vasculogenic ED. Indeed, several reported a durable efficacy of BTX in the treatment of several vasospastic disorders such as Raynaud's phenomenon.12
*Indeed, until now, there is no well-conducted human study that investigated a suitable dose of BTX-A as an ICI for the treatment of ED. Thus, we carried out this prospective, randomized, double-blinded, and controlled trial to test the hypothesis that treatment with BTX-A (50 or 100 U) can exert a durable, safe, and beneficial therapeutic effect for management of drugs non-responders ED patients.
4 | DISCUSSION
Our findings suggest that BTX might provide a safe, effective, and relatively durable improvement of ED. Several mechanisms are proposed for the potential therapeutic effect of BTX in the treatment of many vasculogenic disorders, including ED. For instance, BTX inhibits sympathetic adrenergic or cholinergic vasoconstriction, sensory nerves, and/or endothelial exocytosis of endothelin 1, which are involved in the pathophysiology of erectile dysfunction.8,17 Mounting evidence suggests that the effects BTX are mediated by non–nitric-oxide-mediated mechanism. Instead, it inhibits the neuronal membrane fusion with the synaptic vesicles that contain norepinephrine neurotransmitters. So, preventing the release of norepinephrine rather than nitric oxide.8 These effects might lead to a decrease in the tone of resistance penile vessels, an increase in resting blood flow, and a reduction in persistent cavernosal smooth muscle tone. BTX-A injection induces sinusoidal dilatation of cavernous tissue which seems to be mediated by smooth muscle relaxation.18,19
*Ultimately, these effects are responsible for, at least in part, facilitating an erectile response to sexual stimulation through its modulatory effect on the erectile tissue8,20
5 | CONCLUSIONS
Treatment of refractory ED by single ICI of BTX was found to be effective, durable, and safe. All noted complications were related to ICI of vasoactive agents during subsequent follow-up penile Doppler studies. While ICI of BTX helped around 40% of patients to restart their sexual activities, around 60% of patients were still not able to complete intercourse.
This novel application of ICI BTX demonstrated a considerable long duration of action, which lasts at least 3–6 months. Although both 50 U and 100 U are effective and safe, BTX-100 appears to be more durable. Further studies with different doses are warranted to confirm current results.
Background: Erectile dysfunction (ED) is a socio-economic problem.There are several options for its management including intra-cavernosal injection (ICI).
Objective: To compare the safety, efficacy, and durability of ICI of onabotulinum toxin-A (BTX) in different doses (50 and 100 U) against placebo (saline) in the management of vasculogenic ED non-responding to pharmacological therapy (phosphodiesterase type 5 inhibitors or/and ICI of trimix).
Materials and Methods: A prospective randomized double-blind placebo-controlled trial was conducted between July 2016 and February 2019. A total of 176 patients were randomly assigned (1:1:1) to one of the treatment sequences: Botox 100 U group (BTX-100; 62 patients), Botox 50 U group (BTX-50; 59 patients), or placebo group (55 patients). All patients were followed up for 6 months.
Results: Significant improvement in all parameters, that is, SHIM score & Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), Global Assessment Score (GAS), and Doppler parameters (p < 0.001) was observed in patients of BTX-100 and BTX-50 groups with maximum improvement at the 3rd month of treatment. Around 40% of patients were responders and were able to engage in sexual intercourse. Patients in placebo group did not experience significant improvement (p = 0.264). It was noted that at the 2nd week and 3rd months after treatment, there was no statistically significant difference in the improvement of these parameters in BTX-100 and BTX-50 groups (p > 0.05). In the 6th month, there was a statistically significant difference between the aforementioned groups in favor of BTX-100 (p < 0.01).
Conclusions: Only one-time ICI of BTX (50 U and 100 U) is effective and safe for the treatment of refractory ED. This agent has a considerably long duration of action, particularly BTX-100U seems to be more durable.
1 | INTRODUCTION
Erectile dysfunction (ED), which is defined as a persistent inability to achieve or maintain a penile erection sufficient to permit satisfactory sexual performance, represents a significant medical challenge with an immense sociomedical and economical burden.1
The prevalence of ED is usually associated with other medical comorbidities such as cardiometabolic syndrome, neuropsychological disorders, and depression. The prevalence of ED is anticipated to affect about 1/3 billion patients by the year 20252 with an actual increase in its incidence among juniors.3
Several treatment modalities for ED are available including penile prosthesis, intra-cavernous injection (ICI), intra-urethral therapy, and oral phosphodiesterase type 5 inhibitors (PDE5Is). Despite the advances in oral and intra-urethral treatments, ICI remains a viable and effective second-line therapy for many patients.4-7 Recently, the application of stem cells and gene therapy for ED treatment has shown some early promise but disappointing clinical outcomes.8
Although the current modalities for ED treatment demonstrate some degree of clinical success, many of these modalities suffer from inherent disadvantages such as modest efficacy, lack of durability, and short-term efficacy, and sometimes debilitating side effects.8 Thus, the development of effective, safe, and durable treatment of ED, particularly the refractory vasculogenic erectile dysfunction, is a pressing and unmet medical need.
Approximately four out of five patients with ED are attributed to organic etiologies with multiple signal transduction pathways converge to endothelial dysfunction.9 Thus, effective therapy of vasculogenic ED should be directed toward this factor.
Onabotulinum toxin-A (BTX) is widely used for the treatment of various medical conditions.8,10 BTX exerts multiple pharmacological effects, which may qualify BTX as a therapeutic candidate for the treatment of ED. For instance, it blocks the release of acetylcholine and norepinephrine-mediated sympathetic pathway and increases the expression of vascular endothelial growth factor and CD31.11 The expression of these factors and the activation of its downstream signaling cascades enhance vasodilation and endothelial cell proliferation and thus are involved in the pathophysiology of ED. These findings represent the theoretical and molecular rationale for the potential effects of BTX in the treatment of vasculogenic ED. Indeed, several reported a durable efficacy of BTX in the treatment of several vasospastic disorders such as Raynaud's phenomenon.12
*Indeed, until now, there is no well-conducted human study that investigated a suitable dose of BTX-A as an ICI for the treatment of ED. Thus, we carried out this prospective, randomized, double-blinded, and controlled trial to test the hypothesis that treatment with BTX-A (50 or 100 U) can exert a durable, safe, and beneficial therapeutic effect for management of drugs non-responders ED patients.
4 | DISCUSSION
Our findings suggest that BTX might provide a safe, effective, and relatively durable improvement of ED. Several mechanisms are proposed for the potential therapeutic effect of BTX in the treatment of many vasculogenic disorders, including ED. For instance, BTX inhibits sympathetic adrenergic or cholinergic vasoconstriction, sensory nerves, and/or endothelial exocytosis of endothelin 1, which are involved in the pathophysiology of erectile dysfunction.8,17 Mounting evidence suggests that the effects BTX are mediated by non–nitric-oxide-mediated mechanism. Instead, it inhibits the neuronal membrane fusion with the synaptic vesicles that contain norepinephrine neurotransmitters. So, preventing the release of norepinephrine rather than nitric oxide.8 These effects might lead to a decrease in the tone of resistance penile vessels, an increase in resting blood flow, and a reduction in persistent cavernosal smooth muscle tone. BTX-A injection induces sinusoidal dilatation of cavernous tissue which seems to be mediated by smooth muscle relaxation.18,19
*Ultimately, these effects are responsible for, at least in part, facilitating an erectile response to sexual stimulation through its modulatory effect on the erectile tissue8,20
5 | CONCLUSIONS
Treatment of refractory ED by single ICI of BTX was found to be effective, durable, and safe. All noted complications were related to ICI of vasoactive agents during subsequent follow-up penile Doppler studies. While ICI of BTX helped around 40% of patients to restart their sexual activities, around 60% of patients were still not able to complete intercourse.
This novel application of ICI BTX demonstrated a considerable long duration of action, which lasts at least 3–6 months. Although both 50 U and 100 U are effective and safe, BTX-100 appears to be more durable. Further studies with different doses are warranted to confirm current results.
