Initial Experience with Mirabegron for the Treatment of Neurogenic Lower Urinary Tract Dysfunction

Background: Though anticholinergic drugs are considered the standard treatment for neurogenic detrusor overactivity, it is far from an ideal tool, because of their adverse effects such as Constipation or not respond sufficiently for a substantial proportion of patients. Recently mirabegron has become a commonly used overactive bladder medication in the general population, but few studies about mirabegron for the treatment of neurogenic detrusor overactivity. Objective: To evaluate the efficacy and safety of mirabegron for the treatment of neurogenic lower urinary tract dysfunction. Study Design: Prospective study. Methods: This prospective study included 13 adult patients with neurogenic lower urinary tract dysfunction as a result of spinal cord injury. All patients receiving mirabegron treatment (50 mg once daily) at least 6 weeks. The effective outcomes included the mean urine volume per catheterization, urinary incontinence episodes and Incontinence Specific Quality of Life Instrument. We monitored the blood pressure and heart rate to assess the cardiovascular safety, other adverse events were also recorded. Results: A total of 13 patients were included. After 6 weeks of treatment, all patients ex-perienced a significant increase in the mean volume of per catheterization from 238.46 ± 65.43 ml to 327.69 ± 59.04 ml (p = 0.001). There is a significant reduction in the


Introduction
Detrusor overactivity (DO) is characterized by spontaneous or provoked involuntary detrusor contractions during storage phase in urodynamic investigation [1] [2]. Neurogenic DO (NDO) is DO caused by various neurogenic diseases such as brain tumors, dementia, multiple sclerosis, Parkinson's disease, stroke and spinal cord injury (SCI) [3]. NDO can cause a variety of long-term complications such as urinary incontinence (UI), stones, hydronephrosis, recurrent urinary tract infection and Vesicoureteral reflux (VUR); the most dangerous being damage of renal function. These complications may markedly impact the quality of life of people with SCI, including limiting their behavior, causing social embarrassment and possibly threatening their life [4].
Anticholinergic drugs are considered the standard treatment for NDO. The positive effects of oxybutynin, trospium chloride, tolterodine, propiverine, and imidafenacin in increasing the bladder capacity and reducing the intravesical pressure have been documented in several studies [5]. Nevertheless, treatment with antimuscarinic drugs is frequently discontinued due to side effects (dry mouth and constipation) or a lack of efficacy [6]. In particular in patients with SCI, who suffer from a neurogenic bowel dysfunction, the concomitant antmiuscarinic treatment will worsen the constipation. Therefore, there is a need for therapy alternatives.
In recent years, mirabegron, a β3-adrenoreceptor agonist, was developed to target sympathetic nerve stimulated relaxation of the bladder, a mechanism of action that improves the storage capacity of the bladder without inducing anticholinergic-associated adverse events [7] [8].
Clinical trials have demonstrated its efficacy and safety [9] [10] and observational studies suggest improved persistence and adherence when compared to antimuscarinics [11]. As such, it has become a commonly used overactive bladder medication in the general population [12]. But few studies were carried on the treatment of mirabegron for NDO. The aim of this study was evaluated to evaluate the efficacy and safety of mirabegron for the treatment of neurogenic lower urinary tract dysfunction (NLUTD).

Material and Methods
In this prospective observational study, a total of 13 patients who received treatment with mirabegron 50 mg once daily at least 6 weeks from April to June 2021 in our SCI center were included. All eligible inpatients over 18 years of age with non-acute SCI (i.e. no progression in neurological symptoms in the previous 3 months) were screened for enrollment. The main inclusion criteria were: 1) urodynamic presence of DO; 2) bothersome urinary symptoms (frequency, urgency, urgency incontinence) and at least one episode of urgency/unaware incontinence during the 3-day voiding diary; 3) Patients or their caregivers agreed to perform clean intermittent catheterization (CIC); 4) Patients with previous injection of onabotuliuntoxin were included, if the last injection was at least 12 month before mirabegron treatment.
Though there is a little increase in the BP and HR, no one described headache, palpitation, dry mouth, constipation and other side effects.

Discussion
After SCI, most individuals develop NLUTD, which in the majority of cases requires assisted bladder emptying rather than volitional voiding. CIC is recom-  The β3-adrenergic agonist mirabegron was introduced into the treatment of iOAB in 2012. Its safety and efficacy in the treatment of this condition have been confirmed in a large number of well-designed studies [12]. In this study we also found improvement in the mean volume of per catheterization.
In human bladder, β3-adrenoceptors account for 97% of total β-adrenoceptor messenger RNA [19], and they are thought to be the main subtype mediating relaxation of detrusor smooth muscle during the storage phase [20]. However, β3-adrenoceptors are also expressed in CV tissues, so the treatment with β3adrenoceptor agonists may have "off-target" effects on regulation of the heart and vasculature [21]. In our study, there is a little increase in SBP, DBP and HR, but none of them were significant differences from baseline, similar to the previous studies [22] [23]. And no patients reported dry mouth during the study, so regarding safety, we did not observe severe side effects. There is no doubt some limitations in the present study. The small number of patients included and the lack of a control group for comparison. Furthermore, we had no use urodynamic to evaluated the efficacy of 50 mg mirabegron for the treatment of NLUTD.

Conclusion
Mirabegron is safe and effective in the treatment of neurogenic lower urinary tract dysfunction. It might be a good choice for reducing the cessation of clean intermittent catheterization.

Funding
This study was supported by: Medical Scientific Research Foundation of Guangdong Province, China (grant number A2021221).
Traditional Chinese Medicine of Guangdong Province, China (grant number 20212034).