**1. Introduction**

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease with suprapubic pain or discomfort related to bladder filling, urinary frequency and urgency, resulting in a serious impairment of quality of life [1]. However, the current treatments for IC/BPS struggle to maintain long-term efficacy and the symptoms of IC/BPS are prone to recurrence because of its obscure etiology and pathogenesis [2].

It is proposed that an injured urothelium and neural hypersensitivity of the bladder might exacerbate chronic inflammation and immune responses in IC/BPS patients, causing persistent bladder pain and urinary frequency [3,4]. In fact, bladder pain or discomfort often drives urinary frequency and nocturia [5]. Botulinum toxin A (BoNT/A) might decrease the neural hypersensitivity of the bladder to relieve bladder pain and urination frequency and urgency [6]. However, the average effective duration of BoNT/A injection was only

**Citation:** Li, W.; Zheng, Z.; Ma, K.; Zhang, C.; Li, K.; Tayier, P.; Yao, Y. Preliminary Exploration of a New Therapy for Interstitial Cystitis/Bladder Pain Syndrome: Botulinum Toxin A Combined with Sapylin. *Toxins* **2022**, *14*, 832. https://doi.org/10.3390/ toxins14120832

Received: 14 October 2022 Accepted: 28 November 2022 Published: 30 November 2022

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about 6 months, so repeated injection was required [7]. Therefore, a new therapy to extend the response duration is needed to reduce the burden on patients and health systems.

The immune and inflammatory responses might play a crucial role in the pathogenesis of IC/BPS [1]. Many researchers have shown that inflammatory factors, such as interleukin-6 and tumor necrosis factor-alpha (TNFα), are significantly increased in the bladder tissue of IC/BPS patients [8–10]. In addition, Bosch's research demonstrated that subcutaneous certolizumab pegol, an anti-TNFα agent, significantly improved patients' symptoms compared with placebo therapy [11]. Later, Mishra et al. pointed out that an intravesical instillation of tacrolimus had a significant effect on the treatment of IC/BPS by inhibiting the immune response [12]. These conditions show that immunotherapy for IC/BPS is a reasonable option.

Sapylin (OK-432) is a lyophilized preparation made from a low-virulence strain (Su) of Streptococcus pyogenes (group A) incubated with penicillin [13], which is successfully used as an immunotherapeutic agen<sup>t</sup> in many malignant cancers [14,15]. In addition, many researchers found that Sapylin also had immunotherapeutic effects on bladder cancer, creating the possibility for it to treat bladder diseases [16–18]. In an animal study, researchers found that Sapylin might accelerate wound closure and promote angiogenesis, collagen synthesis and the remodeling process to improve wound healing and reduce seroma formation [19]. These promising results seemed to indicate a possibility that Sapylin might be used as an immunotherapeutic agen<sup>t</sup> in IC/BPS by repairing injured urothelium.

At present, there are many therapeutic methods for relieving IC/BPS symptoms but these are symptomatic and their efficacy is not long lasting. As a consequence, most IC/BPS patients inevitably suffer again and continue to wait for an innovative formulation. Luckily, we found a new treatment scheme (repeated intravesical instillations of Sapylin after BoNT/A injection) that could more persistently improve the symptoms of IC/BPS patients. In this study, we would like to summarize and share the results of our preliminary exploration.
