Molecular surgery of overactive bladder symptome

Overactive bladder syndrome, a common type of micturition disorder, can lead to the loss of bladder control, which is then known as urge incontinence.

First capsaicin (CAP), then resiniferatoxin (RTX), were tried as experimental drugs to inactivate incontinency in the clinical settings (Figure 1). It has been long known that these reflexes in the bladder are mediated by C- and Ad-fiber afferents of nociceptive neurons located in the sacral DRGs.

The Afferon Inc., in the late 90's, patented a method of treating neurogenic urinary dysfunction with RTX (Cruz & Agersborg, 2003), and has enrolled patients affected with urge incontinence due to various neurological diseases. The Afferon Ltd. was admitted into phase II clinical trials.

Currently, Eli Lilly and Company has exclusive worldwide license rights for the commercial use of RTX for the treatment of bladder disease or function. Unfortunately, in contrast to these practices (Foster & Lake, 2014; Guo et al., 2013), RTX is still not a registered drug.

Nevertheless, the effectiveness of intravesical RTX treatment strongly varies from study to study. The reasons for these inconsistencies in the clinical outcome might be manifold: too dilute samples of vanilloids were used, different origins of the latent disease resulting in urinary disfunction, or the simple lack of a significant effect of RTX in a specific type of urinary problem. 

Figure 1.

We would like to pay attention to the fact that strong adsorption of RTX and CAP molecules into the tubes of the application devices might also occur. These technical problems can cause a huge variance in the clinical outcomes. Animal experiments will be required to obtain the appropriate material for these tubes. By using a water-soluble formulation of vanilloids (Appendino, Ech-Chahad, Minassi, De Petrocellis, & Di Marzo, 2010) the adsorption of vanilloid molecules onto the tubes might also be avoidable. The loss of the TRPV1+ nerve endings in the urothelium can serve as a marker for the successful intravesical instillation (Oláh, 2021; Oláh & Jakab, 2024; Oláh & Julius, 2021; Oláh & Kocsis, 2024).

Topical intravesical medication of RTX via transurethral instillation promises several advantages over oral systemic CAP therapy. Intravesically administered RTX penetrates the vesical mucosa and submucosa by diffusion and binds to TRPV1+ nerve endings. The suggested "balloon dilator" method benefits from the increased surface of urothelium due to the thinning of the bladder mucosa (Pecze, Viskolcz, & Olah, 2017).  

References

Appendino, G., Ech-Chahad, A., Minassi, A., De Petrocellis, L., & Di Marzo, V. (2010). Structure-activity relationships of the ultrapotent vanilloid resiniferatoxin (RTX): The side chain benzylic methylene. Bioorg Med Chem Lett, 20(1), 97-99. doi:10.1016/j.bmcl.2009.11.035

Cruz, H., & Agersborg, H. (2003). Urinary incontinence therapy. Patent publication US20040039052A1. doi:https://patents.google.com/patent/US20040039052A1/en

Foster, H. E., Jr., & Lake, A. G. (2014). Use of vanilloids in urologic disorders. Prog Drug Res, 68, 307-317. doi:10.1007/978-3-0348-0828-6_13

Guo, C., Yang, B., Gu, W., Peng, B., Xia, S., Yang, F., . . . Zheng, J. (2013). Intravesical resiniferatoxin for the treatment of storage lower urinary tract symptoms in patients with either interstitial cystitis or detrusor overactivity: a meta-analysis. PLoS One, 8(12), e82591. doi:10.1371/journal.pone.0082591

Oláh, z. (2021). Az USA morfinkrízistől az opioid-leváltó Molekuláris Idegsebészetig. Acheuron/Molekuláris Idegsebészet. doi:https://youtu.be/KZn9euN1svI

Oláh, z., & Jakab, I. (2024). A morfin leváltó Molekuláris Idegsebészet klinikai bevezetésének időszerűségéről. Acheuron/Molekuláris Idegsebészet. doi:https://www.youtube.com/watch?v=RqvSpVuxtFA

Oláh, z., & Julius, D. (2021). A kapszaicin-receptortól a molekuláris idegsebészetig. A-Delta. doi:https://youtu.be/9hDWJUze_qo

Oláh, z., & Kocsis, É. (2024). Molekuláris Idegsebészet. Acheuron Szuperkórház. doi:https://www.acheuron.com/molekularis-idegsebeszet/

Pecze, L., Viskolcz, B., & Olah, Z. (2017). Molecular Surgery Concept from Bench to Bedside: A Focus on TRPV1+ Pain-Sensing Neurons. Front Physiol, 8, 378. doi:10.3389/fphys.2017.00378