Bromelain and Tamsulosin for Distal Ureter Stones Study: Preliminary Results

1. Medical Expulsive Therapy for Symptomatic Distal Ureter Stones: Is the Combination of Bromelain and Tamsulosin More Effective than Tamsulosin Alone? Preliminary Results of a Single-Center Study Palmisano, F. et.al Urologia Internationalis Powerpoint by Wilmark N. Gular, MD

2. Introduction

3. Bromelain is a phytochemical found abundantly in the stem of pineapple (Ananas comosus). • It functions as a protease that exhibit multiple therapeutic potentials. • It has anti-inflammatory, fibrinolytic, and chemotherapeutic properties. Image from: https://www.123rf.com/stock-photo/pineapple.html?sti=lgzj0hlz0sfkisuohv|&mediapopup=19273272

4. Bromelain can inhibit the proinflammatory enzyme cyclooxygenase-2 (COX-2).1 • COX-2 is an enzyme that catalyzes the production of prostaglandin E-2 (PGE-2), a major inflammatory lipid. • Aside from inducing inflammation, PGE-2 also suppresses immunity and promotes tumor progression through angiogenesis and increase in tumor growth. • Bromelain also promotes the production of inflammatory cytokines interleukin 1β, interleukin -6, interferon γ, and tumor necrosis factor-α. However, it stops promoting the activity of the said inflammatory markers when they have already been activated by other mechanisms. 1

5. The prevalence of urolithiasis varies from one to twenty percent. Its incidence is dependent on dietary, genetic, climactic, ethnic, and cultural factors. 2 • In 2015, the European Association of Urology (EAU) has released a guideline on the diagnosis and conservative management of urolithiasis. 3 • In this guideline, medical expulsive therapy (MET) was recommended to facilitate spontaneous passage of ureteral stones. • Pharmacological agents used in MET include α-adrenergic antagonists like tamsulosin. https://www.123rf.com/stock-photo/ureteral_stone.html?&sti=nr94iy32flq7c85hfr|&mediapopup=44204616

6. Aside from the stone and its size, the mucosal layer of the ureter also contribute to passage of urolithiasis. • Mucosal edema may hinder stone egress. Bromelain, through its anti-inflammatory activity, inhibits mucosal edema and works to facilitate spontaneous stone passage. • Palmisano, F. et al. conducted a single-center study in 2018 that evaluated the effect of the bromelain and tamsulosin versus tamsulosin alone as medical expulsive therapy for the spontaneous stone passage of distal ureteral stones. 4

7. Relevance

8. Ureteral stones can be conservatively managed through observation or watchful waiting. However, this period can take up to thirty to forty days and may result to a number of complications necessitating invasive tests and intensive medical management. With medical expulsive therapy, spontaneous stone passage can be observed in a span of ten to twelve days. Alpha-adrenergic blockers such as tamsulosin are the commonly used MET for ureteral stones due to their smooth muscle relaxing property. The addition of an anti-inflammatory such as bromelain may be warranted to decrease the edema in the ureter.

9. Objectives

10. This study aims to establish the safety and efficacy of bromelain and tamsulosin versus tamsulosin alone as medical expulsive therapy for spontaneous passage of symptomatic distal ureteral stones among adults

11. Highlights

12. The study has a prospective cohort design. It was conducted in a one-year period spanning from December 2016 to November 2017. • The primary outcome measured was spontaneous stone passage within thirty days. • Secondary outcomes were the detection of time of spontaneous stone passage, adverse events of MET, and the need for hospitalization or endoscopic treatment.

13. One hundred and twenty two adult subjects (18 to 85 years old) presenting with symptomatic ureteral stones were recruited. • They were given 500 mg of bromelain in 2, 500 gelatin digesting units (GDUs) on an empty stomach along with 0.4mg of tamsulosin. • This regimen was done until spontaneous stone passage with a maximum period of thirty days. • The cases were matched with a historical cohort receiving tamsulosin alone as MET. There was no statistical difference in the baseline characteristics for cases and controls.

14. A total of 114 cases completed the study and these were matched with 114 controls. An intention to treat analysis was performed. Logistic regression was used to correlate expulsion with the use of bromelain with the size of the stone as a variable. • From the 114 cases analyzed, 100 were able to expel the ureteral stone. This was 12.3% higher than the control group receiving tamsulosin alone (87.7 vs 75.4%) and was statistically significant. • When bromelain was added to tamsulosin, the probability of spontaneous stone passage increased by a mean of 3.3.

15. Two episodes of hypotension were recorded, one coming from the cases and one from the control group. • There were no reported side effects related to bromelain use. • The time to self-reported spontaneous stone passage was 11.68 for the bromelain and tamsulosin group and 11.57 for the tamsulosin group. • The 14 cases who did not have spontaneous passage had to undergo through a specific procedure for stone removal. Three cases from this group underwent ureteral stenting while 5 patients underwent extracorporeal shock wave lithotripsy (ESWL) and 6 had to undergo ureteroscopy. • Medical expulsive therapy did not work for 28 controls. Six controls underwent stenting and 18 underwent ESWL while the remaining 4 underwent ureteroscopy.

16. Conclusion

17. The addition of bromelain to tamsulosin was more effective than tamsulosin alone as medical expulsive therapy for spontaneous passage of distal ureteral stones among adults. Furthermore, bromelain had no side effect and was deemed safe.

18. REFERENCES: 1. Rathnavelu, V. et al. Potential Role of Bromelain in Clinical and Therapeutic Applications (Review). Biomedical Reports. July 7, 2016. 2. Trinchieri, A. et al. Epidemiology in Stone Disease. Health Publications: Paris. 2003. 3. Turk, C. et al. European Association of Urology Guidelines on Diagnosis and Conservative Management of Urolithiasis. European Urology. 2016. 4. Palmisano, Franco et.al. Medical Expulsive Therapy for Symptomatic Distal Ureter Stones: Is the Combination of Bromelain and Tamsulosin More Effective than Tamsulosin Alone? Preliminary Results of a Single-Center Study. Urologia Internationalis. May 19, 2018.