Objectives: To assess the safety and efficacy of bromelain plus tamsulosin versus tamsulosin alone as medical expulsive therapy (MET) for promoting spontaneous stone passage (SSP) of symptomatic distal ureter stones. Patients and Methods: One-hundred-fourteen patients with a 4–10 mm distal ureteral stone were enrolled (Group A). Patients self-administered daily bromelain with tamsulosin for 30 days or until SSP or intervention was mandatory. Patients were compared to those from a control group taking tamsulosin as MET (Group B) and matched for the following factors: sex, age ±10%, stone diameter. A logistic regression model evaluated bromelain and the ureteral stone diameter as explanatory variables. Results: SSP rates were 87.7 vs. 75.4% for group A vs. group B respectively (p = 0.016); with no difference observed for the time to self-reported stone expulsion (11.68 vs. 11.57 days; p = 0.91). Considering larger stones (> 5 mm), the SSP rate was 83.3% in group A and 61% in group B (p < 0.01). With each millimeter increment of stone diameter, the probability of SSP decreased by 59.1% (p < 0.0001), while it increased of 3.3 when bromelain was present. Only 3 cases of tamsulosin-related adverse events were recorded. Conclusion: The association of bromelain and tamsulosin as MET increases the probability of SSP of symptomatic distal ureteral stones, with no bromelain-related side effects recorded.

Keywords:
Bromelain, Tamsulosin, Alpha blocker, Renal colic, Ureter stone, Medical expulsive therapy, Urolithiasis
1.
Bultitude M, Rees J: Management of renal colic. BMJ 2012; 345:e5499.
2.
Cupisti A, Pasquali E, Lusso S, Carlino F, Orsitto E, Melandri R: Renal colic in Pisa emergency department: epidemiology, diagnostics and treatment patterns. Intern Emerg Med 2008; 3: 241–244.
3.
Brown J: Diagnostic and treatment patterns for renal colic in US Emergency Departments. Int Urol Nephrol 2006; 38: 87–92.
4.
Türk C, Petřík A, Sarica K, Seitz C, Skolarikos A, Straub M, Knoll T: EAU Guidelines on Diagnosis and Conservative Management of Urolithiasis. Eur Urol 2016; 69: 468–474.
5.
Bader MJ, Eisner B, Porpiglia F, Preminger GM, Tiselius HG: Contemporary management of ureteral stones. Eur Urol 2012; 61: 764–772.
6.
Skolarikos A, Laguna MP, Alivizatos G, Kural AR, de la Rosette JJ: The role for active monitoring in urinary stones: a systematic review. J Endourol 2010; 24: 923–930.
7.
Porpiglia F, Vaccino D, Billia M, Renard J, Cracco C, Ghignone G, Scoffone C, Terrone C, Scarpa RM: Corticosteroids and tamsulosin in the medical expulsive therapy for symptomatic distal ureter stones: single drug or association? Eur Urol 2006; 50: 339–344.
8.
Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Türk C, Wolf JS Jr; EAU/AUA Nephrolithiasis Guideline Panel: 2007 guideline for the management of ureteral calculi. J Urol 2007; 178: 2418–2434.
9.
Segura JW, Preminger GM, Assimos DG, Dretler SP, Kahn RI, Lingeman JE, Macaluso JN Jr: Ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. The American Urological Association. J Urol 1997; 158: 1915–1921.
10.
Borghi L, Meschi T, Amato F, Novarini A, Giannini A, Quarantelli C, Mineo F: Nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double-blind, placebo-controlled study. J Urol 1994; 152: 1095–1098.
11.
Dellabella M, Milanese G, Muzzonigro G: Medical-expulsive therapy for distal ureterolithiasis: randomized prospective study on role of corticosteroids used in combination with tamsulosin-simplified treatment regimen and health-related quality of life. Urology 2005; 66: 712–715.
12.
Furyk JS, Chu K, Banks C, Greenslade J, Keijzers G, Thom O, Torpie T, Dux C, Narula R: Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med 2016; 67: 86–95.
13.
Rathnavelu V, Alitheen NB, Sohila S, Kanagesan S, Ramesh R: Potential role of bromelain in clinical and therapeutic applications. Biomed Rep 2016; 5: 283–288.
14.
Passali D, Bellussi LM, Sarafoleanu C, Loglisci M, Manea C, Iosif C, Passali FM: Penetration of bromelain in serum and rhinosinusal mucosa in patients undergoing endoscopic sinus surgery. J Pharmacol Pharmacother 2017; 8: 128–129.
15.
Tadikonda A, Pentapati KC, Urala AS, Acharya S: Anti-plaque and anti-gingivitis effect of Papain, Bromelain, Miswak and Neem containing dentifrice: a randomized controlled trial. J Clin Exp Dent 2017; 9:e649–e653.
16.
Zhou Z, Wang L, Feng P, Yin L, Wang C, Zhi S, Dong J, Wang J, Lin Y, Chen D, Xiong Y, Peng J: Inhibition of epithelial TNF-α receptors by purified fruit bromelain ameliorates intestinal inflammation and barrier dysfunction in colitis. Front Immunol 2017; 8: 1468.
17.
Cai T, Tiscione D, Gallelli L, Verze P, Palmieri A, Mirone V, Bartoletti R, Malossini G: Serenoa repens associated with selenium and lycopene extract and bromelain and methylsulfonylmethane extract are able to improve the efficacy of levofloxacin in chronic bacterial prostatitis patients. Arch Ital Urol Androl 2016; 88: 177–182.
18.
Gallo L: The effect of a pure anti-inflammatory therapy on reducing prostate-specific antigen levels in patients diagnosed with a histologic prostatitis. Urology 2016; 94: 198–203.
19.
Ye Z, Zeng G, Yang H, Tang K, Zhang X, Li H, Li W, Wu Z, Chen L, Chen X, Liu X, Deng Y, Pan T, Xing J, Wang S, Cheng Y, Gu X, Gao W, Yang J, Zhang Y, Mi Q, Qi L, Li J, Hu W, Liang P, Sun Z, Xu C, Long Y, Liao Y, Liu S, Liu G, Xu X, He W, Chen Z, Xu H: Efficacy and safety of tamsulosin in medical expulsive therapy for distal ureteral stones with renal colic: a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 2017: pii: S0302-2838(17)30972-7.
20.
Abdel-Meguid TA, Tayib A, Al-Sayyad A: Tamsulosin to treat uncomplicated distal ureteral calculi: a double blind randomized placebo-controlled trial. Can J Urol 2010; 17: 5178–5183.
21.
Smith-Bindman R, Aubin C, Bailitz J, et al: Ultrasonography versus computed tomography for suspected nephrolithiasis. N Engl J Med 2014; 371: 1100–1110.
22.
Liu XJ, Wen JG, Wan YD, Hu BW, Wang QW, Wang Y: Role of silodosin as medical expulsive therapy in ureteral calculi: a meta-analysis of randomized controlled trials. Urolithiasis 2018; 46: 211–218.
23.
Gharib T, Mohey A, Fathi A, Alhefnawy M, Alazaby H, Eldakhakhny A: Comparative study between silodosin and tamsulosin in expectant therapy of distal ureteral stones. Urol Int 2018; 101: 161–166.
24.
Seitz C, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U: Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol 2009; 56: 455–471.
25.
Campschroer T, Zhu Y, Duijvesz D, Grobbee DE, Lock MT: Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev 2014; 4:CD008509.
26.
Pickard R, Starr K, MacLennan G, Lam T, Thomas R, Burr J, McPherson G, McDonald A, Anson K, N’Dow J, Burgess N, Clark T, Kilonzo M, Gillies K, Shearer K, Boachie C, Cameron S, Norrie J, McClinton S: Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015; 386: 341–349.
27.
Sur RL, Shore N, L’Esperance J, Knudsen B, Gupta M, Olsen S, Shah O: Silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, double-blinded, placebo-controlled trial. Eur Urol 2015; 67: 959–964.
28.
Hollingsworth JM, Canales BK, Rogers MA, Sukumar S, Yan P, Kuntz GM, Dahm P: Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ 2016; 355:i6112.
29.
Saita A, Bonaccorsi A, Marchese F, Condorelli SV, Motta M: Our experience with nifedipine and prednisolone as expulsive therapy for ureteral stones. Urol Int 2004; 72: 43–45.
30.
Muller S, Marz R, Schmolz M, Drewelow B, Eschmann K, Meiser P: Placebo-controlled randomized clinical trial on the immunomodulating activities of low- and high-dose bromelain after oral administration – new evidence on the antiinflammatory mode of action of bromelain. Phytother Res 2013; 27: 199–204.
31.
Kerkhoffs GM, Struijs PA, de Wit C, Rahlfs VW, Zwipp H, van Dijk CN: A double blind, randomised, parallel group study on the efficacy and safety of treating acute lateral ankle sprain with oral hydrolytic enzymes. Br J Sports Med 2004; 38: 431–435.
32.
Golezar S: Ananas comosus effect on perineal pain and wound healing after episiotomy: a randomized double-blind placebo-controlled clinical trial. Iran Red Crescent Med 2016; 18:e21019.
33.
Braun JM, Schneider B, Beuth HJ: Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS in children with acute sinusitis in Germany. In Vivo 2005; 19: 417–421.
34.
Majid OW, Al-Mashhadani BA: Perioperative bromelain reduces pain and swelling and improves quality of life measures after mandibular third molar surgery: a randomized, double-blind, placebo-controlled clinical trial. J Oral Maxillofac Surg 2014; 72: 1043–1048.
35.
Rosenberg L, Krieger Y, Bogdanov-Berezovski A, Silberstein E, Shoham Y, Singer AJ: A novel rapid and selective enzymatic debridement agent for burn wound management: a multi-center RCT. Burns 2014; 40: 466–474.
36.
Masson M: [Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice]. Fortschr Med 1995; 113: 303–306.
37.
Kane S, Goldberg MJ: Use of bromelain for mild ulcerative colitis. Ann Intern Med 2000; 132: 680.
38.
Gautam SS, Mishra SK, Dash V, Goyal AK, Rath G: Comparative study of extraction, purification and estimation of bromelain from stem and fruit of pineapple plant. Thai J Pharm Sci 2010; 34: 67–76.
39.
Maurer HR: Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001; 58: 1234–1245.
40.
Tuerxun A, Batuer A, Erturhan S, Eryildirim B, Camur E, Sarica K: Impaction and prediction: does ureteral wall thickness affect the success of medical expulsive therapy in pediatric ureteral stones? Urol Int 2017; 98: 436–441.
41.
Yamaguchi K, Minei S, Yamazaki T, Kaya H, Okada K: Characterization of ureteral lesions associated with impacted stones. Int J Urol 1999; 6: 281–285.
42.
Sahbaz A, Aynioglu O, Isik H, Ozmen U, Cengil O, Gun BD, Gungorduk K: Bromelain: a natural proteolytic for intra-abdominal adhesion prevention. Int J Surg 2015; 14: 7–11.
43.
Engwerda CR, Andrew D, Ladhams A, Mynott TL: Bromelain modulates T cell and B cell immune responses in vitro and in vivo. Cell Immunol 2001; 210: 66–75.
44.
Barth H, Guseo A, Klein R: In vitro study on the immunological effect of bromelain and trypsin on mononuclear cells from humans. Eur J Med Res 2005; 10: 325–331.
45.
Onken JE, Greer PK, Calingaert B, Hale LP: Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol 2008; 126: 345–352.
46.
Hale LP, Greer PK, Trinh CT, Gottfried MR: Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease. Clin Immunol 2005; 116: 135–142.
47.
Massagué J: TGFbeta in Cancer. Cell 2008; 134: 215–230.
48.
Bierie B, Moses HL: Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006; 6: 506–520.
49.
Leipner J, Iten F, Saller R: Therapy with proteolytic enzymes in rheumatic disorders. BioDrugs 2001; 15: 779–789.
50.
Tinozzi S, Venegoni A: Effect of bromelain on serum and tissue levels of amoxicillin. Drugs Exp Clin Res 1978; 4: 39–44.
51.
Luerti M, Vignali ML: Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978; 4: 45–48.
52.
Mori S, Ojima Y, Hirose T, Sasaki T, Hashimoto Y: The clinical effect of proteolytic enzyme containing bromelain and trypsin on urinary tract infection evaluated by double blind method. Acta Obstet Gynaecol Jpn 1972; 19: 147–153.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.