Efficacy and safety of bromelain: A systematic review and meta-analysis.

Background: Pineapple has an important role in ethnopharmacology and its enzyme, bromelain, has been extensively investigated for its medicinal properties. Aim: This systematic review and meta-analysis aimed to assess clinical evidence concerning the efficacy and safety of bromelain. Methods: A systematic search was conducted from conception to August 2022 using CINAHL Complete, MEDLINE, ScienceDirect, Scopus, and Thai Journal Online (TJO). The risk of bias was assessed using Risk of Bias 2 or ROBIN-I. A random-effect model with inverse variance weighting and DerSimonian and Laird method was used for meta-analysis. The heterogeneity was evaluated by I2 statistics. Results: We included 54 articles for qualitative summary and 39 articles for meta-analysis. The systematic review found that bromelain presented in serum with retained proteolytic activity after oral absorption. Bromelain may be effective against sinusitis but was not effective for cardiovascular diseases. Pain reduction from oral bromelain was slightly but significantly better than controls (mean difference in pain score = -0.27; 95% CI: -0.45, -0.08; n = 9; I2 = 29%). Adverse events included flatulence, nausea, and headache. Topical bromelain significantly reduced the time to complete debridement (mean difference in time = -6.89 days; 95% CI: -7.94, -5.83; n = 4; I2 = 2%). Adverse events may be irrelevant and include burning sensation, pain, fever, and sepsis. Conclusions: Moderate-quality studies demonstrated the potential of oral bromelain in pain control and topical bromelain in wound care. Major health risks were not reported during the treatment with bromelain.

Feasibility and safety of enzymatic debridement for the prevention of operative escharotomy in circumferential deep burns of the distal upper extremity.

BACKGROUND: Burn-induced compartment syndrome is a severe sequela after circumferential burns of the extremities and is avoidable by immediate release of the underlying pressure under the eschar. Although the current gold standard is operative escharotomy, this procedure carries considerable morbidity. Our study evaluates the safety and effectiveness of immediate enzymatic debridement to prevent the need for operative escharotomy because of burn-induced compartment syndrome in selected patients. PATIENTS AND METHODS: From 2015 to 2017, all patients suffering from deep circumferential burns of the upper extremities requiring operative escharotomy were potential candidates for the treatment algorithm evaluated by this study. Exclusion criteria involved burn trauma > 12 hours, clinically established burn-induced compartment syndrome, intolerance to the enzymatic debriding agent, dry burns requiring presoaking, as well as blast and electrical injuries requiring fasciotomy or carpal tunnel release. All patients with the inclusion criteria received enzymatic debridement with Nexobrid immediately after admission to our burn center. Enzymatic debridement was applied according to the manufacturer's recommendations. After enzymatic debridement, extremities were revisited every 2 hours for 24 hours to determine the need for conversion to conventional operative escharotomy. The indication for and time to skin grafting was reviewed, and functional outcomes assessed during follow-up examination. RESULTS: Included in this sturdy were 13 patients with 20 burned upper extremities. Enzymatic debridement provided a sufficient eschar removal in all patients. Conversion to conventional operative escharotomy was thus not necessary in any patient. Secondary skin grafting was required in 9 patients. Functional outcomes were favorable 11.9 months after burn trauma. CONCLUSION: If the specific contraindications are respected, enzymatic debridement is safe and effective for the prevention of burn-induced compartment syndrome after deep circumferential burns at the upper extremity, and thus making operative escharotomy unnecessary.

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.

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.

Coagulation Abnormalities Following NexoBrid Use: A Case Report.

Patients with major burn injury undergo a series of pathophysiologic changes that begin with a systemic inflammatory response and coagulation abnormalities, similar to those experienced by patients with sepsis or severe trauma. Coagulation changes in patients with burns are generally characterized by procoagulant abnormalities, but alterations in fibrinolysis and anticoagulation factors have also been observed. Around 40% of patients with major burn show changes on standard coagulation tests, and these have been related to the severity of the lesions, smoke inhalation, and administration of intensive fluid resuscitation therapy. Current surgical techniques for debridement of burn lesions are aggressive and associated with considerable blood loss. A fast-acting selective enzymatic debriding agent based on bromelain has been recently developed. NexoBrid is indicated for removing eschar in adults with deep partial- and full-thickness thermal burns. A potential effect of oral bromelain on hemostasis has been described, but it is uncertain whether NexoBrid application has a clinically relevant impact in this regard. We present the clinical case of a patient with burns who showed a coagulation abnormality shortly after NexoBrid use.

A Randomized, Clinical Trial to Evaluate Efficacy and Tolerability of Trypsin:Chymotrypsin as Compared to Serratiopeptidase and Trypsin:Bromelain:Rutoside in Wound Management.

INTRODUCTION: Systemic enzyme therapy can play an important role in maintaining normal inflammatory processes within the body and thereby helps support and speed up healing. In the course of the anti-inflammatory action, enzymes degrade damaged cells and necrotic material and, through the inactivation of mediators and toxic products, they restrict the edema and pain. METHOD: The study conducted at Grant Medical College, Mumbai, India was a clinical trial comparing the efficacy and tolerability of three oral enzyme treatment groups-oral tablets containing trypsin:chymotrypsin (TC) (Chymoral Forte®), serratiopeptidase (S) 5 mg oral tablets, and oral enzyme tablets containing trypsin 48 mg, bromelain 90 mg, and rutoside 100 mg (TBR)-to evaluate their healing potential in surgical wounds after orthopedic surgery. RESULTS: A total of 75 patients were screened, randomized, and divided into three groups in 1:1:1 ratio receiving either of the three treatments. In the TC group, erythema was significantly reduced from 3.44 on day 3 to 1.16 on day 10 (p < 0.01). There was significantly better reduction in erythema scores in the TC group as compared to S and TBR groups (p < 0.05) at each follow-up visit. Similarly reduction in the local irritation, wound discharge, edema, induration, and tenderness score with TC treatment at the end of the study was significantly higher than that observed in the other two groups. In addition TC showed significant reduction in pain on the VAS scale (p < 0.01). Global assessment of response to therapy for efficacy and tolerability was reported to be good to excellent in 88% and 92% of the patients on TC as compared to 12% and 8% with S and 12% and 8% with TBR. CONCLUSION: TC provides a better resolution of symptoms of inflammation after orthopedic surgery as compared to S and TBR, thus facilitating better wound healing. Further studies are warranted to confirm the findings. TRIAL REGISTRATION: Clinical Trial Registry of India (Reg. No. CTRI/2011/07/001920).

Rutoside and Hydrolytic Enzymes Do Not Attenuate Marathon-Induced Inflammation.

INTRODUCTION: Vigorous and prolonged exercise such as marathon running increases inflammatory markers and the risk of upper respiratory illness (URI) in athletes. Nutritional supplements are being tested as countermeasures of exercise-induced inflammation and immune dysfunction. METHODS: In this prospective randomized, double-blind, placebo-controlled phase I trial, healthy male runners (N = 138, age 42 ± 11 yr) were supplemented with rutoside (600-1200 mg·d) and hydrolytic enzymes (540-1080 mg·d bromelain, 288-576 mg·d trypsin) (WOB) or placebo (PL) for 1 wk before and 2 wk after the Munich Marathon 2013. Blood samples were collected 5 wk prerace and immediately, 24 h, and 72 h postrace and analyzed for inflammation biomarkers (interleukins [IL] 6 and 10, high-sensitivity C-reactive protein, and leukocytes). URI rates, assessed by the Wisconsin Upper Respiratory Symptom Survey, were compared between the study groups during the 2-wk period after the marathon race. URI was defined if the Wisconsin Upper Respiratory Symptom Survey score was equal or greater than seven, representing either one severe symptom or seven mild symptoms. RESULTS: Immediately postrace, the increase of IL-6 was not significantly different between the WOB and the PL groups (median [interquartile range]: WOB, 33.8 [22.5-58.8] ng·L; PL, 35.6 [24.8-61.29] ng·L; P = 0.758). No significant group differences were observed for increases of IL-10, high-sensitivity C-reactive protein, or leukocytes pre- to postrace (all P > 0.05). From race day until 2 wk after the marathon race, the percentage of individuals with at least one URI did not significantly differ between the groups (WOB, 50.0%; PL, 51.5%; P = 0.859). CONCLUSION: Supplementation with rutoside and hydrolytic enzymes before and after a marathon race did not attenuate postrace inflammation or decrease URI incidence in nonelite male marathon runners.

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.

OBJECTIVE: To date, the management of patients with chronic bacterial prostatitis (CBP) is not satisfactory, especially in terms of symptoms relief. Here, we evaluated the efficacy and the safety of a combination of serenoa repens, selenium and lycopene extract + bromelain and methylsulfonylmethane extract associated with levofloxacin in patients with CBP. MATERIALS AND METHODS: All patients with clinical and instrumental diagnosis of CBP, admitted to a single Urological Institution from March to June 2015 were enrolled in this phase III study. All enrolled patients were randomized into two groups: Group A received levofloxacin 500 mg o.d. for 14 days associated with lycopene and methylsulfonylmethane; Group B received levofloxacin (500 mg o.d. for 14 days) only. Clinical and microbiological analyses were carried out at the time of admission (T0) and during the followups at 1 month (T1) and 6 months (T2) from the end of the treatment. NIH Chronic Prostatitis Symptom Index (CPSI), International Prostatic Symptom Score (IPSS) and Quality of Well-Being (QoL) questionnaires were used. The main outcome measures were the rate of microbiological cure and the improvement in questionnaire results from baseline at the end of the follow-ups period. RESULTS: Forty patients were enrolled in Group A and 39 in Group B. During the follow-up (T1), we recorded a significant changes in terms of NIH-CPSI and IPSS in Group A (mean difference: 17.6 ± 2.65; 12.2 ± 2.33; p < 0.01; p < 0.05, respectively) and versus Group B at the intergroup analysis (mean difference: -9 ± 1.82; -8.33 ± 1.71; p < 0.05; p < 0.05, respectively). No differences were reported in terms of microbiological findings between the two groups. At the second follow-up visit (T2), questionnaire results demonstrated statistically significant differences between groups (p < 0.001). One patient in Group A (2.5%) and 7 patients (17.9%) in Group B showed a symptomatic and microbiological recurrence (p = 0.02). CONCLUSIONS: The combination of serenoa repens, selenium, lycopene + bromelain and methylsulfonylmethane extracts improved the clinical efficacy of levofloxacin in patients affected by CBP without the development of side effects.

Functional foods: How functional are they? A case report of supplement-induced psychosis.

There is rising evidence of patients' use of alternative and complementary medicine. The percentage of the U.S. population who used at least one dietary supplement increased from 42% in 1988-1994 to 53% in 2003-2006. We present a case of an Asian female in her 40s, with no previous psychiatric illness, who presented to the emergency room following a brief psychotic episode, during which she self-amputated the tips of her fingers, after using multivitamins and herbal supplements including ginseng, gui yuan rou (Chinese herb), astaxanthin, goji (Chinese fruit), selenium, saw palmetto, grape seed extract, citrus bioflavanoid, lutein (zeaxantin), resvexatrol, sun chlorella, spirulina powder, phytoceramides, phytoestrogen, glucosatrin, bromelain plus, and American bee pollen. Comprehensive laboratory workup, drug screening, and diagnostic imaging were negative. Vital signs were stable. Other than the amputated finger tips, the remainder of her physical examination was unremarkable. Her mental status improved significantly after treatment with risperidone 1 mg twice daily, during a five-day psychiatric hospitalization. This case draws attention to the fact that supplements have the potential of producing frank psychosis and require close monitoring and study by physicians.

[Impact of exogenous proteolytic enzymes on immunogenesis in patients with urogenital infections].

The use of systemic enzyme therapy in combination with antibiotics in the treatment of urogenital chlamydia infection in patients of both sexes proved to improve the therapeutic efficacy and to reduce the risk of the side effects.

Novel concentrated cranberry liquid blend, UTI-STAT with Proantinox, might help prevent recurrent urinary tract infections in women.

OBJECTIVES: To determine the safety, tolerability, maximal tolerated dose, and efficacy of a concentrated cranberry liquid blend, UTI-STAT with Proantinox, in female patients with a history of recurrent urinary tract infections (rUTIs). METHODS: The study agent was administered orally at 15, 30, 45, 60, and 75 mL daily for 12 weeks to women with a history of 2.78 ± 0.73 rUTIs <6 months. Blood and urine samples were collected at baseline and weeks 4 and 12. The women took daily doses of the agent. The primary endpoints were the safety, tolerability, and maximal tolerated dose. The secondary endpoints were the efficacy with regard to rUTI and quality-of-life (QOL) symptoms. RESULTS: A total of 28 subjects were included in the study. Of these 28 women, the data from 23 were analyzable. The average age was 46.5 ± 12.8 years. The maximal tolerated dose of UTI-STAT was 75 mL/d, and the recommended dose was set at 60 mL/d. The secondary endpoints demonstrated that only 2 (9.1%) of 23 reported a rUTI, a markedly better rate than the historical data. At 12 weeks, the reduction in worry about rUTIs and increased QOL with regard to the physical functioning domain and role limitations from physical health domain, as measured by the Medical Outcomes Study short-form 36-item questionnaire, were significant (P = .0097). A lower American Urological Association Symptom Index indicating greater QOL was also significant (P = .045). CONCLUSIONS: The novel concentrated cranberry liquid blend showed a good safety profile and tolerability in both pre- and postmenopausal women with history of rUTIs. The secondary endpoints demonstrated its effectiveness in reducing the incidence of rUTI and increasing QOL. Given this evidence, supplementation might be beneficial in the prevention of rUTIs in this population.

Perioperative risks and benefits of herbal supplements in aesthetic surgery.

Most medications, herbal preparations, and nutraceutical supplements have notable effects on biochemical pathways and may influence wound healing, coagulation, and cardiovascular function. They can also interact with other drugs. A large portion of the data available regarding the effects of naturopathic medicines is anecdotal. Marketing of certain products may be misleading and potentially harmful, and quality control standards are highly variable. In order to ensure quality control and standardization of products, it is prudent to work with preparations manufactured by companies that adhere to pharmaceutical (good manufacturing practice [GMP]) standards. However, many of these higher-quality products are not readily available to the public over the counter. A large percentage of patients undergoing plastic surgery use one or more herbal medications, but the disclosure of such medications to allopathic providers is often incomplete. In addition, patients may not understand the importance of discontinuing such medications before surgery. The authors review research on the possible benefits and risks of commonly used herbal medications such as arnica montana, St. John's wort, bromelain, echinacea, ginkgo biloba, ephedra, valerian, and others, focusing on their potentially positive or negative impact during the perioperative period of aesthetic surgery. Good communication with surgical patients, including the administration of a presurgical questionnaire to help identify any use of herbal medications, is emphasized.

[Occupational allergies to bromelain]. / Berufliche Allergien gegen Bromelain.

The protease bromelain originating from the pineapple fruit (Ananas comosus) finds frequent use in industry. Exposure to enzyme dusts has long been known to cause occupational allergies. The present paper reviews the results of the evaluation of literature data concerning occupational airway sensitization due to bromelain. Cases of specific airway sensitization caused by bromelain could be shown clearly by the presented studies. Since the symptoms, results of skin prick tests, detection of specific IgE antibodies and results of specific bronchoprovocation tests are consistent, an immunological mechanism can be assumed.

Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS in children with acute sinusitis in Germany.

The therapeutic efficiency and safety of the proteolytic enzyme bromelaine obtained from pineapple (Bromelain-POS, Ursapharm GmbH, Saarbrücken, Germany) was evaluated in children under the age of 11 years diagnosed with acute sinusitis. Data from 116 patients from 19 centres located across Germany were analysed in a pharmacoepidemiological cohort study. Patient cohorts were either treated with Bromelain-POS (N = 62), in combination with Bromelain-POS and standard therapies (N = 34), or with standard therapies (N = 20). The primary parameter measuring effectiveness of the different treatment groups was the duration of symptoms. The shortest mean period of symptoms was observed in patients treated with Bromelain-POS alone (6.66 days), followed by the standard therapy (7.95 days) and those treated with a combination of Bromelain-POS and the standard therapy (9.06 days). Patients of the Bromelain-POS monotherapy group showed a statistically significant faster recovery from symptoms (p = 0.005) compared to the other treatment groups. One 10-year-old male patient, with a known pineapple allergy, showed a self-limiting mild allergic reaction. No other unwanted side-effects were reported. This trial documents that the proteolytic pineapple enzyme Bromelain-POS is widely used in the treatment of young children diagnosed with acute sinusitis in Germany and that the use of proteolytic enzymes can benefit such patients.

Safety and efficacy of a proteolytic enzyme for enzymatic burn debridement: a preliminary report.

A prospective, non-comparative study design was used to describe our experience with a bromelain-derived debriding agent, Debridase, in 130 patients with 332 deep second degree and third degree burns treated between 1984 and 1999. Debridase was applied after saturating the burns with a moist dressing for 2-24h. Debridase was applied for a period of 4h under an occlusive dressing. Mean patient age was 18.6 +/- 19.3, 42 (32.3%) were female, and 63 (48.5%) were children under age 18. Most burns were small. Debridase was applied once in 241 (72.6%) of the 332 wounds, twice in 67 (20.18%) cases, three times in 12 (3.61%) cases, and four times in 2 (0.6%) cases. The percentage debridement by number of applications was 89 +/- 21% for a single application, 77 +/- 27% for two, and 62 +/- 27% for three Debridase applications, respectively. There were no significant adverse events. The availability of a fast acting, reliable and complication-free enzymatic debriding agent may open new horizons and provide a new treatment modality for burns.

A double blind, randomised, parallel group study on the efficacy and safety of treating acute lateral ankle sprain with oral hydrolytic enzymes.

OBJECTIVE: To compare the effectiveness and safety of the triple combination Phlogenzym (rutoside, bromelain, and trypsin) with double combinations, the single substances, and placebo. DESIGN: Multinational, multicentre, double blind, randomised, parallel group design with eight groups structured according to a factorial design. SETTING: Orthopaedic surgery and emergency departments in 27 European hospitals. PARTICIPANTS: A total of 721 patients aged 16-53 years presenting with acute unilateral sprain of the lateral ankle joint. PRIMARY EFFICACY CRITERIA: (a) Pain on walking one or two steps, as defined by the patient on a visual analogue scale. (b) The range of motion, as measured by the investigator and expressed as a sum of flexion and extension. (c) The volume of the injured ankle measured with a volometer. RESULTS: At the primary end point at seven days, the greatest reduction in pain was in the bromelain/trypsin group (73.7%). The Phlogenzym group showed a median reduction of 60.3%, and the placebo group showed a median reduction of 73.3%. The largest increase in range of motion (median) was in the placebo group (60% change from baseline). The Phlogenzym group showed a median increase of 42.9%. The biggest decrease in swelling was in the trypsin group (3.9% change from baseline). The Phlogenzym group showed a -2.30% change from baseline and the placebo group a -2.90% change. In the subgroup analysis of patients who did not use a Caligamed brace, Phlogenzym was superior to placebo for the summarising directional test of the primary efficacy criteria (MW = 0.621; LB-CI 0.496; p = 0.029; one sided Wei-Lachin procedure). The vast majority of doctors and patients rated the tolerability of all treatments tested as very good or at least good. CONCLUSIONS: Phlogenzym was not found to be superior to the three two-drug combinations, the three single substances, or placebo for treatment of patients with acute unilateral sprain of the lateral ankle joint. The small subgroup of patients treated without the support of a Caligamed brace showed evidence of superiority of Phlogenzym over placebo. Further research is warranted to study this effect of Phlogenzym in patients treated without ankle support.

[Effect of phlogenzym in long-term treatment of patients with multiple sclerosis]. / Efektyvnist' flohenzymu pry tryvalomu zastosuvanni u khvorykh na rozsiianii skleroz.

An assessment was carried out of clinical effectiveness of the drug phlogenzym in 74 patients with remitting, remitting-progressive, and secondary progressive course of multiple sclerosis. Phlogenzym intake for up to one to three years resulted in decline in the incidence of complications, with their degree having come to be lower, duration of remissions longer, progression of the illness slowed down. The data secured suggest to us that phlogenzym is a safe agent. It can, we believe used in a therapeutic regimen for those patients presenting with remitting and remitting-progressive types of the course of the disease.