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Abstracts

LE Magazine May 2008
Abstracts

Bromelain

Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies.

Bromelain, an extract from the pineapple plant, has been demonstrated to show anti-inflammatory and analgesic properties and may provide a safer alternative or adjunctive treatment for osteoarthritis. All previous trials, which have been uncontrolled or comparative studies, indicate its potential use for the treatment of osteoarthritis. This paper reviews the mechanism of its putative therapeutic actions, those clinical trials that have assessed its use in osteoarthritis to date, as well as considering the safety implications of this supplement for osteoarthritis and reviewing the evidence to date regarding the dosage for treating this condition. The data available at present indicate the need for trials to establish the efficacy and optimum dosage for bromelain and the need for adequate prospective adverse event monitoring in such chronic conditions as osteoarthritis.

Evid Based Complement Alternat Med. 2004 Dec;1(3):251-257

Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs.

OBJECTIVE: The objective of this study was to establish the non-inferiority of an oral enzyme therapy (Phlogenzym-(PE)) as compared to the non-steroidal anti-inflammatory drug (NSAID) diclofenac (DC) in patients with osteoarthritis (OA) of the hip. METHODS: Ninety patients presenting with painful episodes of OA of the hip were treated for 6 weeks in one study centre in a phase III, randomised, double blind, parallel group trial. Altogether, 45 patients were treated in the PE group and 45 patients were treated in the DC group. Primary efficacy criteria were: WOMAC dimensions pain, joint stiffness and function, and Lequesne index as multiple endpoint according to O’Brien. The efficacy criteria were analysed applying the test of non-inferiority with regard to mean changes and frequencies, t-test, U test, ANCOVA and descriptive methods. RESULTS: Within the 6 weeks observation period, the adjusted changes from baseline to endpoint of the target parameters worked out as follows (adjusted differences, mean +/- SEM): WOMAC subscale pain (PE -10.3 +/- 1.2, DC -9.5 +/- 1.2), WOMAC subscale joint stiffness (PE -3.9 +/- 0.5, DC -3.6 +/- 0.5), WOMAC subscale physical function (PE -31.7 +/- 3.5, DC -29.7 +/- 3.5), Lequesne’s index (PE -2.89 +/- 0.47, DC -2.27 +/- 0.47). Non-inferiority of PE as compared to DC with regard to the O’Brien’s global sum of the standardised adjusted changes from baseline to endpoint in pain, stiffness, physical function, and Lequesne’s index was established with p = 0.0025. PE was simultaneously non-inferior as compared to DC with regard to the 4 single endpoints: WOMAC subscale pain (p = 0.0033), WOMAC subscale joint stiffness (p = 0.0061), WOMAC subscale physical function (p = 0.0039), Lequesne’s index (p = 0.0008) (closed test procedure). The equivalence tests remained insignificant due to comparatively lower effects of DC. For 71.1% of the PE patients and for 61.4% of the DC patients rates of good or very good global investigator assessments of efficacy were calculated (test of non-inferiority: p = 0.0011). In the majority of patients, tolerability was judged in both drug groups as very good or good. CONCLUSION: This trial showed significant non-inferiority from 6 weeks treatment with PE in patients with OA of the hip with regard to the WOMAC dimensions pain, stiffness and physical function, to Lequesne’s index, to the investigator and patients assessments of efficacy, and to the responder rates based on pain, physical function, and patient assessment of efficacy. With regard to drug tolerability some tendencies in favour of PE were detected. However, in this study there was no real difference between PE and DC 100 mg/day, implying an equal benefit-risk relation between the substances. PE may well be recommended for the treatment of patients with osteoarthritis of the hip with signs of inflammation as indicated by a high pain level.

Clin Exp Rheumatol. 2006 Jan-Feb;24(1):25-30

Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee--a double-blind prospective randomized study.

The aim of this study was to compare the efficacy and safety of an oral enzyme-rutosid combination (ERC) containing rutosid and the enzymes bromelain and trypsin, with that of diclofenac in patients with osteoarthritis (OA) of the knee. A total of 103 patients presenting with painful episodes of OA of the knee were treated for 6 weeks in two study centers in a randomized, double-blind, parallel group trial. Altogether, 52 patients were treated in the ERC group and 51 patients were treated in the diclofenac group. Primary efficacy criteria were Lequesne’s Algofunctional Index (LFI) and a ‘complaint index’, including pain at rest, pain on motion and restricted function. The efficacy criteria were analyzed by applying the Wilcoxon-Mann-Whitney test that provides the Mann-Whitney estimator (MW) as a measure of relevance. Non-inferiority was considered to be proven if the lower bound of the 97.5% one-sided confidence interval (CI-LB) was higher than MW = 0.36 (benchmark of not yet relevant inferiority). Both treatments resulted in clear improvements. Within the 6-week observation period, the mean value of the LFI decreased from 13.0 to 9.4 in the ERC group and from 12.5 to 9.4 in the diclofenac group. Non-inferiority of ERC was demonstrated by both primary criteria, LFI (MW = 0.5305; CI-LB = 0.4171) and complaint index (MW = 0.5434; CI-LB = 0.4296). Considerable improvements were also seen in secondary efficacy criteria, with a slight tendency towards superiority of ERC. The global judgment of efficacy by physician resulted in at least good ratings for 51.4% of the ERC patients, and for 37.2% of the diclofenac patients. In the majority of patients tolerability was judged in both drug groups as very good or good. The current study indicates that ERC can be considered as an effective and safe alternative to NSAIDs such as diclofenac in the treatment of painful episodes of OA of the knee. Placebo-controlled studies are now needed to confirm these results.

Clin Rheumatol. 2004 Oct;23(5):410-5

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.

Br J Sports Med. 2004 Aug;38(4):431-5

Systemic enzyme therapy in the treatment and prevention of post-traumatic and postoperative swelling.

PURPOSE OF THE STUDY: The authors concentrate on the use of enzyme therapy in traumatology. They monitored SET efficiency in the treatment and prophylazis of swelling in the postoperative period after the internal fixation of fractures of long bones and compared it with the effect of standard antiswelling seu antioedematous drugs on the basis of aescin. MATERIAL: A group of 60 patients was followed after the fixation of long bones. The average age was 42 years (range, 12-79 years). Fractures were treated by intrameduilary fixation or by external fixators. The patients were split into two groups. In 30 patients only Phlogenzym was administered for the treatment and prevention of posttraumatic and postoperative swelling. Another 30 patients--the control group--were treated by standard antioedematic drugs on the basis of aescin. The same analgesics were applied in both groups. METHODS: The group of patients with systemic enzyme therapy were treated by Phlogenzym in the dosage 3 times 3 tablets in the first three days after operation and subsequently 3 times 2 tablets in the remaining follow-up period. In the postoperative period the changes of operated limb volume was monitored. The circumference of a limb was measured in the area of the largest oedema and 10 cm distally. Then the volume of this part of limb was calculated as the volume of conical frustum. The measurements were performed on postoperative days 1, 3, 5, 7, 10 and 14. The volume value of the 1st day was used as starting value (100%). The values of subsequent measurements were then compared to this starting value in both group of patients. Evaluation of the resorption of traumatic and postoperative haematoma and analgesis effect of Phlogenzym was also made. RESULTS: In the group of patients who were administered with Phlogenzym after operation the reduction of the posttraumatic and postoperative swelling was continuous and significantly faster in compared with patients of the control group. A remarkable difference was revealed by the measurement on 5th postoperative day--in patients treated by Phlogenzym the starting value of the volume of the operated in limb was reduced on average by almost 8%. In contrast, in the control group treated by standard drugs this value slightly increased above 100%. At the end of the first postoperative week the monitored volume was on average reduced by 12% in the SET group compared with 1.45% in the control group. At the end of the follow-up--on 14th postoperative day the volume was reduced in the SET group by almost 17% compared with 9% in the control group. There was also an evidently good analgesic effect of the drug. The total consumption of analgesics of patients in the SET group was significantly lower, particularly in the early postoperative period. In the course of the follow-up of both groups no marked differences were recorded in the changes of the volume of operated limbs in dependence on the method of fixation applied (intramedullary or external), sex of the patient or on the affected limb (lower or upper). The patients tolerated Phlogenzym very well, only one female patient suffered temporarily from poor digestion which, however, did not require to interrupt the administration of the drug. No other undesirable effects occurred. DISCUSSION: Fixation of long bones belongs to the most frequent operations in traumatological and orthopaedic departments of all levels. One of the factors which may have an unfavourable effect on the final result of fixation is a prolonged post-trauma or postoperative swelling. The results of the study prove a clearly positive effect of system enzymotherapy on the reduction of oedema accompanying the trauma and inflammation. The study proved a statistical significance of the acceleration of the reduction of oedema in patients treated by Phlogenzym as compared to the control group treated by a standard antioedematous drugs. CONCLUSION: The authors verified that systemic enzyme therapy could influence significantly the results of traumatological surgery. Simple administration per os, efficient oedema reduction and thus accelerated healing, antiophlogistic and analgesic effect--all these advantages justify the application of this therapeutic method what can be recommended as a part of the complex treatment in traumatology with both conservative and surgical approaches.

Acta Chir Orthop Traumatol Cech. 2001;68(1):45-9

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.

In Vivo. 2005 Mar-Apr;19(2):417-21

In vivo antitumoral activity of stem pineapple (Ananas comosus) bromelain.

Stem bromelain (EC 3.4.22.32) is a major cysteine proteinase, isolated from pineapple ( Ananas comosus) stem. Its main medicinal use is recognized as digestive, in vaccine formulation, antitumoral and skin debrider for the treatment of burns. To verify the identity of the principle in stem fractions responsible for the antitumoral effect, we isolated bromelain to probe its pharmacological effects. The isolated bromelain was obtained from stems of adult pineapple plants by buffered aqueous extraction and cationic chromatography. The homogeneity of bromelain was confirmed by reverse phase HPLC, SDS-PAGE and N-terminal sequencing. The in vivo antitumoral/antileukemic activity was evaluated using the following panel of tumor lines: P-388 leukemia, sarcoma (S-37), Ehrlich ascitic tumor (EAT), Lewis lung carcinoma (LLC), MB-F10 melanoma and ADC-755 mammary adenocarcinoma. Intraperitoneal administration of bromelain (1, 12.5, 25 mg/kg), began 24 h after tumor cell inoculation in experiments in which 5-fluorouracil (5-FU, 20 mg/kg) was used as positive control. The antitumoral activity was assessed by the survival increase (% survival index) following various treatments. With the exception of MB-F10 melanoma, all other tumor-bearing animals had a significantly increased survival index after bromelain treatment. The largest increase ( approximately 318 %) was attained in mice bearing EAT ascites and receiving 12.5 mg/kg of bromelain. This antitumoral effect was superior to that of 5-FU, whose survival index was approximately 263 %, relative to the untreated control. Bromelain significantly reduced the number of lung metastasis induced by LLC transplantation, as observed with 5-FU. The antitumoral activity of bromelain against S-37 and EAT, which are tumor models sensitive to immune system mediators, and the unchanged tumor progression in the metastatic model suggests that the antimetastatic action results from a mechanism independent of the primary antitumoral effect.

Planta Med. 2007 Oct;73(13):1377-83

Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults.

There is preliminary clinical evidence to support the contention that the anti-inflammatory and analgesic properties of bromelain help to reduce symptoms of osteo- and rheumatoid arthritis. However, there have been no controlled studies of its effects on joint health in healthy subjects who lack such diagnosis. The current study investigated the effects of bromelain on mild acute knee pain of less than 3 months duration in otherwise healthy adults. The study was an open, dose-ranging postal study in volunteers who had been recruited through newspaper and magazine articles. Two validated questionnaires (WOMAC knee health Index and the Psychological Well-Being Index) were completed at baseline and after one month’s intervention with bromelain, randomly allocated to volunteers as either 200 mg or 400 mg per day. Seventy seven subjects completed the study. In both treatment groups, all WOMAC symptom dimension scores were significantly reduced compared with baseline, with reductions in the final battery (total symptom score) of 41 and 59% (P = 0.0001 and <0.0001) in the low and high dose groups respectively. In addition, improvements in total symptom score (P = 0.036) and the stiffness (P = 0.026) and physical function (P = 0.021) dimensions were significantly greater in the high-dose (400 mg per day) compared with the low-dose group. Compared to baseline, overall psychological well-being was significantly improved in both groups after treatment (P = 0.015 and P = 0.0003 in the low and high dose groups respectively), and again, a significant dose-response relationship was observed. We conclude that bromelain may be effective in ameliorating physical symptoms and improving general well-being in otherwise healthy adults suffering from mild knee pain in a dose-dependant manner. Double blind, placebo-controlled studies are now warranted to confirm these results.

Phytomedicine. 2002 Dec;9(8):681-6

Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice.

METHOD: In an open case observation study involving patients with blunt injuries to the musculoskeletal system, the efficacy and tolerability of high-dose Bromelain POS, a plant-derived enzyme preparation, were investigated. The investigating physician was an orthopedic surgeon who, in addition to the usual therapeutic measures, treated 59 of his patients with the bromelaine preparation. The duration of the application was determined by the nature and severity of the lesion, and varied between one and three weeks. The test criteria were swelling, pain at rest and during movement, and tenderness. These parameters were evaluated on the day of the injury and on five subsequent dates. RESULTS: Treatment with bromelaine resulted in a clear reduction in all four parameters tested. Both swelling and the symptoms of pain had improved appreciably at all evaluation time points as compared with baseline. The tolerability of the preparation was very good, and patient compliance was correspondingly high.

Fortschr Med. 1995 Jul 10;113(19):303-6

Natural treatment of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is one of the most common long-term illnesses in the United States, affecting approximately 14% of the population. CRS is a challenging condition to treat, partly due to its multifaceted, poorly understood pathophysiology. Treatment goals include maintaining open drainage and decreasing inflammation while improving tissue integrity and limiting causative factors. This review covers the etiology, pathology, and diagnosis of CRS, as well as mainstream and alternative treatments. Discussion of alternative therapeutics includes nutrients and botanicals (ascorbic acid, bromelain, N-acetylcysteine, quercetin, undecylenic acid, and Urtica dioica and other herbal medicines) and procedures (nasal irrigation and naso-sympatico treatments). The influences of diet and air quality on CRS are also discussed.

Altern Med Rev. 2006 Sep;11(3):196-207

Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease.

Bromelain is a mixture of proteinases derived from pineapple stem that is marketed in health food stores as a “digestive aid”. Orally administered bromelain was anecdotally reported to induce clinical and endoscopic remission of ulcerative colitis in two patients whose disease was refractory to multi-agent conventional medical therapy. However, the potential efficacy of bromelain in colitis has not yet been tested rigorously in either animals or humans. In this study, the clinical and histologic severity of inflammatory bowel disease (IBD) was determined in IL-10-/- mice treated orally with bromelain in vivo. Daily treatment with oral bromelain beginning at age 5 weeks decreased the incidence and severity of spontaneous colitis in C57BL/6 IL-10-/- mice. Bromelain also significantly decreased the clinical and histologic severity of colonic inflammation when administered to piroxicam-exposed IL-10-/- mice with established colitis. Proteolytically active bromelain was required for anti-inflammatory effects in vivo. Adverse effects of dermatitis, hair loss, and weight loss due to mucositis were rare, dose related, and were not seen in wild-type mice treated orally with up to 1,000 mg bromelain/kg/day for 18 weeks. Although the exact mechanisms by which exogenous proteinases affect bowel inflammation have not yet been determined, the results justify additional studies of this complementary biologically based approach to treatment of IBD.

Clin Immunol. 2005 Aug;116(2):135-42

Role of bromelain in the treatment of patients with pityriasis lichenoides chronica.

OBJECTIVES: Pityriasis lichenoides chronica (PLC) is a skin disease of unknown etiology. Uncertainty about the etiopathogenesis of this skin disease is the reason for the unpredictable and non optimal efficacy of therapies available for its treatment. The aim of the present study was to evaluate the efficacy of bromelain, a crude aqueous extract of the stems and immature fruit of pineapple, in the treatment of PLC. MATERIALS AND METHODS: Eight patients (3 males and 5 females) with PLC were enrolled in the study and treated for three months with oral bromelain (40 mg 3 times a day for 1 month, 40 mg twice a day for 1 month and 40 mg/day for 1 month). RESULTS: All patients showed complete clinical recovery after treatment. In 12 months of follow up, two patients experienced relapse 5-6 months after suspension of therapy but responded to another brief cycle of therapy. No side effects were encountered during therapy. CONCLUSIONS: In conclusion bromelain can be considered an effective therapeutic option for PLC; its efficacy could be related to its anti-inflammatory, immunomodulatory and/or anti-viral properties.

J Dermatolog Treat. 2007;18(4):219-22

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