Report for Brighton and Hove Health and Wellbeing Board (HWBB) and Clinical Commissioning Group (CCG) 9.8.13 By John Kapp, 22, Saxon Rd Hove BN3 4LE, 01273 417997, [email protected] CURING THE NHS AND DEPRESSED PATIENTS BY MASS-COMMISSIONING THE MINDFULNESS COURSE The crisis in the NHS is caused by the following factors, which can be solved locally by councillors initiating culture change
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Bromelain: a literature review and discussion of its therapeutic applicationsBromelain: A Literature Review and
Discussion of its Therapeutic Applications
Gregory S. Kelly, N.D.
Abstract First introduced as a therapeutic compound in 1957, bromelain’s actions include:(1) inhibition of platelet aggregation; (2) fibrinolytic activity; (3) anti-inflammatory action;(4) anti-tumor action; (5) modulation of cytokines and immunity; (6) skin debridementproperties; (7) enhanced absorption of other drugs; (8) mucolytic properties; (9) digestiveassistance; (10) enhanced wound healing; and (11) cardiovascular and circulatoryimprovement. Bromelain is well absorbed orally and available evidence indicates thatit’s therapeutic effects are enhanced with higher doses. Although all of its mechanismsof action are still not completely resolved, it has been demonstrated to be a safe andeffective supplement.
(Alt Med Rev 1996;1(4):243-257) Description
Pineapple has been used as a medicinal plant in several native cultures and bromelain has been known chemically since 1876. In 1957, bromelain was introduced as a therapeuticcompound when Heinicke found it in high concentrations in pineapple stems.
Bromelain is a general name for a family of sulfhydryl proteolytic enzymes obtained from Ananas comosus, the pineapple plant. It is usually distinguished as either fruit bromelainor stem bromelain depending on its source, with all commercially available bromelain beingderived from the stem.1 The term bromelain will be used to refer to stem bromelain in theremainder of this article.
Bromelain’s primary component is a sulfhydryl proteolytic fraction. Bromelain also contains a peroxidase, acid phosphatase, several protease inhibitors, and organically bound cal-cium. When the proteolytic fraction of bromelain is purified and extracted, the result is a potentproteolytic enzyme in vitro; however, this component has been shown to be physiologicallyinactive in vivo for many of the conditions where bromelain has a beneficial effect.2 It appearsthat a great deal of the physiological activity of bromelain is not accounted for in its proteolyticfraction and it is likely that the beneficial effects of bromelain are due to multiple factors, not toone single factor that can be isolated.
To date, eight basic proteolytically active components have been detected in the stem.
The two main components have been labeled F4 and F5. The proteinase considered to be themost active fraction has been designated as F9, which comprises about 2% of the total proteins.
It is estimated that 50% of the proteins in F4 and F5 are glycosylated, whereas F9 was found tobe unglycosylated. The optimal pH for the F4 and F5 fractions is between 4.0 and 4.5 and for F9close to a neutral pH.3 The entire extract of bromelain has been shown to exhibit its activity overa pH range of 4.5 to 9.8.4 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 243
Copyright1996 Thorne Research, Inc. All Rights Reserv Figure 1. Bromelain’s Impact on the Kinin System & Coagulation
Absorption and Availability
natural source, different sources can exhibit variability in their physiological activity, even the gastrointestinal tract of animals, with up when their proteolytic activity is the same.
Bromelain is not heat stable so it’s physiologi- stances detected in the blood after oral admin- cal activity can be further reduced by improper istration. The highest concentration of brome- lain is found in the blood 1 hour after admin-istration; however, its proteolytic activity israpidly deactivated,5 probably by the normalplasma protease controls and serum alpha2-macroglobulin.
Page 244 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Inflammatory Effects of Arachidonic
———————————————————————————— ———————————————————————————— vasodilation, inhibit platelet aggregation thrombin time(PT) and activatedpartial thrombo- plastin time (APTT) are markedly prolonged.8 used to indicate the activity of bromelain; with Bromelain’s fibrinolytic activity has been at- published research varying in the designation tributed to the enhanced conversion of plas- utilized. Rorer units (R.U.), gelatin dissolv- minogen to plasmin, which limits the spread ing units (G.D.U.), and milk clotting units of the coagulation process by degrading fi- sures of activity. One gram of bromelain stan- dardized to 2000 M.C.U. would be approxi- as well as indirect actions involving other en- mately equal to 1 gram with 1200 G.D.U. of zyme systems in exerting its anti-inflamma- activity or 8 grams with 100,000 R.U. of ac- tory effect. Both etodolac and bromelain in- hibit the inflammatory pain in rats in a dose-dependent manner.10 Bromelain was the most Platelet Aggregation, Fibrinolysis and
potent of nine anti-inflammatory substances Anti-Inflammatory Activity
tested on experimentally-induced edemas inrats;11 while prednisone and bromelain have been shown to be comparable in their ability melain prevents aggregation of blood plate- to reduce inflammation in rats.12 Treatment lets was reported in 1972. Bromelain was ad- ministered orally to 20 volunteers with a his- shown to decrease significantly the heat- tory of heart attack or stroke, or with high evoked immunoreactive substance P release platelet aggregation values. Bromelain de- creased aggregation of blood platelets in 17of the subjects and normalized values in 8 of Mechanism of Action
the 9 subjects who previously had high aggre-gation values.6 In vitro studies have demon- strated that bromelain inhibits platelet aggre- lets, activates the kinin system and the clot- gation stimulated by ADP or epinephrine, as ting cascade by stimulating the conversion of well as by prostaglandin precursors, in a dose- Hageman factor to an active protease (factor XIIa). Factor XIIa then activates the kinin sys- tem by converting plasma prekallikrein into agent in vitro and in vivo; however, its effect kallikrein, and continues the intrinsic path of is more evident in purified fibrinogen solutions the clotting cascade by converting factor XI than in plasma. This is probably due to the to its active form. Kallikrein, in an autocata- antiproteases present in plasma. A dose-depen- lytic loop, accelerates the activation of Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 245
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Bromelain’s Impact on Selected Mediators
of Acute Inflammation
———————————————————————————— ———————————————————————————— brinogen to fibrin (seeFigure 1). Fibrin then determine the effects ofbromelain on the plasmakallikrein system, bradykinin levels and plasma exudation at the inflammatory site were cascade.16 This indicates that bromelain’s examined in rats. Bromelain (5 and 7.5 mg/ action is in part a result of inhibiting the generation of bradykinin at the inflammatory bradykinin levels at the inflammatory site and site via depletion of the plasma kallikrein a parallel decrease of the prekallikrein levels system, as well as limiting the formation of in sera. Plasma exudation was also reduced activity in sera was elevated after treatment significant reduction in pain and edema, as with bromelain, although it was unchanged in well as enhanced circulation to the injured site.
the pouch fluid.14 The levels of high molecular weight (HMW) kininogen and pre-kallikrein repair begins with the conversion of plasmi- in rat plasma were markedly reduced after nogen to plasmin, which then acts to degrade single injection of bromelain (10 mg/kg, i.v.) fibrin into smaller components which can be and gradually recovered over a 72 hour period.
rats, bromelain has been shown to stimulate the conversion of plasminogen to plasmin, re- sulting in increased fibrinolysis. This mini- mizes venous stasis, facilitates drainage, in- reduction in Factor X and prothrombin, both creases permeability and restores the tissue’s of which are needed for the activation of Page 246 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission CELL MEMBRANE
Figure 2. Bromelain’s Proposed Effect on Prostaglandin Synthesis.
prostaglandins, PGI2 and PGE2 over throm- may also be due to its ability to selectively modulate the biosynthesis of thromboxanes inhibit cyclooxygenase, which is required for prostaglandins with opposite actions which the synthesis of series 2 prostaglandins, result- ultimately influence activation of cyclic-3,5- ing in a decrease in both pro and anti-inflam- adenosine (cAMP), an important cell-growth matory prostaglandins. Rather than blocking the arachidonic acid cascade at the enzyme cyclooxygenase, like NSAIDs, bromelain may or thrombin to platelets activates the enzymes selectively decrease thromboxane generation phospholipase C and phospholipase A2 which prostacyclin (PGI2) in favor of prostacyclin (see Figure 2). Bromelain, similar to NSAIDs, has been shown to inhibit PGE2, however, its action is significantly weaker.16 Table 2 lists bromelain’s impact on selected mediators of plasmin by the oral administration of brome-lain, has been shown to inhibit the release of Antitumor
arachidonic acid from cell membranes, result- ing in decreased platelet aggregation and melain on cancer patients was in 1972. Twelve modulation of the series 2 prostaglandins.17 It patients with ovarian and breast tumors were is also hypothesized that bromelain therapy given 600 mg of bromelain daily for from 6 leads to a relative increase of the endogenous Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 247
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Table 3 Selected Cytokines and their physiological activities
——————————————————————————————Interleukin-1 induces proliferation of fibroblastsincreases leukocyte adhesion, synthesis of PGI2 and stimulates production of collagenases and increases increases acute phase responses; including fever induction, slow wave sleep,neutrophilia, hemodynamic effects, decreasingappetite and increasing synthesis of acutephase proteins activates resting T cells and macrophagesstimulates ACTH and glucocorticoid releasestimulates synthesis of IL-2 and IFN-gammaincreases NK cell activity induces proliferation of fibroblastsincreases leukocyte adhesion, synthesis of PGI2 and stimulates production of collagenases and increases increases acute phase responses; including fever induction, slow wave sleep,neutrophilia, hemodynamic effects, decreasingappetite and increasing synthesis of acutephase proteins cytotoxic to some tumor cellssimilar actions as IL-1 on T cells and macrophagesinhibits lipoprotein lipaseinhibits hematapoetic stem cells enhances maturation of activated T and B cellsinhibits growth of fibroblastsstimulates growth of hematopoetic progenitor cells activates macrophagesinduces expression of HLA class II moleculesantiviral activityactivates endothelial cellssuppresses hematopoetic progenitor cells Page 248 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission months to several years, with reported resolu- Immunity
tion of some of the cancerous masses and a decrease in metastasis.19 Bromelain in doses T-cell CD44 molecules from lymphocytes and of over 1000 mg daily has been combined with to affect T-cell activation. The highly purified bromelain protease F9 was tested on the ad- vincristine, and has been reported to result in hesion of peripheral blood lymphocytes (PBL) to human umbilical vein endothelial cells tastasis of Lewis lung cancer cells implanted reduced the expression of CD44, but F9 was about 10 times more active than bromelain; antimetastatic potential was demonstrated by having about 97% inhibition of CD44 expres- both the active and inactive bromelain, with sion. The results indicate that F9 selectively or without proteolytic and anticoagulant prop- decreases the CD44 mediated binding of PBL Cytokine Induction
response depends on T cells and macrophages, (35% bromelain in a lipid base) can be benefi- along with the polypeptide factors they pro- cial in the elimination of burn debris and in duce, called cytokines, which play a key role acceleration of healing. A non-proteolytic in communication during normal immunologi- component of bromelain is responsible for this cal response as well as infectious, inflamma- tory, and neoplastic disease states. Table 3 lists escharase, has no hydrolytic enzyme activity against normal protein substrates or various glycosaminoglycan substrates and its activity varies greatly from preparation to preparation.27 mononuclear cells. Treatment leads to the plete debridement on experimental burns in production of tumor necrosis factor-alpha rats in an average of 1.9 days as compared to (TNF-alpha), interleukin-1-beta (IL-1 beta), collagenase, which required an average of 10.6 and interleukin-6 (IL-6) in a time and dose- the interface with living tissue. It is hypoth- which had no effect alone, synergistically esized that bromelain activates collagenase in increased TNF-alpha production when applied living tissue which then attacks the denatured together with the enzymes.23,24 The tryptic but collagen in the eschar. This produces a demar- not the autolytic fractions of papain and cation between living and dead tissue. With very little scraping, using a tongue depressor, inducing capacity for TNF production than the all of the eschar can be removed and a bed untreated enzyme.25 Trypsin alone had only a suitable for grafting results. By using brome- lain, grafting can occur as soon as 24 hours after the accident. Utilizing bromelain cream tion may explain the antitumor effects ob- in the treatment of burns usually results in served after oral administration of polyenzyme minimal or no scar tissue formation.
Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 249
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission administered four times a day along with the in frostbite eschar removal was extrapolated following antibiotics either alone or in com- and investigated. In the initial trial, no debri- bination; penicillin, chloramphenicol, eryth- dement other than that of the superficial lay- romycin or novobiacin. A control group of 56 ers of the eschar was noted. Although third patients was treated with antibiotics alone. Of degree burn injuries debrided to a graftable bed the 23 patients who had been unsuccessfully after two topical applications of bromelain, treated with antibiotics, 22 responded favor- frostbite injuries remained unaffected.29 ably to the combined treatment. In every dis-ease state studied there was a significant re- Potentiation of Antibiotics
duction in morbidity when the combination ofbromelain and antibiotics was used as opposed Antibiotic potentiation is one of the pri- to antibiotics alone. Another group of 106 mary uses of bromelain in several foreign cases was treated with bromelain alone, with countries. Bromelain can modify the perme- results comparable to those obtained with an- ability of organs and tissues to different drugs.
It prolongs sleeping time in mice administered pentobarbital30 and increases spinal levels of tis were placed on standard therapy, which in- penicillin and gentamycin in rats. In humans, cluded antihistamines and analgesic agents, bromelain has been documented to increase along with antibiotics if indicated. Twenty blood and urine levels of antibiotics16 and re- three of the patients received bromelain four sults in higher blood and tissue levels of tetra- times daily, while the remaining 25 received a cycline and amoxycillin when they are admin- placebo. Of the patients receiving bromelain, 83% had complete resolution of nasal mucosal inflammation compared with only 52% in the bromelain concurrently with amoxycillin or placebo group. Improvement in breathing oc- tetracyclin resulted in increased serum levels curred in 78% of those receiving bromelain as and concentrations of both antibiotics in uterus, compared to 68% in those receiving placebo.
ovarian tubes, and ovaries as compared with In the patients not receiving antibiotic treat- controls. This effect was not generated by in- ment, 85% of patients receiving bromelain had domethacin, an anti-inflammatory drug which complete resolution of inflammation of the acts as a cyclooxygenase inhibitor, which in- dicates that bromelain has some undetermined breathing difficulties. Only 40% of the placebo activity that enhances absorption and tissue group had a similar outcome with respect to distribution of antibiotics.32 A three-fold in- inflammation, while 53% reported resolution crease in the level of tetracycline in serum af- ter oral ingestion of 540 mg of enterically- coated bromelain has also been demonstrated other medicines by bromelain may be due to enhanced absorption, as well as increased permeability of the diseased tissue which therapy was instituted for 53 hospitalized pa- enhances the access of the antibiotic to the tients with the following conditions; pneumo- site of the infection. It is also thought that nia, bronchitis, cutaneous staphylococcus in- the use of bromelain may provide a similar fection, thrombophlebitis, cellulitis, pyelone- access to specific and non-specific compo- phritis and perirectal and rectal abscesses.
Twenty three of the patients had been on anti- enhancing the body’s utilization of its own biotic therapy without success. Bromelain was Page 250 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Mucolytic Properties
gastric ulcers in experimental animals.40 In an melain or papain, to remove excessive cervi- extensive study of the effect of bromelain on cal mucus was demonstrated in 1954. Obser- the gastric mucosa, it was found that brome- vations following its use demonstrated that lain increased the uptake of radioactive sulfur pseudo and actual space-occupying lesions could be more positively identified, and in- creased uptake of these substances may allow flammatory changes of the canal and its glands the gastric mucosa to heal more rapidly under could be visualized with greater accuracy.36 consistency were investigated in vitro and in fect of bromelain on enterotoxin receptor ac- vivo. Of the enzymes tested, bromelain exerted tivity in porcine small intestine, orally admin- the most potent lowering effect on sputum vis- istered bromelain inhibited enterotoxin attach- cosity and also showed a tendency to increase ment to pig small intestine in a dose-depen- dent manner. Attachment was negligible after treatment. Serum biochemical analysis and histopathological examination of treated pig- lets showed no adverse effects with the bro- bronchiectasis, or pulmonary abscess, those melain treatment. Administration of bromelain receiving bromelain orally showed a decrease may therefore be useful for preventing entero- in the volume and purulence of the sputum.17 These results support the effectiveness ofbromelain in decreasing the viscosity of Surgical Procedures and
sputum so that it can be more easily cleared Musculoskeletal Injuries
in the treatment of inflammation and soft tis- Digestive Aid
sue injuries. An early clinical trial on brome- lain was conducted on 74 boxers with bruises as a digestive enzyme following pancreatec- on the face and haematomas of the orbits, lips, tomy, in cases of exocrine pancreas insuffi- ears, chest and arms. Bromelain was given four ciency and in other intestinal disorders.38 Be- times a day for 4 days or until all signs of bruis- cause of its wide pH range, bromelain has ac- ing had disappeared. A control group of 72 tivity in the stomach as well as the small in- boxers were given a placebo. In 58 of the box- testine. It has also been shown to be an ad- ers taking bromelain, all signs of bruising equate replacement for pepsin and trypsin in cleared completely in four days, with the re- cases of deficiency. The combination of ox maining 16 requiring 8-10 days for complete bile, pancreatin and bromelain is effective in clearance. In the control group, only 10 had lowering stool fat excretion in patients with complete clearance within four days, with the pancreatic steatorrhoea. In addition, this com- remainder requiring seven to fourteen days for bination resulted in a gain in weight in most cases as well as an enhanced subjective feel- ing of well being. Symptomatic improvement melain was investigated in traumatically-in- was also noted in relation to pain, flatulence duced hindleg edema in rats. After enteral ap- plication of bromelain a significant reductionof the edema could be observed, however, Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 251
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Conditions in which Bromelain has
Documented Therapeutic Benefits
to 2.0 days, as compared with controls receiv- ArthritisAthletic and musculoskeletal injuries gery were given bromelain four times a day starting 72 hours prior to surgery. At 24 hours after surgery, 75% of these patients were evaluated as having mild or no inflammation, in contrast to only 19% of a group receiving a placebo. Twenty-four hours after surgery, pain MaldigestionPancreatic insufficiency and Steatorrhea was either absent or mild in 38% of brome- lain-treated patients, as opposed to 13% re- ceiving placebo. After 72 hours, this increased to 75% of those in the bromelain group, as compared to only 38% in the placebo group.45 patients with blunt injuries to the musculosk-eletal system, the efficacy and tolerability of parenteral application only resulted in a mini- high-dose bromelain, in addition to the usual mal therapeutic effect. Although enterally-ap- therapeutic measures, was investigated. Treat- plied enzymes are thought to be degraded in ment with bromelain resulted in a clear reduc- the gut, the better results were obtained after tion in all four parameters tested; swelling, oral administration of bromelain, supporting pain at rest and during movement, and ten- the observation that bromelain can be absorbed by the gut without losing its biological prop-erties.11 Cardiovascular and Circulatory
Fifty-five pre-surgical patients were di- Applications
vided into two groups. Group one, consisting of 22 patients, took bromelain four times a dayfor 48-72 hours prior to surgery and contin- prevents aggregation of human blood plate- ued for 72 hours after surgery. Group two, con- lets in vivo and in vitro, prevents or minimizes sisting of 33 patients, took bromelain starting the severity of angina pectoris and transcient on the day of surgery, with the first dose ad- ischemic attacks (TIA), is useful in the pre- ministered one hour prior to surgery. Fifty per- cent of group one and 42.4% of group two had thrombophlebitis, may break down cholesterol complete disappearance of pain and inflam- plaques, and exerts a potent fibrinolytic activ- mation within 72 hours. Pain and inflamma- ity. If administered for prolonged time peri- tion persisted past 72 hours in only one mem- ods, bromelain also exerts an anti-hyperten- ber of the group supplemented with brome- lain for three days prior to surgery, as opposed to five members of the group that started bromelain to 14 patients with angina pectoris supplementation one hour prior to surgery. In resulted in the disappearance of symptoms in a separate study, supplementation of brome- all patients within 4 to 90 days.48 Similar lain starting 48-72 hours prior to surgery re- results have been observed in patients taking duced the average number of days for com- between 500-700 mg/day of bromelain. After plete disappearance of pain from 3.5 to 1.5, and disappearance of inflammation from 6.9 reappear after a variable period of time, often Page 252 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission not been demonstrated in humans at any dos- coronary infarct after administration of potas- sium and magnesium orotate along with 120- enzymes should not be underestimated, for 400 mg of bromelain per day has also been they cause, in particular, IgE-mediated respi- ratory allergies of both the immediate type and the late-phase of immediate type with pre- acute thrombophlebitis, bromelain, in addition dominantly respiratory symptoms. Allergy to to analgesics, was shown to decrease all symp- bromelain has been reported in workers of a toms of inflammation; including, pain, edema, blood-grouping laboratory, and investigation tenderness, skin temperature, and disability.50 indicates that (1) bromelain is a strong sensi- tizer, (2) sensitization usually occurs due to these conditions may be due to its ability to inhalation and not to ingestion, (3) bromelain breakdown fibrinous plaques. Bromelain has allergy is occupationally acquired, and ad- been shown to dissolve arteriosclerotic plaque equate precautions are necessary.53 The risk in rabbit aorta in vivo and in vitro.2 It is likely of sensitization to enzymes due to inhalation that bromelain also increases vessel wall as a result of occupational exposure is very permeability to oxygen and nutrients while increasing blood fluidity, both of which aid in react with the sera in about 28% of personswith IgE allergic response to honeybee Toxicity, Side Effects and Allergic
venom.55 Bromelain, along with horseradish Reactions
peroxidase and ascorbate oxidase are recog-nized by the IgE of sera from patients who are low toxicity, with an LD50 greater than 10g/ kg. Toxicity tests on dogs, with increasing as a meat tenderizer and to clarify beer, are levels of bromelain up to 750 mg/kg adminis- considered as potential ingestive allergens and tered daily, showed no toxic effects after six may represent an unrecognized cause of an months. Dosages of1.5 g/kg/day administered allergic reaction following a meal. As with to rats show no carcinogenic or teratogenic ef- other food substances, a small segment of the population, particularly those with a sensitiv- ity to pineapple, may be sensitive to oral have not been observed. Bromelain supple- supplementation with bromelain. As contact allergens, the enzymes play a minor role; how- have no effect on heart rate or blood pressure; ever, it is thought that skin testing with iso- however, increasing doses up to 1840 mg have lated proteases like bromelain may induce sys- been shown to increase the heart rate propor- temic reactions in susceptible individuals, even tionately. In some cases an increase of up to 80% of the baseline has been reported, whichmay be a result of bromelain’s influence onIL-1 and TNF production. Maximum effectswere seen at 2 hours but some residual effectremained at 24 hours. At doses above 700 mg,palpitations and subjective discomfort havebeen reported. Blood pressure changes have Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 253
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Table 5. Considerations and Instructions for Prescribing Bromelain
Is there a history of occupational inhalant/skin contact with Bromelain? If yes, consider possibility of allergic reaction.
Does the patient have allergic reactions to bee stings, olive tree pollen orpineapple? If yes, consider possibility of allergic reaction.
Is there a history of heart palpitations? If yes, limit to 460 mg ofbromelain per day.
Dose 4 times per day for best results.
Dosage ranges typically from 500-1000 mg/day with up to 2000 mg/daycommon.
If used pre-surgery or to minimize trauma from sporting activities, beginbromelain supplementation 72 hours prior to event.
Enhances effectiveness of antibiotics and absorption of glucosamine andpossibly bioflavonoids, so supplement in conjunction with these substances.
Best results might be obtained if taken away from food, however, therapeuticefficacy has been demonstrated when bromelain is supplemented prior to orwith meals.
Indications for the Use of Bromelain
for supplementation with oral bromelain.
1. It inhibits blood platelet aggregation, favorably modulates prostaglandin formation administered prior to a traumatic event, i.e.
physiological action for as long as it is administered, with no evidence indicating and improve the action of other substances when they are administered in combination.
lacking in side effects, so it can be used without concern in doses from 200 to 2000 stimulate fever and acute phase response, and its demonstrated ability to increase the heart 4. It is a protein and seems to be as easily rate, bromelain may assist in generating an metabolized as other dietary proteins.
Page 254 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Bromelain has a wide range of conditions fect at doses as low as 160 mg/day, however, for which it has well documented therapeutic there is a general consensus among research- ers that the best results occur when bromelainis given in doses above 500 mg per day and Dosage and Prescription
that results improve in a dose-dependent man- Instructions
ner with higher levels of bromelain supplemen-tation. Bromelain has been demonstrated to be well absorbed after an oral dose and has been strate an enhanced efficacy of bromelain when shown to be safe at high doses for prolonged it is administered between meals. It is gener- periods of time. For the conditions discussed in this review, bromelain has shown itself to away from food unless it is being used as a digestive aid, because it is believed that other-wise, it will tend to act as a digestive enzymeand its therapeutic benefit may be diminished.
While this may in fact be the case, the clinical Rowan AD, Buttle DJ, Barrett AJ. The cysteine studies conducted on bromelain have not fol- proteinases of the pineapple plant. Biochem J1990;266:869-875.
Taussig SJ, Nieper HA. Bromelain: its use in prevention and treatment of cardiovascular efits in doses as small as 160 mg/day; how- disease, present status. J IAPM 1979;6:139- ever, it is thought that, for most conditions, best results occur starting at a dose of 750- Harrach T, Eckert K, Schulze-Forster K, et al.
1000 mg/day. Most research on bromelain has Isolation and partial characterization of basic been done utilizing divided doses, usually four proteinases from stem bromelain. J ProteinChem 1995;14:41-52.
per day, and findings indicate that results are Jeung A. Encyclopedeia of Common Natural dose-dependent. See table 5 for a summary of Ingredients Used in Foods, Drugs, and Cosmetics. New York, NY: John Wiley &Sons;1980:74-76.
White RR, Crawley FE, Vellini M, et al.
Bioavailability of 125I bromelain after oral administration to rats. Biopharm Drug Dispos of clinical applications for more than 35 years.
Although its mechanisms of action has not Heinicke RM, Van der Wal M, Yokoyama MM.
been completed resolved, bromelain has dem- Effect of bromelain on human platelet aggrega onstrated a beneficial effect on the kinin sys- tion. Experientia 1972;28:844-845.
tem, the coagulation cascade, the cytokine sys- Morita AH, Uchida DA, Taussig SJ. Chromato tem, and prostaglandin synthesis. Bromelain graphic fractionation and characterization ofthe active platelet aggregation inhibitory factor is believed to enhance the absorption of fla- from bromelain. Arch Inter Phar Ther vonoids and has been shown to increase ab- Livio M, Bertoni MP, De Gaetano G, et al.
these nutrients are given. It may also enhance prothrombin complex factors and plateletaggregation in the rat - A preliminary report.
absorption and utilization of many other sub- Drugs Expt Clin Res 1978;4:49-53.
stances; however, to date research in this area De-Giuli M, Pirotta F. Bromelain: interaction has focused primarily on antibiotics. Brome- lain has been shown to exert a beneficial ef- specific antiserum. Drugs Exp Clin Res1978;4:21-23.
Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 255
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Inoue K, Motonaga A, Dainaka J, et al. Effect Desser L, Rehberger A. Induction of tumor of etodolac on prostaglandin E2 biosynthesis, necrosis factor in human peripheral-blood mononuclear cells by proteolytic enzymes.
formation. Prostaglandins Leukot Essent Fatty Desser L, Rehberger A, Kokron E, et al.
Uhlig G, Seifert J. The effect of proteolytic Cytokine synthesis in human peripheral blood mononuclear cells after oral administration of edema. Fortschr Med 1981;99:554-556.
Vellini M, Desideri D, Milanese A, et al.
Possible involvement of eicosanoids in the Munzig E, Eckert K, Harrach T, et al. Brome- pharmacological action of bromelain.
lain protease F9 reduces the CD44 mediated Arzneimittelforschung 1986;36:110-112.
adhesion of human peripheral blood lympho- Yonehara N, Shibutani T, Inoki R. Contribu- cytes to human umbilical vein endothelial tion of substance P to heat-induced edema in cells. FEBS Lett 1995;351:215-218.
Houck JC, Chang CM, Klein G. Isolation of an effective debriding agent from the stems of Kumakura S, Yamashita M, Tsurufuji S. Effect pineapple plants. Int J Tissue React of bromelain on kaolin-induced inflammation in rats. Eur J Pharmacol 1988;150:295-301.
Klaue P, Dilbert G, Hinke G, et al. Tier- Uchida Y, Katori M. Independent consumption of high and low molecular weight kininogens enzymatischen lokalbehandlung subdermaler in vivo. Adv Exp Med Biol 1986;198:113-118.
verbrennungen mit bromelain. Therapiewoche1979;29:796-799.
Taussig SJ, Batkin S. Bromelain, the enzymecomplex of pineapple (Ananas comosus) and its clinical application. An update. J eschar debridement by bromelain. Ann Emerg Ethnopharmacol 1988;22:191-203.
Schafer A, Adelman B. Plasmin inhibition of Moss JN, Frazier CV, Martin GJ. Bromelains, platelet function and of arachidonic acid the pharmacology of the enzymes. Arch Int metabolism. J Clin Invest 1985;75:456-461.
Felton GE. Fibrinolytic and antithrombotic Tinozzi S, Venegoni A. Effect of bromelain on action of bromelain may eliminate thrombosis serum and tissue levels of amoxycillin. Drugs Luerti M, Vignali ML. Influence of bromelain Gerard G. Anti-cancer therapy with bromelain.
on penetration of antibiotics in uterus, salpinx and ovary. Drugs Expt Clin Res 1978;4:45-48.
Nieper HA. A program for the treatment of cancer. Krebs 1974;6:124-127.
tetracyclin in conbination with bromelain byoral application. Arzneim-Forsch 1972;22:410- Taussig SJ, Szekerczes J, Batkin S. Inhibition of tumor growth in vitro by bromelain, anextract of the pineapple plant (Ananas Neubauer RA. A plant protease for potentia- comosus). Planta Med 1985;6:538-539.
tion of and possible replacement of antibiotics.
Exp Med Surg 1961;19:143-160 Batkin S, Taussig SJ, Szekerezes J.
Antimetastatic effect of bromelain with or Ryan RE. A double-blind clinical evaluation of without its proteolytic and anticoagulant bromelains in the treatment of acute sinusitis.
action of papain and bromelain on the uterus.
teolytic enzymes and amylase induce cytokine production in human peripheral blood mono- Suzuki K, Niho T, Yamada H, et al. [Experi- nuclear cells in vitro. Cancer Biother mental study of the effects of bromelain on the sputum consistency in rabbits]. NipponYakurigaku Zasshi 1983;81:211-216.
Page 256 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Knill-Jones RP, Pearce H, Batten J, et al.
Gutfreund A, Taussig S, Morris A. Effect of oral bromelain on blood pressure and heart rate pancreatic insufficiency. Brit Med J 1970;4:21.
of hypertensive patients. Haw Med Jour Nair C. Double-blind cross-over trial of an Gailhofer G, Wilders-Truschnig M, Smolle J, enzyme preparation in pancreatic steatorrhea.
J Asso Phys Ind 1981;29:207-209.
occupational allergy. Clin Allergy Seligman B. Bromelain—an anti-inflammatory agent—thrombophlebitis. No toxicity.
Chida T. A study on dose-response relationship of occupational allergy in a pharmaceutical Felton G. Does Kinin released by pineapple plant. Sangyo Igaku 1986;28:77-86.
Tretter V, Altmann F, Kubelka V, et al. Fucose prostaglandin E1-like compound. Haw Med J alpha 1,3-linked to the core region of glyco- protein N-glycans creates an important epitope for IgE from honeybee venom allergic indi- enterotoxigenic Escherichia coli receptor activity in piglet small intestine. Gut Batanero E, Villalba M, Monsalve RI, et al.
Cross-reactivity between the major allergen Blonstein JL. Control of swelling in boxing from olive pollen and unrelated glycoproteins: injuries. Practitioner 1960;185:78.
evidence of an epitope in the glycan moiety ofthe allergen. J Allergy Clin Immunol tion of a plant proteolytic enzyme for thecontrol of inflammation and pain. J Dent Med Wuthrich B. Proteolytic enzymes: potential allergens for the skin and respiratory tract?Hautarzt 1985;36:123-125.
Tassman GC, Zafran JN, Zayon GM. Adouble-blind crossover study of a plantproteolytic enzyme in oral surgery. J Dent Med1965;20:51-54.
Masson M. Bromelain in blunt injuries of thelocomotor system. A study of observedapplications in general practice. Fortschr Med1995;113:303-306.
Giacca S. Clinical experiments with bromelainin peripheral venous diseases and chronicbronchitic states. Minerva Med1965;56:Suppl.104.
Nieper HA. Effect of bromelain on coronaryheart disease and angina pectoris. Acta MedEmpirica 1978;5:274-278.
Nieper HA. Decrease of the incidence ofcoronary heart infarct by Mg- and K-orotateand bromelain. Acta Med Empirica1977;12:614-618.
Seligman B. Oral bromelains as adjuncts in thetreatment of acute thrombophlebitis. Angiology1969;20:22-26.
Taussig SJ, Yokoyama MM, Chinen N, et al.
Bromelain: A proteolytic enzyme and itsclinical application. HirJ Med Sci1975;24:185-193.
Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 257
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Guideline vulvovaginal candidosis (2010) of the german society for gynecology and obstetrics, the working group for infections and infectimmunology in gynecology and obstetrics, the german society of dermatology, the board of german dermatologists and the german speaking mycological society
Diagnosis,Therapy and Prophylaxis of Fungal DiseasesGuideline vulvovaginal candidosis (2010) of the german society forgynecology and obstetrics, the working group for infections andinfectimmunology in gynecology and obstetrics, the german societyof dermatology, the board of german dermatologists and the germanspeaking mycological societyProf. Dr. med. Werner Mendling, Vivantes – Klinikum im Fr