Bromelain – The Wonder Supplement

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Bromelain – The Wonder Supplement

I first experienced

bromelain firsthand several years ago when I was bitten by a brown

recluse spider on the front of my upper left leg – in three places no

less. This was the second time I had been bitten. The first time, I

was bitten at the very topmost part of my left leg on the inside where

it joined the pelvic area, and that bite resulted in the loss of a

chunk of flesh and, much worse, being crippled for several months

thanks to the treating physician botching the treatment and thrusting

his deadening needle into the bursal sac. Since I did not want to

repeat that ugly memory and I had was in my first few years of studying

natural health, I decided to try to handle it myself.

One of the people I consulted for help was an old naturopathic healer who claimed to have been a doctor in Russia before immigrating to the United States

many decades ago. He suggested that, among other things, I made sure

that I used bromelain , which he called a wonder supplement.

And so, armed with garlic

(which I took internally and used externally), some hydrogen peroxide,

otc ointment, some antibiotic for my son's dog Dice, a vial of

homeopathic ledum pallustre, and bromelain, I began to treat the

spider bites. For a couple of days it was touch and go it seemed, as

the bites continue to redden and swell and the radiating areas of red

and pink grew until it encompassed an area about 6 inches by 12

inches. But then the tide turned and the bites began to get better.

Within a little over a week, they were mostly healed and within two

weeks there was virtually no sign of the bites.

Earlier this month, another brown

recluse struck. Again in the same general vicinity (I think the damn

things are aiming for something and one of these days they might score a hit! YIKES!) This time, being a bit wiser, or so I hope, I caught it

very early on and again decided to treat it myself – this time with a bit of tea

tree oil at the beginning and constant colloidal silver, aloe vera, apple cider vinegar, ledum palustre and my old

friend, bromelain. This time the tables were turned on the second day

after beginning treatment and today (June 15th 2007) the bite is almost completely healed.

I am convinced that

bromelain, a supplement with many extraordinary uses, is a big reason I

was successful both times. After the initial success against the

recluse bite, I researched bromelain quite a bit and would like to

share with you a study that, while a bit technical, should give a good

indication of just how amazing bromelain is.

Bromelain: 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 debridement properties;

(7) enhanced absorption of other drugs; (8) mucolytic properties; (9)

digestive assistance; (10) enhanced wound healing; and (11)

cardiovascular and circulatory improvement. Bromelain is well absorbed

orally and available evidence indicates that it's therapeutic effects

are enhanced with higher doses. Although all of its mechanisms of

action are still not completely resolved, it has been demonstrated to

be a safe and effective 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 therapeutic compound 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 bromelain or stem bromelain depending on

its source, with all commercially available bromelain being derived

from the stem.1 The term bromelain will be used to refer to stem bromelain in the remainder 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 calcium. When the proteolytic fraction of

bromelain is purified and extracted, the result is a potent proteolytic

enzyme in vitro; however, this component has been shown to be

physiologically inactive in vivo for many of the conditions where

bromelain has a beneficial effect.2 It appears that a great

deal of the physiological activity of bromelain is not accounted for in

its proteolytic fraction and it is likely that the beneficial effects

of bromelain are due to multiple factors, not to one 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 the most 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 to be unglycosylated. The optimal pH for the F4

and F5 fractions is between 4.0 and 4.5 and for F9 close to a neutral

pH.3 The entire extract of bromelain has been shown to exhibit its activity over a pH range of 4.5 to 9.8.4

Since

bromelain is derived from a natural source, different sources can

exhibit variability in their physiological activity, even when their

proteolytic activity is the same. Bromelain is not heat stable so it's

physiological activity can be further reduced by improper processing or

storage conditions.

Absorption and Availability

Bromelain

is absorbed intact through the gastrointestinal tract of animals, with

up to 40% of the high molecular weight substances detected in the blood

after oral administration. The highest concentration of bromelain is

found in the blood 1 hour after administration; however, its

proteolytic activity is rapidly deactivated,5 probably by the normal plasma protease controls and serum alpha2-macroglobulin.

A variety

of designations have been used to indicate the activity of bromelain;

with published research varying in the designation utilized. Rorer

units (R.U.), gelatin dissolving units (G.D.U.), and milk clotting

units (M.C.U.) are the most commonly used measures of activity. One

gram of bromelain standardized to 2000 M.C.U. would be approximately

equal to 1 gram with 1200 G.D.U. of activity or 8 grams with 100,000

R.U. of activity.

Platelet Aggregation, Fibrinolysis and Anti-Inflammatory Activity

The first

conclusive evidence that bromelain prevents aggregation of blood

platelets was reported in 1972. Bromelain was administered orally to 20

volunteers with a history of heart attack or stroke, or with high

platelet aggregation values. Bromelain decreased aggregation of blood

platelets in 17 of the subjects and normalized values in 8 of the 9

subjects who previously had high aggregation values.6 In vitro studies have demonstrated that bromelain inhibits platelet aggregation stimulated by ADP or epinephrine, as well as by prostaglandin precursors, in a dose-dependent manner.7

Bromelain

is an effective fibrinolytic agent in vitro and in vivo; however, its

effect is more evident in purified fibrinogen solutions than in plasma.

This is probably due to the antiproteases present in plasma. A

dose-dependent reduction of serum fibrinogen level is seen in rats

following administration of bromelain, and at the highest

concentrations of bromelain, both prothrombin time (PT) and activated

partial thromboplastin time (APTT) are markedly prolonged.89 Bromelain's

fibrinolytic activity has been attributed to the enhanced conversion of

plasminogen to plasmin, which limits the spread of the coagulation

process by degrading fibrin.

 

Bromelain

seems to have both direct as well as indirect actions involving other

enzyme systems in exerting its anti-inflammatory effect. Both etodolac

and bromelain inhibit the inflammatory pain in rats in a dose-dependent

manner.10 Bromelain was the most potent of nine anti-inflammatory substances tested on experimentally-induced edemas in rats;11 while prednisone and bromelain have been shown to be comparable in their ability to reduce inflammation in rats.12

Treatment with bromelain and emorfazone has been shown to decrease

significantly the heat-evoked immunoreactive substance P release and

subsequent edema in a rat model.13

Mechanism of Action

Surface

contact, by collagen or platelets, activates the kinin system and the

clotting cascade by stimulating the conversion of Hageman factor to an

active protease (factor XIIa). Factor XIIa then activates the kinin

system by converting plasma prekallikrein into kallikrein, and

continues the intrinsic path of the clotting cascade by converting

factor XI to its active form. Kallikrein, in an autocatalytic loop,

accelerates the activation of Hageman factor, which continues to

potently activate both the kinin system and the clotting cascade. In

addition, Kallikrein cleaves (HMWK) to produce bradykinin, a potent

stimulator of both increased vascular permeability and pain. The

activation of the clotting cascade will culminate in the conversion of

fibrinogen to fibrin (see Figure 1). Fibrin then forms a protective

matrix around the injured area. This matrix inhibits tissue drainage,

promotes edema and blocks circulation of blood flow.

In order to

determine the effects of bromelain on the plasma kallikrein system,

bradykinin levels and plasma exudation at the inflammatory site were

examined in rats. Bromelain (5 and 7.5 mg/kg) caused a dose-dependent

decrease of bradykinin levels at the inflammatory site and a parallel

decrease of the prekallikrein levels in sera. Plasma exudation was also

reduced dose dependently. Bradykinin-degrading activity in sera was

elevated after treatment with bromelain, although it was unchanged in

the pouch fluid.14 The levels of high molecular weight (HMW)

kininogen and pre-kallikrein in rat plasma were markedly reduced after

single injection of bromelain (10 mg/kg, i.v.) and gradually recovered

over a 72 hour period. The level of low molecular weight (LMW)

kininogen was not changed during this period.15

Bromelain-treated

rats also show a reduction in Factor X and prothrombin, both of which

are needed for the activation of fibrinogen to fibrin through the

common pathway of the intrinsic and extrinsic cascade.16

This indicates that bromelain's action is in part a result of

inhibiting the generation of bradykinin at the inflammatory site via

depletion of the plasma kallikrein system, as well as limiting the

formation of fibrin by reduction of clotting cascade intermediates.

These actions result in significant reduction in pain and edema, as

well as enhanced circulation to the injured site.

After the

formation of a clot, vessel repair begins with the conversion of

plasminogen to plasmin, which then acts to degrade fibrin into smaller

components which can be removed by monocytes and macrophages. In rats,

bromelain has been shown to stimulate the conversion of plasminogen to

plasmin, resulting in increased fibrinolysis. This minimizes venous

stasis, facilitates drainage, increases permeability and restores the

tissue's biological continuity.16

The

therapeutic effect of bromelain may also be due to its ability to

selectively modulate the biosynthesis of thromboxanes and

prostacyclins; two groups of prostaglandins with opposite actions which

ultimately influence activation of cyclic-3,5-adenosine (cAMP), an

important cell-growth modulating compound.

The binding

of epinephrine, collagen, or thrombin to platelets activates the

enzymes phospholipase C and phospholipase A2 which release arachidonic

acid from membrane phospholipids (phosphatidylcholine and

phosphatidylinositol). Table 1 lists the inflammatory actions of

arachidonic acid metabolites.

Plasminogen,

which is activated to plasmin by the oral administration of bromelain,

has been shown to inhibit the release of arachidonic acid from cell

membranes, resulting in decreased platelet aggregation and modulation

of the series 2 prostaglandins.17 It is also hypothesized that bromelain therapy leads to a relative increase of the endogenous prostaglandins, PGI2 and PGE2 over thromboxane A2.18

Non-steroidal

anti-inflammatory drugs inhibit cyclooxygenase, which is required for

the synthesis of series 2 prostaglandins, resulting in a decrease in

both pro and anti-inflammatory prostaglandins. Rather than blocking the

arachidonic acid cascade at the enzyme cyclooxygenase, like NSAIDs,

bromelain may selectively decrease thromboxane generation and change

the ratio of thromboxane/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 inflammation.

 

Antitumor

The first

documented use of oral bromelain on cancer patients was in 1972. Twelve

patients with ovarian and breast tumors were given 600 mg of bromelain

daily for from 6 months to several years, with reported resolution of

some of the cancerous masses and a decrease in metastasis.19

Bromelain in doses of over 1000 mg daily has been combined with

chemotherapeutic agents such as 5-FU and vincristine, and has been

reported to result in tumor regression.19,20

Bromelain

has also decreased lung metastasis of Lewis lung cancer cells implanted

in mice in a dose-dependent manner. This antimetastatic potential was

demonstrated by both the active and inactive bromelain, with or without

proteolytic and anticoagulant properties.21,22

Cytokine Induction

The

successful initiation of an immune response depends on T cells and

macrophages, along with the polypeptide factors they produce, called

cytokines, which play a key role in communication during normal

immunological response as well as infectious, inflammatory, and

neoplastic disease states. Table 3 lists cytokines and their activities.

 

Bromelain,

papain, and amylase have all been demonstrated to induce cytokine

production in human peripheral blood mononuclear cells. Treatment leads

to the production of tumor necrosis factor-alpha (TNF-alpha),

interleukin-1-beta (IL-1 beta), and interleukin-6 (IL-6) in a time and

dose-dependent manner. Interferon-alpha (IFN-alpha) and

interferon-gamma (IFN-gamma), which had no effect alone,

synergistically increased TNF-alpha production when applied together

with the enzymes.23,24 The tryptic but not the autolytic

fractions of papain and bromelain have a higher (10- to 40-fold)

inducing capacity for TNF production than the untreated enzyme.25 Trypsin alone had only a small inducing effect.

The ability

to induce cytokine production may explain the antitumor effects

observed after oral administration of polyenzyme preparations.

Immunity

Bromelain

has been shown to remove T-cell CD44 molecules from lymphocytes and to

affect T-cell activation. The highly purified bromelain protease F9 was

tested on the adhesion of peripheral blood lymphocytes (PBL) to human

umbilical vein endothelial cells (HUVEC). Both bromelain and protease

F9 reduced the _expression of CD44, but F9 was about 10 times more

active than bromelain; having about 97% inhibition of CD44 _expression.

The results indicate that F9 selectively decreases the CD44 mediated

binding of PBL to HUVEC.26

Debridement

Bromelain

applied topically as a cream (35% bromelain in a lipid base) can be

beneficial in the elimination of burn debris and in acceleration of

healing. A non-proteolytic component of bromelain is responsible for

this effect. This component, referred to as escharase, has no

hydrolytic enzyme activity against normal protein substrates or various

glycosaminoglycan substrates and its activity varies greatly from

preparation to preparation.27

Topical

bromelain has achieved complete debridement on experimental burns in

rats in an average of 1.9 days as compared to collagenase, which

required an average of 10.6 days for similar results.28

Topical

bromelain separates eschar at the interface with living tissue. It is

hypothesized that bromelain activates collagenase in living tissue

which then attacks the denatured collagen in the eschar. This produces

a demarcation between living and dead tissue. With very little

scraping, using a tongue depressor, all of the eschar can be removed

and a bed suitable for grafting results. By using bromelain, grafting

can occur as soon as 24 hours after the accident. Utilizing bromelain

cream in the treatment of burns usually results in minimal or no scar

tissue formation.

The

applicability of topical bromelain in frostbite eschar removal was

extrapolated and investigated. In the initial trial, no debridement

other than that of the superficial layers of the eschar was noted.

Although third degree burn injuries debrided to a graftable bed after

two topical applications of bromelain, frostbite injuries remained

unaffected.29

Potentiation of Antibiotics

Antibiotic

potentiation is one of the primary uses of bromelain in several foreign

countries. Bromelain can modify the permeability of organs and tissues

to different drugs. It prolongs sleeping time in mice administered

pentobarbital30 and increases spinal levels of penicillin

and gentamycin in rats. In humans, bromelain has been documented to

increase blood and urine levels of antibiotics16 and results in higher

blood and tissue levels of tetracycline and amoxycillin when they are

administered concurrently with bromelain.31

Treatment

of 18 women with 80 mg of bromelain concurrently with amoxycillin or

tetracyclin resulted in increased serum levels and concentrations of

both antibiotics in uterus, ovarian tubes, and ovaries as compared with

controls. This effect was not generated by indomethacin, an

anti-inflammatory drug which acts as a cyclooxygenase inhibitor, which

indicates that bromelain has some undetermined activity that enhances

absorption and tissue distribution of antibiotics.32 A

three-fold increase in the level of tetracycline in serum after oral

ingestion of 540 mg of enterically-coated bromelain has also been

demonstrated in a double blind test.33

Combined

bromelain and antibiotic therapy was instituted for 53 hospitalized

patients with the following conditions; pneumonia, bronchitis,

cutaneous staphylococcus infection, thrombophlebitis, cellulitis,

pyelonephritis and perirectal and rectal abscesses. Twenty three of the

patients had been on antibiotic therapy without success. Bromelain was

administered four times a day along with the following antibiotics

either alone or in combination; penicillin, chloramphenicol,

erythromycin or novobiacin. A control group of 56 patients was treated

with antibiotics alone. Of the 23 patients who had been unsuccessfully

treated with antibiotics, 22 responded favorably to the combined

treatment. In every disease state studied there was a significant

reduction in morbidity when the combination of bromelain and

antibiotics was used as opposed to antibiotics alone. Another group of

106 cases was treated with bromelain alone, with results comparable to

those obtained with antibiotic treatment.34

Forty eight

patients with acute sinusitis were placed on standard therapy, which

included antihistamines and analgesic agents, along with antibiotics if

indicated. Twenty three of the patients received bromelain four times

daily, while the remaining 25 received a placebo. Of the patients

receiving bromelain, 83% had complete resolution of nasal mucosal

inflammation compared with only 52% in the placebo group. Improvement

in breathing occurred in 78% of those receiving bromelain as compared

to 68% in those receiving placebo. In the patients not receiving

antibiotic treatment, 85% of patients receiving bromelain had complete

resolution of inflammation of the nasal mucosa and complete resolution

of breathing difficulties. Only 40% of the placebo group had a similar

outcome with respect to inflammation, while 53% reported resolution of

breathing difficulty.35

The

potentiation of antibiotics and other medicines by bromelain may be due

to enhanced absorption, as well as increased permeability of the

diseased tissue which enhances the access of the antibiotic to the site

of the infection. It is also thought that the use of bromelain may

provide a similar access to specific and non-specific components of the

immune system, therefore, enhancing the body's utilization of its own

healing resources.

Mucolytic Properties

The topical

use of the enzymes, bromelain or papain, to remove excessive cervical

mucus was demonstrated in 1954. Observations following its use

demonstrated that pseudo and actual space-occupying lesions could be

more positively identified, and inflammatory changes of the canal and

its glands could be visualized with greater accuracy.36

Effects of

bromelain on rabbit sputum consistency were investigated in vitro and

in vivo. Of the enzymes tested, bromelain exerted the most potent

lowering effect on sputum viscosity and also showed a tendency to

increase the sputum volume.37

In a

clinical study of 124 patients hospitalized with chronic bronchitis,

pneumonia or bronchopneumonia, bronchiectasis, or pulmonary abscess,

those receiving bromelain orally showed a decrease in the volume and

purulence of the sputum.17 These results support the effectiveness of

bromelain in decreasing the viscosity of sputum so that it can be more

easily cleared from the respiratory tract.

Digestive Aid

Bromelain

has been used successfully as a digestive enzyme following

pancreatectomy, in cases of exocrine pancreas insufficiency and in

other intestinal disorders.38 Because of its wide pH range,

bromelain has activity in the stomach as well as the small intestine.

It has also been shown to be an adequate replacement for pepsin and

trypsin in cases of deficiency. The combination of ox bile, pancreatin

and bromelain is effective in lowering stool fat excretion in patients

with pancreatic steatorrhoea. In addition, this combination resulted in

a gain in weight in most cases as well as an enhanced subjective

feeling of well being. Symptomatic improvement was also noted in

relation to pain, flatulence and stool frequency.39

Bromelain has been reported to heal gastric ulcers in experimental animals.40

In an extensive study of the effect of bromelain on the gastric mucosa,

it was found that bromelain increased the uptake of radioactive sulfur

by 50% and glucosamine by 30 -90%. Increased uptake of these substances

may allow the gastric mucosa to heal more rapidly under the influence

of bromelain.41

In a study

designed to examine the effect of bromelain on enterotoxin receptor

activity in porcine small intestine, orally administered bromelain

inhibited enterotoxin attachment to pig small intestine in a

dose-dependent manner. Attachment was negligible after treatment. Serum

biochemical analysis and histopathological examination of treated

piglets showed no adverse effects with the bromelain treatment.

Administration of bromelain may therefore be useful for preventing

enterotoxin-induced diarrhea.42

Surgical Procedures and Musculoskeletal Injuries

Bromelain

also has therapeutic effects in the treatment of inflammation and soft

tissue injuries. An early clinical trial on bromelain was conducted on

74 boxers with bruises on the face and haematomas of the orbits, lips,

ears, chest and arms. Bromelain was given four times a day for 4 days

or until all signs of bruising had disappeared. A control group of 72

boxers were given a placebo. In 58 of the boxers taking bromelain, all

signs of bruising cleared completely in four days, with the remaining

16 requiring 8-10 days for complete clearance. In the control group,

only 10 had complete clearance within four days, with the remainder

requiring seven to fourteen days for resolution.43

The

edema-reducing property of bromelain was investigated in

traumatically-induced hindleg edema in rats. After enteral application

of bromelain a significant reduction of the edema could be observed,

however, parenteral application only resulted in a minimal therapeutic

effect. Although enterally-applied enzymes are thought to be degraded

in the gut, the better results were obtained after oral administration

of bromelain, supporting the observation that bromelain can be absorbed

by the gut without losing its biological properties.11

Fifty-five

pre-surgical patients were divided into two groups. Group one,

consisting of 22 patients, took bromelain four times a day for 48-72

hours prior to surgery and continued for 72 hours after surgery. Group

two, consisting of 33 patients, took bromelain starting on the day of

surgery, with the first dose administered one hour prior to surgery.

Fifty percent of group one and 42.4% of group two had complete

disappearance of pain and inflammation within 72 hours. Pain and

inflammation persisted past 72 hours in only one member of the group

supplemented with bromelain for three days prior to surgery, as opposed

to five members of the group that started supplementation one hour

prior to surgery. In a separate study, supplementation of bromelain

starting 48-72 hours prior to surgery reduced the average number of

days for complete disappearance of pain from 3.5 to 1.5, and

disappearance of inflammation from 6.9 to 2.0 days, as compared with

controls receiving no bromelain.44

Sixteen

patients undergoing oral surgery 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 was either absent or mild in 38% of

bromelain-treated patients, as opposed to 13% receiving placebo. After

72 hours, this increased to 75% of those in the bromelain group, as

compared to only 38% in the placebo group.45

In an

observation study involving 59 patients with blunt injuries to the

musculoskeletal system, the efficacy and tolerability of high-dose

bromelain, in addition to the usual therapeutic measures, was

investigated. Treatment with bromelain resulted in a clear reduction in

all four parameters tested; swelling, pain at rest and during movement,

and tenderness.46

Cardiovascular and Circulatory Applications

Research

has indicated that bromelain prevents aggregation of human blood

platelets in vivo and in vitro, prevents or minimizes the severity of

angina pectoris and transcient ischemic attacks (TIA), is useful in the

prevention and treatment of thrombosis and thrombophlebitis, may break

down cholesterol plaques, and exerts a potent fibrinolytic activity. If

administered for prolonged time periods, bromelain also exerts an

anti-hypertensive effect in experimental animals.2,47

Administration of 400-1000

mg/day of bromelain to 14 patients with angina pectoris resulted in the

disappearance of symptoms in all patients within 4 to 90 days.48

Similar results have been observed in patients taking between 500-700

mg/day of bromelain. After discontinuing bromelain, angina attacks

reappear after a variable period of time, often triggered by stressful

experiences.2

A drastic

reduction in the incidence of coronary infarct after administration of

potassium and magnesium orotate along with 120-400 mg of bromelain per

day has also been reported.49

In a study

involving 73 patients with acute thrombophlebitis, bromelain, in

addition to analgesics, was shown to decrease all symptoms of

inflammation; including, pain, edema, tenderness, skin temperature, and

disability.40

The ability

of bromelain to influence these conditions may be due to its ability to

breakdown fibrinous plaques. Bromelain has been shown to dissolve

arteriosclerotic plaque in rabbit aorta in vivo and in vitro.2 It is

likely that bromelain also increases vessel wall permeability to oxygen

and nutrients while increasing blood fluidity, both of which aid in

these conditions.

Toxicity, Side Effects and Allergic Reactions

Bromelain

is considered to have very low toxicity, with an LD50 greater than

10g/kg. Toxicity tests on dogs, with increasing levels of bromelain up

to 750 mg/kg administered daily, showed no toxic effects after six

months. Dosages of1.5 g/kg/day administered to rats show no

carcinogenic or teratogenic effects. 51

In human

clinical tests, side effects have not been observed. Bromelain

supplementation up to 460 mg has been shown to have no effect on heart

rate or blood pressure; however, increasing doses up to 1840 mg have

been shown to increase the heart rate proportionately. In some cases an

increase of up to 80% of the baseline has been reported, which may be a

result of bromelain's influence on IL-1 and TNF production. Maximum

effects were seen at 2 hours but some residual effect remained at 24

hours. At doses above 700 mg, palpitations and subjective discomfort

have been reported. Blood pressure changes have not been demonstrated

in humans at any dosage level.52

The

allergenic potential of proteolytic enzymes should not be

underestimated, for they cause, in particular, IgE-mediated respiratory

allergies of both the immediate type and the late-phase of immediate

type with predominantly respiratory symptoms. Allergy to bromelain has

been reported in workers of a blood-grouping laboratory, and

investigation indicates that (1) bromelain is a strong sensitizer, (2)

sensitization usually occurs due to inhalation and not to ingestion,

(3) bromelain allergy is occupationally acquired, and adequate

precautions are necessary.53 The risk of sensitization to enzymes due to inhalation as a result of occupational exposure is very high (up to 50%).54

Bromelain has been shown to cross-react with the sera in about 28% of persons with IgE allergic response to honeybee venom.55

Bromelain, along with horseradish peroxidase and ascorbate oxidase are

recognized by the IgE of sera from patients who are hypersensitive to

olive tree pollen.56

Bromelain

and papain, due to their use as a meat tenderizer and to clarify beer,

are considered as potential ingestive allergens and may represent an

unrecognized cause of an allergic reaction following a meal. As with

other food substances, a small segment of the population, particularly

those with a sensitivity to pineapple, may be sensitive to oral

supplementation with bromelain. As contact allergens, the enzymes play

a minor role; however, it is thought that skin testing with isolated

proteases like bromelain may induce systemic reactions in susceptible

individuals, even at very high dilution.53,57

Indications for the Use of Bromelain

There are several compelling reasons for supplementation with oral bromelain.

1. It

inhibits blood platelet aggregation, favorably modulates prostaglandin

formation and minimizes risk of coronary atherosclerotic disease.

2. It

continues to provide a desired physiological action for as long as it

is administered, with no evidence indicating that a tolerance develops.

 

3. It is

considered to be non-toxic and lacking in side effects, so it can be

used without concern in doses from 200 to 2000 mg for prolonged periods

of time.

4. It is a protein and seems to be as easily metabolized as other dietary proteins.

5. It is well absorbed and seems to have greater therapeutic impact when administered orally as opposed to intravenously

6. While

effective for inflammation and injury, it is even more effective if

administered prior to a traumatic event, i.e. surgery or athletic

competition.

7. It seems to enhance the absorption of and improve the action of other substances when they are administered in combination.

8. Because

of its impact on the cytokine system, particularly IL-1 and TNF, which

stimulate fever and acute phase response, and its demonstrated ability

to increase the heart rate, bromelain may assist in generating an

acute-stage healing response.

Bromelain has a wide range of conditions for which it has well documented therapeutic efficacy (see Table 4).

 

Dosage and Prescription Instructions

Available

research does not demonstrate an enhanced efficacy of bromelain when it

is administered between meals. It is generally recommended that

bromelain be taken away from food unless it is being used as a

digestive aid, because it is believed that otherwise, it will tend to

act as a digestive enzyme and its therapeutic benefit may be

diminished. While this may in fact be the case, the clinical studies

conducted on bromelain have not followed this protocol.

Bromelain

has shown therapeutic benefits in doses as small as 160 mg/day;

however, it is thought that, for most conditions, best results occur

starting at a dose of 750-1000

mg/day. Most research on bromelain has been done utilizing divided

doses, usually four per day, and findings indicate that results are

dose-dependent. See Table 5 for a summary of prescription instructions.

Conclusion

Bromelain

has been used for a variety of clinical applications for more than 35

years. Although its mechanisms of action has not been completed

resolved, bromelain has demonstrated a beneficial effect on the kinin

system, the coagulation cascade, the cytokine system, and prostaglandin

synthesis. Bromelain is believed to enhance the absorption of

flavonoids and has been shown to increase absorption of glucosamine, so

bromelain supplemention should be considered when these nutrients are

given. It may also enhance absorption and utilization of many other

substances; however, to date research in this area has focused

primarily on antibiotics. Bromelain has been shown to exert a

beneficial effect at doses as low as 160 mg/day, however, there is a

general consensus among researchers that the best results occur when

bromelain is given in doses above 500 mg per day and that results

improve in a dose-dependent manner with higher levels of bromelain

supplementation. Bromelain has been demonstrated to be well absorbed

after an oral dose and has been shown to be safe at high doses for

prolonged periods of time. For the conditions discussed in this review,

bromelain has shown itself to be an effective supplement.

References

1. Rowan AD, Buttle DJ, Barrett AJ. The cysteine proteinases of the pineapple plant. Biochem J 1990;266:869-875.

2. Taussig SJ, Nieper HA. Bromelain: its use in prevention and

treatment of cardiovascular disease, present status. J IAPM

1979;6:139-151.

3. Harrach T, Eckert K, Schulze-Forster K, et al. Isolation and partial

characterization of basic proteinases from stem bromelain. J Protein

Chem 1995;14:41-52.

4. Jeung A. Encyclopedeia of Common Natural Ingredients Used in Foods,

Drugs, and Cosmetics. New York, NY: John Wiley & Sons;1980:74-76.

5. White RR, Crawley FE, Vellini M, et al. Bioavailability of 125I

bromelain after oral administration to rats. Biopharm Drug Dispos

1988;9:397-403.

6. Heinicke RM, Van der Wal M, Yokoyama MM. Effect of bromelain on human platelet aggrega tion. Experientia 1972;28:844-845.

7. Morita AH, Uchida DA, Taussig SJ. Chromato graphic fractionation and

characterization of the active platelet aggregation inhibitory factor

from bromelain. Arch Inter Phar Ther 1979;239:340-350.

8. Livio M, Bertoni MP, De Gaetano G, et al. Effect of bromelain on

fibrinogen level, prothrombin complex factors and platelet aggregation

in the rat - A preliminary report. Drugs Expt Clin Res 1978;4:49-53.

9. De-Giuli M, Pirotta F. Bromelain: interaction with some protease

inhibitors and rabbit specific antiserum. Drugs Exp Clin Res

1978;4:21-23.

10. Inoue K, Motonaga A, Dainaka J, et al. Effect of etodolac on

prostaglandin E2 biosynthesis, active oxygen generation and bradykinin

formation. Prostaglandins Leukot Essent Fatty Acids 1994;51:457-462.

11. Uhlig G, Seifert J. The effect of proteolytic enzymes (traumanase) on posttraumatic edema. Fortschr Med 1981;99:554-556.

12. Vellini M, Desideri D, Milanese A, et al. Possible involvement of

eicosanoids in the pharmacological action of bromelain.

Arzneimittelforschung 1986;36:110-112.

13. Yonehara N, Shibutani T, Inoki R. Contribution of substance P to

heat-induced edema in rat paw. J Pharmacol Exp Ther 1987;242:1071-1076.

14. Kumakura S, Yamashita M, Tsurufuji S. Effect of bromelain on

kaolin-induced inflammation in rats. Eur J Pharmacol 1988;150:295-301.

15. Uchida Y, Katori M. Independent consumption of high and low

molecular weight kininogens in vivo. Adv Exp Med Biol 1986;198:113-118.

16. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple

(Ananas comosus) and its clinical application. An update. J

Ethnopharmacol 1988;22:191-203.

17. Schafer A, Adelman B. Plasmin inhibition of platelet function and

of arachidonic acid metabolism. J Clin Invest 1985;75:456-461.

18. Felton GE. Fibrinolytic and antithrombotic action of bromelain may

eliminate thrombosis in heart patients. Med Hypotheses

1980;6:1123-1133.

19. Gerard G. Anti-cancer therapy with bromelain. Agress 1972;3:261-274.

20. Nieper HA. A program for the treatment of cancer. Krebs 1974;6:124-127.

21. Taussig SJ, Szekerczes J, Batkin S. Inhibition of tumor growth in

vitro by bromelain, an extract of the pineapple plant (Ananas comosus).

Planta Med 1985;6:538-539.

22. Batkin S, Taussig SJ, Szekerezes J. Antimetastatic effect of

bromelain with or without its proteolytic and anticoagulant activity. J

Cancer Res Clin Oncol 1988;114:507.

23. Desser L, Rehberger A, Paukovits W. Proteolytic enzymes and amylase

induce cytokine production in human peripheral blood mononuclear cells

in vitro. Cancer Biother 1994;9:253-263.

24. Desser L, Rehberger A. Induction of tumor necrosis factor in human

peripheral-blood mononuclear cells by proteolytic enzymes. Oncology

1990;47:475-477.

25. Desser L, Rehberger A, Kokron E, et al. Cytokine synthesis in human

peripheral blood mononuclear cells after oral administration of

polyenzyme preparations. Oncology 1993;50:403-407.

26. Munzig E, Eckert K, Harrach T, et al. Bromelain protease F9 reduces

the CD44 mediated adhesion of human peripheral blood lymphocytes to

human umbilical vein endothelial cells. FEBS Lett 1995;351:215-218.

27. Houck JC, Chang CM, Klein G. Isolation of an effective debriding

agent from the stems of pineapple plants. Int J Tissue React

1983;5:125-134.

28. Klaue P, Dilbert G, Hinke G, et al. Tier-experimentelle

untersuchungen zur enzymatischen lokalbehandlung subdermaler

verbrennungen mit bromelain. Therapiewoche 1979;29:796-799.

29. Ahle NW, Hamlet MP. Enzymatic frostbite eschar debridement by bromelain. Ann Emerg Med 1987;16:1063-1065.

30. Moss JN, Frazier CV, Martin GJ. Bromelains, the pharmacology of the enzymes. Arch Int Pharmacodyn 1963;145:168.

31. Tinozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxycillin. Drugs Expt Clin Res 1978;4:39-44.

32. Luerti M, Vignali ML. Influence of bromelain on penetration of

antibiotics in uterus, salpinx and ovary. Drugs Expt Clin Res

1978;4:45-48.

33. Renzinni G, Varengo M. The absorption of tetracyclin in conbination

with bromelain by oral application. Arzneim-Forsch 1972;22:410-412.

34. Neubauer RA. A plant protease for potentiation of and possible replacement of antibiotics. Exp Med Surg 1961;19:143-160

35. Ryan RE. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache 1967;7:13-17.

36. Hunter RG, Henry GW, Heinicke RM. The action of papain and bromelain on the uterus. Am J Ob Gyn 1957;73:867-873.

37. Suzuki K, Niho T, Yamada H, et al. [Experimental study of the

effects of bromelain on the sputum consistency in rabbits]. Nippon

Yakurigaku Zasshi 1983;81:211-216.

38. Knill-Jones RP, Pearce H, Batten J, et al. Comparative trial of

Nutrizym in chronic pancreatic insufficiency. Brit Med J 1970;4:21.

39. Balakrishnan V, Hareendran A, Sukumaran Nair C. Double-blind

cross-over trial of an enzyme preparation in pancreatic steatorrhea. J

Asso Phys Ind 1981;29:207-209.

40. Seligman B. Bromelain-an anti-inflammatory agentÑthrombophlebitis. No toxicity. Angiology 1962;13:508-510.

41. Felton G. Does Kinin released by pineapple stem bromelain stimulate

production of prostaglandin E1-like compound. Haw Med J 1976;2:39-47.

42. Mynott TL, Luke RK, Chandler DS. Oral administration of protease

inhibits enterotoxigenic Escherichia coli receptor activity in piglet

small intestine. Gut 1996;38:28-32.

43. Blonstein JL. Control of swelling in boxing injuries. Practitioner 1960;185:78.

44. Tassman GC, Zafran JN, Zayon GM. Evaluation of a plant proteolytic

enzyme for the control of inflammation and pain. J Dent Med

1964;19:73-77.

45. Tassman GC, Zafran JN, Zayon GM. A double-blind crossover study of

a plant proteolytic enzyme in oral surgery. J Dent Med 1965;20:51-54.

46. Masson M. Bromelain in blunt injuries of the locomotor system. A

study of observed applications in general practice. Fortschr Med

1995;113:303-306.

47. Giacca S. Clinical experiments with bromelain in peripheral venous

diseases and chronic bronchitic states. Minerva Med 1965;56:Suppl.104.

48. Nieper HA. Effect of bromelain on coronary heart disease and angina pectoris. Acta Med Empirica 1978;5:274-278.

49. Nieper HA. Decrease of the incidence of coronary heart infarct by

Mg- and K-orotate and bromelain. Acta Med Empirica 1977;12:614-618.

50. Seligman B. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology 1969;20:22-26.

51. Taussig SJ, Yokoyama MM, Chinen N, et al. Bromelain: A proteolytic

enzyme and its clinical application. HirJ Med Sci 1975;24:185-193.

52. Gutfreund A, Taussig S, Morris A. Effect of oral bromelain on blood

pressure and heart rate of hypertensive patients. Haw Med Jour

1978;37:143-146.

53. Gailhofer G, Wilders-Truschnig M, Smolle J, Ludvan M. Asthma caused

by bromelain: an occupational allergy. Clin Allergy 1988;18:445-450.

54. Chida T. A study on dose-response relationship of occupational

allergy in a pharmaceutical plant. Sangyo Igaku 1986;28:77-86.

55. Tretter V, Altmann F, Kubelka V, et al. Fucose alpha 1,3-linked to

the core region of glycoprotein N-glycans creates an important epitope

for IgE from honeybee venom allergic individuals. Int Arch Allergy

Immunol 1993;102:259-266.

56. Batanero E, Villalba M, Monsalve RI, et al. Cross-reactivity

between the major allergen from olive pollen and unrelated

glycoproteins: evidence of an epitope in the glycan moiety of the

allergen. J Allergy Clin Immunol 1996;97:1264-1271.

57. Wuthrich B. Proteolytic enzymes: potential allergens for the skin and respiratory tract?

[Guest guest]

That's great that you had such good results Tony, really pleased for

you and thanks for the info on Bromelain which I'll read when my

brain can take it in ;-)

 

Do you know that a manufacturing Homeopathic Pharmacy can make a

remedy from anything? I'm sure there will be somewhere will have a

Brown Recluse Spider remedy, but if not, it can be made up for you,

and that should do the trick. I suspect you're in the USA so I don't

know who, over here either Ainsworths or Freemans would do it, but we

don't have many brown recluse spiders here.

 

Just a thought to add to your arsenal...........

 

oleander soup , " Tony " wrote:

>

>

> Bromelain – The Wonder Supplement

>

> I first experienced bromelain firsthand several years ago when I was

> bitten by a brown recluse spider on the front of my upper left leg –

> in three places no less. This was the second time I had been

bitten.

> The first time, I was bitten at the very topmost part of my left

leg on

> the inside where it joined the pelvic area, and that bite resulted

in

> the loss of a chunk of flesh and, much worse, being crippled for

several

> months thanks to the treating physician botching the treatment and

> thrusting his deadening needle into the bursal sac. Since I did not

> want to repeat that ugly memory and I had was in my first few years

of

> studying natural health, I decided to try to handle it myself.

>

> One of the people I consulted for help was an old naturopathic

healer

> who claimed to have been a doctor in Russia before immigrating to

the

> United States many decades ago. He suggested that, among other

things,

> I made sure that I used bromelain , which he called a wonder

supplement.

>

> And so, armed with garlic (which I took internally and used

externally),

> some hydrogen peroxide, otc ointment, some antibiotic for my son's

> dog Dice, a vial of homeopathic ledum pallustre, and bromelain, I

began

> to treat the spider bites. For a couple of days it was touch and

go it

> seemed, as the bites continue to redden and swell and the radiating

> areas of red and pink grew until it encompassed an area about 6

inches

> by 12 inches. But then the tide turned and the bites began to get

> better. Within a little over a week, they were mostly healed and

within

> two weeks there was virtually no sign of the bites.

>

> Earlier this month, another brown recluse struck. Again in the same

> general vicinity (I think the damn things are aiming for something

and

> one of these days they might score a hit! YIKES!) This time, being

a

> bit wiser, or so I hope, I caught it very early on and again

decided to

> treat it myself – this time with a bit of tea tree oil at the

> beginning and constant colloidal silver, aloe vera, apple cider

vinegar,

> ledum palustre and my old friend, bromelain. This time the tables

were

> turned on the second day after beginning treatment and today (June

15th

> 2007) the bite is almost completely healed.

>

> I am convinced that bromelain, a supplement with many extraordinary

> uses, is a big reason I was successful both times. After the initial

> success against the recluse bite, I researched bromelain quite a

bit and

> would like to share with you a study that, while a bit technical,

should

> give a good indication of just how amazing bromelain is.

>

> Bromelain: 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 debridement

properties;

> (7) enhanced absorption of other drugs; (8) mucolytic properties;

(9)

> digestive assistance; (10) enhanced wound healing; and (11)

> cardiovascular and circulatory improvement. Bromelain is well

absorbed

> orally and available evidence indicates that it's therapeutic

effects

> are enhanced with higher doses. Although all of its mechanisms of

action

> are still not completely resolved, it has been demonstrated to be a

safe

> and effective 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 therapeutic compound 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 bromelain or stem bromelain depending

on

> its source, with all commercially available bromelain being derived

from

> the stem.1 The term bromelain will be used to refer to stem

bromelain in

> the remainder 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 calcium. When the proteolytic

fraction

> of bromelain is purified and extracted, the result is a potent

> proteolytic enzyme in vitro; however, this component has been shown

to

> be physiologically inactive in vivo for many of the conditions where

> bromelain has a beneficial effect.2 It appears that a great deal of

the

> physiological activity of bromelain is not accounted for in its

> proteolytic fraction and it is likely that the beneficial effects of

> bromelain are due to multiple factors, not to one 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 the most 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 to be unglycosylated. The optimal pH for the

F4 and

> F5 fractions is between 4.0 and 4.5 and for F9 close to a neutral

pH.3

> The entire extract of bromelain has been shown to exhibit its

activity

> over a pH range of 4.5 to 9.8.4

>

> Since bromelain is derived from a natural source, different sources

can

> exhibit variability in their physiological activity, even when their

> proteolytic activity is the same. Bromelain is not heat stable so

it's

> physiological activity can be further reduced by improper

processing or

> storage conditions.

>

> Absorption and Availability

>

> Bromelain is absorbed intact through the gastrointestinal tract of

> animals, with up to 40% of the high molecular weight substances

detected

> in the blood after oral administration. The highest concentration of

> bromelain is found in the blood 1 hour after administration;

however,

> its proteolytic activity is rapidly deactivated,5 probably by the

normal

> plasma protease controls and serum alpha2-macroglobulin.

>

> A variety of designations have been used to indicate the activity of

> bromelain; with published research varying in the designation

utilized.

> Rorer units (R.U.), gelatin dissolving units (G.D.U.), and milk

clotting

> units (M.C.U.) are the most commonly used measures of activity. One

gram

> of bromelain standardized to 2000 M.C.U. would be approximately

equal to

> 1 gram with 1200 G.D.U. of activity or 8 grams with 100,000 R.U. of

> activity.

>

> Platelet Aggregation, Fibrinolysis and Anti-Inflammatory Activity

>

> The first conclusive evidence that bromelain prevents aggregation of

> blood platelets was reported in 1972. Bromelain was administered

orally

> to 20 volunteers with a history of heart attack or stroke, or with

high

> platelet aggregation values. Bromelain decreased aggregation of

blood

> platelets in 17 of the subjects and normalized values in 8 of the 9

> subjects who previously had high aggregation values.6 In vitro

studies

> have demonstrated that bromelain inhibits platelet aggregation

> stimulated by ADP or epinephrine, as well as by prostaglandin

> precursors, in a dose-dependent manner.7

>

> Bromelain is an effective fibrinolytic agent in vitro and in vivo;

> however, its effect is more evident in purified fibrinogen solutions

> than in plasma. This is probably due to the antiproteases present in

> plasma. A dose-dependent reduction of serum fibrinogen level is

seen in

> rats following administration of bromelain, and at the highest

> concentrations of bromelain, both prothrombin time (PT) and

activated

> partial thromboplastin time (APTT) are markedly prolonged.89

Bromelain's

> fibrinolytic activity has been attributed to the enhanced

conversion of

> plasminogen to plasmin, which limits the spread of the coagulation

> process by degrading fibrin.

>

> Bromelain seems to have both direct as well as indirect actions

> involving other enzyme systems in exerting its anti-inflammatory

effect.

> Both etodolac and bromelain inhibit the inflammatory pain in rats

in a

> dose-dependent manner.10 Bromelain was the most potent of nine

> anti-inflammatory substances tested on experimentally-induced

edemas in

> rats;11 while prednisone and bromelain have been shown to be

comparable

> in their ability to reduce inflammation in rats.12 Treatment with

> bromelain and emorfazone has been shown to decrease significantly

the

> heat-evoked immunoreactive substance P release and subsequent edema

in a

> rat model.13

>

> Mechanism of Action

>

> Surface contact, by collagen or platelets, activates the kinin

system

> and the clotting cascade by stimulating the conversion of Hageman

factor

> to an active protease (factor XIIa). Factor XIIa then activates the

> kinin system by converting plasma prekallikrein into kallikrein, and

> continues the intrinsic path of the clotting cascade by converting

> factor XI to its active form. Kallikrein, in an autocatalytic loop,

> accelerates the activation of Hageman factor, which continues to

> potently activate both the kinin system and the clotting cascade. In

> addition, Kallikrein cleaves (HMWK) to produce bradykinin, a potent

> stimulator of both increased vascular permeability and pain. The

> activation of the clotting cascade will culminate in the conversion

of

> fibrinogen to fibrin (see Figure 1). Fibrin then forms a protective

> matrix around the injured area. This matrix inhibits tissue

drainage,

> promotes edema and blocks circulation of blood flow.

>

> In order to determine the effects of bromelain on the plasma

kallikrein

> system, bradykinin levels and plasma exudation at the inflammatory

site

> were examined in rats. Bromelain (5 and 7.5 mg/kg) caused a

> dose-dependent decrease of bradykinin levels at the inflammatory

site

> and a parallel decrease of the prekallikrein levels in sera. Plasma

> exudation was also reduced dose dependently. Bradykinin-degrading

> activity in sera was elevated after treatment with bromelain,

although

> it was unchanged in the pouch fluid.14 The levels of high molecular

> weight (HMW) kininogen and pre-kallikrein in rat plasma were

markedly

> reduced after single injection of bromelain (10 mg/kg, i.v.) and

> gradually recovered over a 72 hour period. The level of low

molecular

> weight (LMW) kininogen was not changed during this period.15

>

> Bromelain-treated rats also show a reduction in Factor X and

> prothrombin, both of which are needed for the activation of

fibrinogen

> to fibrin through the common pathway of the intrinsic and extrinsic

> cascade.16 This indicates that bromelain's action is in part a

result of

> inhibiting the generation of bradykinin at the inflammatory site via

> depletion of the plasma kallikrein system, as well as limiting the

> formation of fibrin by reduction of clotting cascade intermediates.

> These actions result in significant reduction in pain and edema, as

well

> as enhanced circulation to the injured site.

>

> After the formation of a clot, vessel repair begins with the

conversion

> of plasminogen to plasmin, which then acts to degrade fibrin into

> smaller components which can be removed by monocytes and

macrophages. In

> rats, bromelain has been shown to stimulate the conversion of

> plasminogen to plasmin, resulting in increased fibrinolysis. This

> minimizes venous stasis, facilitates drainage, increases

permeability

> and restores the tissue's biological continuity.16

>

> The therapeutic effect of bromelain may also be due to its ability

to

> selectively modulate the biosynthesis of thromboxanes and

prostacyclins;

> two groups of prostaglandins with opposite actions which ultimately

> influence activation of cyclic-3,5-adenosine (cAMP), an important

> cell-growth modulating compound.

>

> The binding of epinephrine, collagen, or thrombin to platelets

activates

> the enzymes phospholipase C and phospholipase A2 which release

> arachidonic acid from membrane phospholipids (phosphatidylcholine

and

> phosphatidylinositol). Table 1 lists the inflammatory actions of

> arachidonic acid metabolites.

>

> Plasminogen, which is activated to plasmin by the oral

administration of

> bromelain, has been shown to inhibit the release of arachidonic acid

> from cell membranes, resulting in decreased platelet aggregation and

> modulation of the series 2 prostaglandins.17 It is also hypothesized

> that bromelain therapy leads to a relative increase of the

endogenous

> prostaglandins, PGI2 and PGE2 over thromboxane A2.18

>

> Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase, which

is

> required for the synthesis of series 2 prostaglandins, resulting in

a

> decrease in both pro and anti-inflammatory prostaglandins. Rather

than

> blocking the arachidonic acid cascade at the enzyme cyclooxygenase,

like

> NSAIDs, bromelain may selectively decrease thromboxane generation

and

> change the ratio of thromboxane/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

inflammation.

>

> </BromelainT3.jpg>

>

> Antitumor

>

> The first documented use of oral bromelain on cancer patients was in

> 1972. Twelve patients with ovarian and breast tumors were given 600

mg

> of bromelain daily for from 6 months to several years, with reported

> resolution of some of the cancerous masses and a decrease in

> metastasis.19 Bromelain in doses of over 1000 mg daily has been

combined

> with chemotherapeutic agents such as 5-FU and vincristine, and has

been

> reported to result in tumor regression.19,20

>

> Bromelain has also decreased lung metastasis of Lewis lung cancer

cells

> implanted in mice in a dose-dependent manner. This antimetastatic

> potential was demonstrated by both the active and inactive

bromelain,

> with or without proteolytic and anticoagulant properties.21,22

>

> Cytokine Induction

>

> The successful initiation of an immune response depends on T cells

and

> macrophages, along with the polypeptide factors they produce, called

> cytokines, which play a key role in communication during normal

> immunological response as well as infectious, inflammatory, and

> neoplastic disease states. Table 3 lists cytokines and their

activities.

>

> </Bromelain1.jpg>

>

> Bromelain, papain, and amylase have all been demonstrated to induce

> cytokine production in human peripheral blood mononuclear cells.

> Treatment leads to the production of tumor necrosis factor-alpha

> (TNF-alpha), interleukin-1-beta (IL-1 beta), and interleukin-6 (IL-

6) in

> a time and dose-dependent manner. Interferon-alpha (IFN-alpha) and

> interferon-gamma (IFN-gamma), which had no effect alone,

synergistically

> increased TNF-alpha production when applied together with the

> enzymes.23,24 The tryptic but not the autolytic fractions of papain

and

> bromelain have a higher (10- to 40-fold) inducing capacity for TNF

> production than the untreated enzyme.25 Trypsin alone had only a

small

> inducing effect.

>

> The ability to induce cytokine production may explain the antitumor

> effects observed after oral administration of polyenzyme

preparations.

>

> Immunity

>

> Bromelain has been shown to remove T-cell CD44 molecules from

> lymphocytes and to affect T-cell activation. The highly purified

> bromelain protease F9 was tested on the adhesion of peripheral blood

> lymphocytes (PBL) to human umbilical vein endothelial cells (HUVEC).

> Both bromelain and protease F9 reduced the _expression of CD44, but

F9

> was about 10 times more active than bromelain; having about 97%

> inhibition of CD44 _expression. The results indicate that F9

selectively

> decreases the CD44 mediated binding of PBL to HUVEC.26

>

> Debridement

>

> Bromelain applied topically as a cream (35% bromelain in a lipid

base)

> can be beneficial in the elimination of burn debris and in

acceleration

> of healing. A non-proteolytic component of bromelain is responsible

for

> this effect. This component, referred to as escharase, has no

hydrolytic

> enzyme activity against normal protein substrates or various

> glycosaminoglycan substrates and its activity varies greatly from

> preparation to preparation.27

>

> Topical bromelain has achieved complete debridement on experimental

> burns in rats in an average of 1.9 days as compared to collagenase,

> which required an average of 10.6 days for similar results.28

>

> Topical bromelain separates eschar at the interface with living

tissue.

> It is hypothesized that bromelain activates collagenase in living

tissue

> which then attacks the denatured collagen in the eschar. This

produces a

> demarcation between living and dead tissue. With very little

scraping,

> using a tongue depressor, all of the eschar can be removed and a bed

> suitable for grafting results. By using bromelain, grafting can

occur as

> soon as 24 hours after the accident. Utilizing bromelain cream in

the

> treatment of burns usually results in minimal or no scar tissue

> formation.

>

> The applicability of topical bromelain in frostbite eschar removal

was

> extrapolated and investigated. In the initial trial, no debridement

> other than that of the superficial layers of the eschar was noted.

> Although third degree burn injuries debrided to a graftable bed

after

> two topical applications of bromelain, frostbite injuries remained

> unaffected.29

>

> Potentiation of Antibiotics

>

> Antibiotic potentiation is one of the primary uses of bromelain in

> several foreign countries. Bromelain can modify the permeability of

> organs and tissues to different drugs. It prolongs sleeping time in

mice

> administered pentobarbital30 and increases spinal levels of

penicillin

> and gentamycin in rats. In humans, bromelain has been documented to

> increase blood and urine levels of antibiotics16 and results in

higher

> blood and tissue levels of tetracycline and amoxycillin when they

are

> administered concurrently with bromelain.31

>

> Treatment of 18 women with 80 mg of bromelain concurrently with

> amoxycillin or tetracyclin resulted in increased serum levels and

> concentrations of both antibiotics in uterus, ovarian tubes, and

ovaries

> as compared with controls. This effect was not generated by

> indomethacin, an anti-inflammatory drug which acts as a

cyclooxygenase

> inhibitor, which indicates that bromelain has some undetermined

activity

> that enhances absorption and tissue distribution of antibiotics.32 A

> three-fold increase in the level of tetracycline in serum after oral

> ingestion of 540 mg of enterically-coated bromelain has also been

> demonstrated in a double blind test.33

>

> Combined bromelain and antibiotic therapy was instituted for 53

> hospitalized patients with the following conditions; pneumonia,

> bronchitis, cutaneous staphylococcus infection, thrombophlebitis,

> cellulitis, pyelonephritis and perirectal and rectal abscesses.

Twenty

> three of the patients had been on antibiotic therapy without

success.

> Bromelain was administered four times a day along with the following

> antibiotics either alone or in combination; penicillin,

chloramphenicol,

> erythromycin or novobiacin. A control group of 56 patients was

treated

> with antibiotics alone. Of the 23 patients who had been

unsuccessfully

> treated with antibiotics, 22 responded favorably to the combined

> treatment. In every disease state studied there was a significant

> reduction in morbidity when the combination of bromelain and

antibiotics

> was used as opposed to antibiotics alone. Another group of 106

cases was

> treated with bromelain alone, with results comparable to those

obtained

> with antibiotic treatment.34

>

> Forty eight patients with acute sinusitis were placed on standard

> therapy, which included antihistamines and analgesic agents, along

with

> antibiotics if indicated. Twenty three of the patients received

> bromelain four times daily, while the remaining 25 received a

placebo.

> Of the patients receiving bromelain, 83% had complete resolution of

> nasal mucosal inflammation compared with only 52% in the placebo

group.

> Improvement in breathing occurred in 78% of those receiving

bromelain as

> compared to 68% in those receiving placebo. In the patients not

> receiving antibiotic treatment, 85% of patients receiving bromelain

had

> complete resolution of inflammation of the nasal mucosa and complete

> resolution of breathing difficulties. Only 40% of the placebo group

had

> a similar outcome with respect to inflammation, while 53% reported

> resolution of breathing difficulty.35

>

> The potentiation of antibiotics and other medicines by bromelain

may be

> due to enhanced absorption, as well as increased permeability of the

> diseased tissue which enhances the access of the antibiotic to the

site

> of the infection. It is also thought that the use of bromelain may

> provide a similar access to specific and non-specific components of

the

> immune system, therefore, enhancing the body's utilization of its

own

> healing resources.

>

> Mucolytic Properties

>

> The topical use of the enzymes, bromelain or papain, to remove

excessive

> cervical mucus was demonstrated in 1954. Observations following its

use

> demonstrated that pseudo and actual space-occupying lesions could be

> more positively identified, and inflammatory changes of the canal

and

> its glands could be visualized with greater accuracy.36

>

> Effects of bromelain on rabbit sputum consistency were investigated

in

> vitro and in vivo. Of the enzymes tested, bromelain exerted the most

> potent lowering effect on sputum viscosity and also showed a

tendency to

> increase the sputum volume.37

>

> In a clinical study of 124 patients hospitalized with chronic

> bronchitis, pneumonia or bronchopneumonia, bronchiectasis, or

pulmonary

> abscess, those receiving bromelain orally showed a decrease in the

> volume and purulence of the sputum.17 These results support the

> effectiveness of bromelain in decreasing the viscosity of sputum so

that

> it can be more easily cleared from the respiratory tract.

>

> Digestive Aid

>

> Bromelain has been used successfully as a digestive enzyme following

> pancreatectomy, in cases of exocrine pancreas insufficiency and in

other

> intestinal disorders.38 Because of its wide pH range, bromelain has

> activity in the stomach as well as the small intestine. It has also

been

> shown to be an adequate replacement for pepsin and trypsin in cases

of

> deficiency. The combination of ox bile, pancreatin and bromelain is

> effective in lowering stool fat excretion in patients with

pancreatic

> steatorrhoea. In addition, this combination resulted in a gain in

weight

> in most cases as well as an enhanced subjective feeling of well

being.

> Symptomatic improvement was also noted in relation to pain,

flatulence

> and stool frequency.39

>

> Bromelain has been reported to heal gastric ulcers in experimental

> animals.40 In an extensive study of the effect of bromelain on the

> gastric mucosa, it was found that bromelain increased the uptake of

> radioactive sulfur by 50% and glucosamine by 30 -90%. Increased

uptake

> of these substances may allow the gastric mucosa to heal more

rapidly

> under the influence of bromelain.41

>

> In a study designed to examine the effect of bromelain on

enterotoxin

> receptor activity in porcine small intestine, orally administered

> bromelain inhibited enterotoxin attachment to pig small intestine

in a

> dose-dependent manner. Attachment was negligible after treatment.

Serum

> biochemical analysis and histopathological examination of treated

> piglets showed no adverse effects with the bromelain treatment.

> Administration of bromelain may therefore be useful for preventing

> enterotoxin-induced diarrhea.42

>

> Surgical Procedures and Musculoskeletal Injuries

>

> Bromelain also has therapeutic effects in the treatment of

inflammation

> and soft tissue injuries. An early clinical trial on bromelain was

> conducted on 74 boxers with bruises on the face and haematomas of

the

> orbits, lips, ears, chest and arms. Bromelain was given four times

a day

> for 4 days or until all signs of bruising had disappeared. A control

> group of 72 boxers were given a placebo. In 58 of the boxers taking

> bromelain, all signs of bruising cleared completely in four days,

with

> the remaining 16 requiring 8-10 days for complete clearance. In the

> control group, only 10 had complete clearance within four days,

with the

> remainder requiring seven to fourteen days for resolution.43

>

> The edema-reducing property of bromelain was investigated in

> traumatically-induced hindleg edema in rats. After enteral

application

> of bromelain a significant reduction of the edema could be observed,

> however, parenteral application only resulted in a minimal

therapeutic

> effect. Although enterally-applied enzymes are thought to be

degraded in

> the gut, the better results were obtained after oral administration

of

> bromelain, supporting the observation that bromelain can be

absorbed by

> the gut without losing its biological properties.11

>

> Fifty-five pre-surgical patients were divided into two groups. Group

> one, consisting of 22 patients, took bromelain four times a day for

> 48-72 hours prior to surgery and continued for 72 hours after

surgery.

> Group two, consisting of 33 patients, took bromelain starting on

the day

> of surgery, with the first dose administered one hour prior to

surgery.

> Fifty percent of group one and 42.4% of group two had complete

> disappearance of pain and inflammation within 72 hours. Pain and

> inflammation persisted past 72 hours in only one member of the group

> supplemented with bromelain for three days prior to surgery, as

opposed

> to five members of the group that started supplementation one hour

prior

> to surgery. In a separate study, supplementation of bromelain

starting

> 48-72 hours prior to surgery reduced the average number of days for

> complete disappearance of pain from 3.5 to 1.5, and disappearance of

> inflammation from 6.9 to 2.0 days, as compared with controls

receiving

> no bromelain.44

>

> Sixteen patients undergoing oral surgery 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 was either absent or mild in 38% of

> bromelain-treated patients, as opposed to 13% receiving placebo.

After

> 72 hours, this increased to 75% of those in the bromelain group, as

> compared to only 38% in the placebo group.45

>

> In an observation study involving 59 patients with blunt injuries

to the

> musculoskeletal system, the efficacy and tolerability of high-dose

> bromelain, in addition to the usual therapeutic measures, was

> investigated. Treatment with bromelain resulted in a clear

reduction in

> all four parameters tested; swelling, pain at rest and during

movement,

> and tenderness.46

>

> Cardiovascular and Circulatory Applications

>

> Research has indicated that bromelain prevents aggregation of human

> blood platelets in vivo and in vitro, prevents or minimizes the

severity

> of angina pectoris and transcient ischemic attacks (TIA), is useful

in

> the prevention and treatment of thrombosis and thrombophlebitis, may

> break down cholesterol plaques, and exerts a potent fibrinolytic

> activity. If administered for prolonged time periods, bromelain also

> exerts an anti-hypertensive effect in experimental animals.2,47

>

> Administration of 400-1000 mg/day of bromelain to 14 patients with

> angina pectoris resulted in the disappearance of symptoms in all

> patients within 4 to 90 days.48 Similar results have been observed

in

> patients taking between 500-700 mg/day of bromelain. After

discontinuing

> bromelain, angina attacks reappear after a variable period of time,

> often triggered by stressful experiences.2

>

> A drastic reduction in the incidence of coronary infarct after

> administration of potassium and magnesium orotate along with 120-

400 mg

> of bromelain per day has also been reported.49

>

> In a study involving 73 patients with acute thrombophlebitis,

bromelain,

> in addition to analgesics, was shown to decrease all symptoms of

> inflammation; including, pain, edema, tenderness, skin temperature,

and

> disability.40

>

> The ability of bromelain to influence these conditions may be due

to its

> ability to breakdown fibrinous plaques. Bromelain has been shown to

> dissolve arteriosclerotic plaque in rabbit aorta in vivo and in

vitro.2

> It is likely that bromelain also increases vessel wall permeability

to

> oxygen and nutrients while increasing blood fluidity, both of which

aid

> in these conditions.

>

> Toxicity, Side Effects and Allergic Reactions

>

> Bromelain is considered to have very low toxicity, with an LD50

greater

> than 10g/kg. Toxicity tests on dogs, with increasing levels of

bromelain

> up to 750 mg/kg administered daily, showed no toxic effects after

six

> months. Dosages of1.5 g/kg/day administered to rats show no

carcinogenic

> or teratogenic effects. 51

>

> In human clinical tests, side effects have not been observed.

Bromelain

> supplementation up to 460 mg has been shown to have no effect on

heart

> rate or blood pressure; however, increasing doses up to 1840 mg have

> been shown to increase the heart rate proportionately. In some

cases an

> increase of up to 80% of the baseline has been reported, which may

be a

> result of bromelain's influence on IL-1 and TNF production. Maximum

> effects were seen at 2 hours but some residual effect remained at 24

> hours. At doses above 700 mg, palpitations and subjective discomfort

> have been reported. Blood pressure changes have not been

demonstrated in

> humans at any dosage level.52

>

> The allergenic potential of proteolytic enzymes should not be

> underestimated, for they cause, in particular, IgE-mediated

respiratory

> allergies of both the immediate type and the late-phase of immediate

> type with predominantly respiratory symptoms. Allergy to bromelain

has

> been reported in workers of a blood-grouping laboratory, and

> investigation indicates that (1) bromelain is a strong sensitizer,

(2)

> sensitization usually occurs due to inhalation and not to

ingestion, (3)

> bromelain allergy is occupationally acquired, and adequate

precautions

> are necessary.53 The risk of sensitization to enzymes due to

inhalation

> as a result of occupational exposure is very high (up to 50%).54

>

> Bromelain has been shown to cross-react with the sera in about 28%

of

> persons with IgE allergic response to honeybee venom.55 Bromelain,

along

> with horseradish peroxidase and ascorbate oxidase are recognized by

the

> IgE of sera from patients who are hypersensitive to olive tree

pollen.56

>

> Bromelain and papain, due to their use as a meat tenderizer and to

> clarify beer, are considered as potential ingestive allergens and

may

> represent an unrecognized cause of an allergic reaction following a

> meal. As with other food substances, a small segment of the

population,

> particularly those with a sensitivity to pineapple, may be

sensitive to

> oral supplementation with bromelain. As contact allergens, the

enzymes

> play a minor role; however, it is thought that skin testing with

> isolated proteases like bromelain may induce systemic reactions in

> susceptible individuals, even at very high dilution.53,57

>

> Indications for the Use of Bromelain

>

> There are several compelling reasons for supplementation with oral

> bromelain.

>

> 1. It inhibits blood platelet aggregation, favorably modulates

> prostaglandin formation and minimizes risk of coronary

atherosclerotic

> disease.

>

> 2. It continues to provide a desired physiological action for as

long as

> it is administered, with no evidence indicating that a tolerance

> develops.

>

> 3. It is considered to be non-toxic and lacking in side effects, so

it

> can be used without concern in doses from 200 to 2000 mg for

prolonged

> periods of time.

>

> 4. It is a protein and seems to be as easily metabolized as other

> dietary proteins.

>

> 5. It is well absorbed and seems to have greater therapeutic impact

when

> administered orally as opposed to intravenously

>

> 6. While effective for inflammation and injury, it is even more

> effective if administered prior to a traumatic event, i.e. surgery

or

> athletic competition.

>

> 7. It seems to enhance the absorption of and improve the action of

other

> substances when they are administered in combination.

>

> 8. Because of its impact on the cytokine system, particularly IL-1

and

> TNF, which stimulate fever and acute phase response, and its

> demonstrated ability to increase the heart rate, bromelain may

assist in

> generating an acute-stage healing response.

>

> Bromelain has a wide range of conditions for which it has well

> documented therapeutic efficacy (see Table 4).

>

> </BromelainT4.jpg>

>

> Dosage and Prescription Instructions

>

> Available research does not demonstrate an enhanced efficacy of

> bromelain when it is administered between meals. It is generally

> recommended that bromelain be taken away from food unless it is

being

> used as a digestive aid, because it is believed that otherwise, it

will

> tend to act as a digestive enzyme and its therapeutic benefit may be

> diminished. While this may in fact be the case, the clinical studies

> conducted on bromelain have not followed this protocol.

>

> Bromelain has shown therapeutic benefits in doses as small as 160

> mg/day; however, it is thought that, for most conditions, best

results

> occur starting at a dose of 750-1000 mg/day. Most research on

bromelain

> has been done utilizing divided doses, usually four per day, and

> findings indicate that results are dose-dependent. See Table 5 for a

> summary of prescription instructions.

>

> Conclusion

>

> Bromelain has been used for a variety of clinical applications for

more

> than 35 years. Although its mechanisms of action has not been

completed

> resolved, bromelain has demonstrated a beneficial effect on the

kinin

> system, the coagulation cascade, the cytokine system, and

prostaglandin

> synthesis. Bromelain is believed to enhance the absorption of

flavonoids

> and has been shown to increase absorption of glucosamine, so

bromelain

> supplemention should be considered when these nutrients are given.

It

> may also enhance absorption and utilization of many other

substances;

> however, to date research in this area has focused primarily on

> antibiotics. Bromelain has been shown to exert a beneficial effect

at

> doses as low as 160 mg/day, however, there is a general consensus

among

> researchers that the best results occur when bromelain is given in

doses

> above 500 mg per day and that results improve in a dose-dependent

manner

> with higher levels of bromelain supplementation. Bromelain has been

> demonstrated to be well absorbed after an oral dose and has been

shown

> to be safe at high doses for prolonged periods of time. For the

> conditions discussed in this review, bromelain has shown itself to

be an

> effective supplement.

>

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>