Bromelain

Bromelain, also called ‘pineapple extract,’ is a combination of several compounds, including a large amount of a special protein-digesting enzyme. This enzyme is able to be digested and thus affect the blood and body, rather than just the stomach and intestines.

When Bromelain is in the stomach, it will help the body break down and digest protein. Supplementation of bromelain can also reduce nasal inflammation, meaning it acts as a decongestant.

If taken between meals, bromelain can benefit the immune system and protect the body from cancer. Bromelain’s effects on fat cells are also under investigation, with promising preliminary evidence.

Bromelain’s anti-inflammatory properties are responsible for several of its effects, including its ability to decongest the nasal cavity. Further research is needed to determine the mechanism through which bromelain survives the digestive system.

There are many anecdotes that say bromelain supplementation will cause semen to taste like pineapple, but no studies have tested this claim.

The standard dose for bromelain depends on the goal of supplementation. If the goal is to aid digestion, the standard dose is between 200 – 2,000mg, taken with a meal.

If the goal of supplementation is not digestion related, does range from 200 - 800mg.

Bromelain is typically taken between meals to avoid potential degradation in the stomach. The large range for the standard dose is due to the variations in the enzymatic potential of bromelain, which is standardized by milk clotting units (MCU), or gelatin dissolving units (GDU).

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects bromelain has on your body, and how strong these effects are.

Grade	Level of Evidence [show legend]
	Robust research conducted with repeated double-blind clinical trials
	Multiple studies where at least two are double-blind and placebo controlled
	Single double-blind study or multiple cohort studies
	Uncontrolled or observational studies only

Level of Evidence ? The amount of high quality evidence. The more evidence, the more we can trust the results.	Outcome	Magnitude of effect ? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.	Consistency of research results ? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.	Notes
	Muscle Soreness	Minor	- See 2 studies	It is possible bromelain might reduce muscle soreness, but currently the evidence does not support this claim (although the trial to note a failure of bromelain also noted a failure with Ibuprofen, a known active drug)
	Incidence of Type 1 Diabetes	-	- See study
	Symptoms of Osteoarthritis	-	- See study	No significant influence on symptoms of osteoarthritis when tested
	Inflammation	Minor	- See study	Requires more evidence, but at the moment appears somewhat effective
	Nasal Congestion	Minor	- See study	The potency at this moment in time does not appear remarkable.
	Subjective Well-Being	Minor	- See study	Minor improvements in well being secondary to reducing joint pain

Studies Excluded from Consideration

• Confounded with Trypsin and Rutin (as rutoside dihydrate)^[1][2][3][4]

1.1Sources

Bromelain is a crude extract that comes from pineapples, particularly the stems or immature fruits; thus Bromelain is sometimes referred to as Pineapple extract.

1.2Composition

Bromelain is a mixture of:^[5][6]

• Thiol Endo-peptidases, such as Ananain and Comosain.^[7][8] These tend to be seen as the main active components.

• Phosphatases

• Glucosidases

• Peroxidases

• Cellulases

• Glycoproteins

• Proteinase Inhibitors, such as Cystatin^[9]

The overall mixture of Bromelain tends to have enzymatic activity on analyl, glycyl, and leucyl bonds and has a broad enzymatic profile.

1.3Processing

Bromelain is usually produced by cooling pineapple juice and then subjecting it to centrifugation, ultrafiltration and lyophilization.^[6] Alpha-macroglobulin is usually added to aqueous solutions, as Bromelain can self-digest in solution.^[10][6] However, extraction can feasibly come from other sections of the pineapple such as the peels and rind.^[11]

The final product is a yellowish powder which retains the aromatic properties of pineapples.

2.1Intestinal Absorption

Bromelain appears to be absorbed from the intestines and is bioactive. It is absorbed enzymatically active in the intestines of man^[12] at around 40%^[6] with a half-life of around 6-9 hours.^[12] Oral bioavailability of bromelain has been replicated elsewhere.^[6]

2.2Circulating in Serum

Circulating concentrations of 5000pg/mL enzymatically active bromelain have been noted in vivo 48 hours after oral ingestion of 8.6g Bromelain.^[12] An AUC of 2.5-4mcg bromelain is estimated between 3-51 hours after 8.6g orally ingested.^[12]

While circulating in serum, Bromelain associates with the anti-proteinases alpha-2-macroglobulin and antichymotrypain.^[12] Beinding to these anti-proteinases reduces the enzymatic activity of bromelain, but does not abolish it.^[13]

Despite being a quaternary protein in size, Bromelain appears to be absorbed and enzymatically active.

2.3Cytology

Bromelain appears to be able to transverse a cell membrane and retain enzymatic activity.^[14][15][16]

The general idea of Bromelain and digestion, as well as the entire protease class, is that they may contribute for an otherwise impaired digestive system.^[17] Bromelain has some other effects extending beyond its activities as a protease, however.

3.1Gastric

Bromelain has been shown effective in reducing dyspepsia in persons without heliobactor pylori infections when in conjunction with other nutraceuticals.^[18]

3.2Intestinal

Via its protease activities, bromelain can slow down intestinal motility in rats and in vitro.^[19] Its activities are inhibited by PAR-2 (receptor sensitive to proteases) as well as PDE4 and PLC downstream of the receptor, suggesting mechanisms of action.^[19]

3.3Colonic

An oral dose of 2-20mg bromelain in drinking water once daily is able to reduce inflammation in a murine model of colonic inflammation, and theoretically may aid inflammatory bowel disease (IBD).^[20] Controlled doses of 2mg and 5mg showed benefit, although 2mg was too low to be significantly different than control.^[20]

4.1Mechanisms

Bromelain, in vitro, can straight up remove (possibly through digesting) select receptors on T-cells; CD6-8, CD44 and an isoform of CD45, Leu8/LAM1 and E2/MIC2 are removed from T-cells after incubation with Bromelain.^[16] CD2-3 and CD28 were confirmed to be unaffected. Vicariously through these receptor changes, Bromelain can increase CD2 expression (normally hindered by CD44) and increase T-cell binding to monocytes via CD2 and via mechanisms not mediated by receptors^[16] the former of which are due to CD44 elimination.^[21] Bromelain has previously been shown to enhance T-cell binding to autologous E rosettes^[22] and is also implicated in CD36 elimination from macrophages, reducing formation of foam cells.^[23]

Elimination of the receptor proteins CD128a/CXCR1 and CD128b/CXCR2, receptors for IL-8 and related molecules, also occurs after Bromelain incubation.^[24] Elimination of these receptors in particular causes less neutrophil recruitment to the site of inflammation by reducing chemokine signalling efficacy.^[25]

Bromelain also appears to inhibit signal transduction in T0 cells that results in inhibition of ERK2 phosphorylation and p21ras activation^[26] and can inhibit the COX2 enzyme as well as reduce activation of NF-kB.^[27][28]

In general, it appears Bromelain eliminates the receptors on immune cells that respond to (mostly) pro-inflammatory signals. Without this needed junction in signalling, pro-inflammation doesn't occur as much and a relative state of anti-inflammation appears to occur.

4.2Efficacy and Potency

Doses in rats around 10mg/kg bodyweight appear to be approximately as effective as dexamethasone in some studies^[29][30] and other animal or in vitro studies compare its potency against standard NSAID treatment (aspirin, diclofenac) with similar potencies.^{[31][32][33][34]}

4.3Inflammation and Exercise

One study conducted with protease supplementation (Bromelain and Papain) found that protease enzymes circulating in serum were able to attenuate muscle damage associated with exercise and preserve power output over time.^[35] These effects have been noted before with protease supplementation in general, and seems to be more due to that property rather than Bromelain per se.^[36] Protections seems to be confered against ischemia-reperfusion injury as well, although the study in question here is confounded with trypsin and rutin ingestion.^[37]

Preliminary research suggests it can reduce markers of muscle breakdown and soreness, while preserving power output. Possibly a good idea for sports athletes, although it might have to be pre-loaded

4.4Type 1 Diabetes Risk

An in vitro study investigating the immunomodulatory effect of Bromelain noted that Bromelain was able to reduce the inflammatory insult on Pancreatic Beta-cells, and hypothesized that Bromelain could aid Type 1 Diabetes.^[38] Subsequently, one small study investigated whether protease supplementation was able to reduce the risk of developing Type 1 Diabetes Mellitus (TIDM) in a population of persons who tested positive for antibodies that put them at risk for TIDM was conducted. A daily dose of 90mg bromelain (with 100mg rutinoside and 48mg trypsin) showed positive biochemical changes in immune status but did not significantly affect rate of Type 1 Diabetes development over 8 years (24 months of supplementation) in these 20 persosn.^[39]

5.1Mechanisms

In vitro and in rats, an increase in p53 expression and an increase in the Bax/Bcl-2 ratio are seen after incubation with Bromelain.^[27][28]

6.1Blood Flow

Bromelain possesses both fibrolytic and anti-platelet functioning, .

When looking at Bromelain in vitro, it appears to reduce both platelet aggregation as well as binding of platelets to endothelium^[40] via its enzymatic components.^[41] Bromelain is effective at inhibiting 6-11% of thrombus formation at an oral dose of 60mg/kg bodyweight in rat mesenteric vessels.^[40] The fibrolytic functions are also tied in with enzymatic activity, and the two confer protective effects from artherosclerosis.^[42][43]

6.2Cardioprotection

According to a Meta-Analysis of 223 studies,^[43] 3 interventions have been conducted in rats investigating cardiovascular protection from Bromelain; these studies varied in research goals investigating platelet adhesion,^[40] Akt/FOXO protection from ischemia,^[44] and allograph atherosclerosis.^[45] Although all studies showed benefit with Bromelain supplementation with no apparent side effects, their measures and research goals varied too widely to be harmonized.^[43]

The same Meta-Analysis^[43] found 4 human trials investigating Bromelain and Cardiovascular health, one of which is not indexed online and is in German.^[46][47][41] The studies showed promise, but had low internal validity; only one was double blinded and placebo controlled.^[46]

6.3Artherogenesis

Bromelain appears to have the ability to prevent macrophages (an immune cell) from turning into foam cells via eliminating the CD36 receptor.^[23] Foam cells are pro-artherogenic immune cells which contribute to arterial plaque formation.^[48]

Overall, Bromelain has many mechanisms which suggest it can be quite a heart healthy compound; mostly acting in blood vessels rather than cardiac tissue. The studies conducted on humans, however, are of lesser quality and have not since been replicated

7.1Beta-amyloid

Beta-amyloid is a protein known as the 'age pigment' due to its association with aging; it is suspected of contributing to Alzheimer's Disease.

After oral ingestion, bromelain is complexed with Macroglobulin. This complex appears to be able to degrade beta-amyloid pigmentation while Macroglobulin complexes with intrinsically produced proteins are ineffective. This is a mechanism by which Bromelain may offer neuroprotection.^[49]

Interventions into neuroprotection and Bromelain have been less promising. One intervention looking at protease supplementation and Multiple Sclerosis found no significant treatment effects of oral protease enzymes.^[50]

Bromelain from Pineapple Stem (stem bromelain) has been shown to inhibit adipogenesis in vitro using 3T3-L1 adipocytes.^[51] A dose-dependent suppression of triglyceride accumulation was seen up to 50ug/mL enzymatically active bromelain, in where the effects were saturated; enzymatically inactive bromelain was ineffective.^[51] There was about 25% less triglycerides after treatment at this level over the 8 days of incubation, and was 30% more potent than all-trans retinoic acid and 1,25-dihydroxycalciferol.^[51]

It seems to inhibit mid and late phase adipogenesis, as mRNA of C/EBPβ and C/EBPδ as well as mitotic clonal expansion are unaffected yet mRNA C/EBPα and PPARγ are suppressed, more than halfing their relative mRNA levels.^[51] This inhibition of mid to late phase adipogenesis shows in late stage markers of adipocyte differentiation, as the proteins Lipoprotein Lipase (LPL), aP2, Fatty acid Synthase (FAS) and CD36 are all markedly reduced.^[51] A downregulation of perilipin in these cells remained during maturation, and this inhibition stays even if bromelain is removed from the medium during late-phase differentiation.^[51]

PPARγ appears to have reduced phosphorylation via Akt, although Akt phorphorylation per se is unaffected.^[51] TNF-α being increased may also contribute.

Apoptosis of mature cells was seen as increasingly dose-dependent with minimal effects at 10ug/mL, moderate effects at the inhibitory saturation point of 50ugmL, and significnat apoptosis at 100ug/mL.^[51]

A single but sexy in vitro study; too soon to draw any conclusions, but it looks quite interesting

Bromelain may reduce complications with acute sinusitis known as a 'stuffed nose' to a greater extent than placebo.^[52][53][54] One study conducted noted that 83% of persons using bromelain had reductions in nasal inflammation as compared to 52% of the placebo.^[55] Bromelain appears to reduce the length it takes to alleviate sinusitis significantly, yet combining bromelain with traditional therapy for sinusitis appears to reduce the efficacy of both.^[56]

Might clear your nose if you have the sniffles

10.1Intestinal transport

Bromelain appears to have the ability to increase bioavailability (percent absorbed) and reduce the side-effects associated with anti-biotics such as penicillins and tetracyclins after oral administration.^[6][57] When looking into Bromelain and other compounds, it appears that a general motif of protease compounds (especially Bromelain) allowing larger molecules to pass through the intestines easier. This has been shown with a 6.7-fold increase in the bioavailability of low-molecular weight heparin,^[58] flurescein,^[59] and reduced glutathione.^[59] It's interactions on bioavailability with tetracycline are not clear, as one study found an increase in bioavailability^[60] yet another did not.^[61]

10.2Phlogenzym

Phlogenzym is a brand name product consisting of Bromelain at 90mg, trypsin at 48mg and rutoside trihydrate at 100mg; usually adminstered in an enteric capsule. Several studies use this blend of enzymes rather than isolated Bromelain.^[1][2][3][4]

The most well known ability of pineapples (despite bromelain's abilities against inflammation, digestion, and pharmacokinetic profile of being a blood borne active enzyme; a possibility that was once thought impossible) is the fact that pineapples flavor semen...

The volatile components in pineapple that may contribute to flavor and aroma include a series of beta-hydroxy esters such as methyl beta-hydroxyoctanoates and hexanoates (although in isolation their smell is reported repulsive, suggesting they contribute to the taste) and octalactones, which 'express the coconut-like smell of other lactones'.^[62] Other compounds that are suspect are methyl butanoates that, along with methyl hexanoate, comprise over 74% of total volatiles.^[63] It is likely that some of these compounds may flavor semen.

There are no clinical trials into isolated the compound(s) that flavor semen, unfortunately.

12.1General

Side-effects with moderate to higher dosages (400-800mg) tend to be gastrointestinal in nature, including pasty feces and farting.^[6] Oral administration of 500mg/kg bodyweight in rats does not seem to be associated with general side-effects.^[64]

12.2Clinical

After an attempted oral toxicity test in animals, no deaths could be seen with dosages up to 10g/kg bodyweight in rats, mice, or rabbits.^[64]

Lethal doses of injections were 37mg/kg in mice and 85mg/kg in rats.^[64]

1. ^ a b Mialovyts'ka OA. Effect of phlogenzym in long-term treatment of patients with multiple sclerosis. Lik Sprava. (2003)
2. ^ a b Kerkhoffs GM, et al. A double blind, randomised, parallel group study on the efficacy and safety of treating acute lateral ankle sprain with oral hydrolytic enzymes. Br J Sports Med. (2004)
3. ^ a b Shahid SK, et al. Efficacy and safety of phlogenzym--a protease formulation, in sepsis in children. J Assoc Physicians India. (2002)
4. ^ a b Szczurko O, et al. Naturopathic treatment of rotator cuff tendinitis among Canadian postal workers: a randomized controlled trial. Arthritis Rheum. (2009)
5. ^ Rowan AD, Buttle DJ. Pineapple cysteine endopeptidases. Methods Enzymol. (1994)
6. ^ a b c d e f g Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci. (2001)
7. ^ Harrach T, et al. Isolation and partial characterization of basic proteinases from stem bromelain. J Protein Chem. (1995)
8. ^ Purification and characterization of multiple forms of the pineapple-stem-derived cysteine proteinases ananain and comosain.
9. ^ Irene D, et al. Resonance assignments and secondary structure of a phytocystatin from Ananas comosus. Biomol NMR Assign. (2012)
10. ^ Yoshioka S, et al. Inactivation kinetics of enzyme pharmaceuticals in aqueous solution. Pharm Res. (1991)
11. ^ Ketnawa S, Chaiwut P, Rawdkuen S. Extraction of bromelain from pineapple peels. Food Sci Technol Int. (2011)
12. ^ a b c d e Castell JV, et al. Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Am J Physiol. (1997)
13. ^ Bioavailability of Therapeutically used Hydrolytic Enzymes.
14. ^ White RR, et al. Bioavailability of 125I bromelain after oral administration to rats. Biopharm Drug Dispos. (1988)
15. ^ Dave S, et al. Hexafluoroisopropanol-induced helix-sheet transition of stem bromelain: correlation to function. Int J Biochem Cell Biol. (2010)
16. ^ a b c Hale LP, Haynes BF. Bromelain treatment of human T cells removes CD44, CD45RA, E2/MIC2, CD6, CD7, CD8, and Leu 8/LAM1 surface molecules and markedly enhances CD2-mediated T cell activation. J Immunol. (1992)
17. ^ Roxas M. The role of enzyme supplementation in digestive disorders. Altern Med Rev. (2008)
18. ^ Pellicano R, et al. Benefit of dietary integrators for treating functional dyspepsia: a prospective pilot study. Minerva Gastroenterol Dietol. (2009)
19. ^ a b Borrelli F, et al. Inhibitory effects of bromelain, a cysteine protease derived from pineapple stem (Ananas comosus), on intestinal motility in mice. Neurogastroenterol Motil. (2011)
20. ^ a b Hale LP, et al. Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease. Clin Immunol. (2005)
21. ^ CD44 antibody against In(Lu)-related p80, lymphocyte-homing receptor molecule inhibits the binding of human erythrocytes to T cells.
22. ^ Scheffel JW, Kim YB. Characterization of autologous erythrocyte rosette-forming cells in Minnesota miniature swine. Cell Immunol. (1981)
23. ^ a b Mahajan S, et al. Stem Bromelain-Induced Macrophage Apoptosis and Activation Curtail Mycobacterium tuberculosis Persistence. J Infect Dis. (2012)
24. ^ Hale LP, Greer PK, Sempowski GD. Bromelain treatment alters leukocyte expression of cell surface molecules involved in cellular adhesion and activation. Clin Immunol. (2002)
25. ^ Fitzhugh DJ, et al. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. (2008)
26. ^ Mynott TL, et al. Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells. J Immunol. (1999)
27. ^ a b Kalra N, et al. Regulation of p53, nuclear factor kappaB and cyclooxygenase-2 expression by bromelain through targeting mitogen-activated protein kinase pathway in mouse skin. Toxicol Appl Pharmacol. (2008)
28. ^ a b Bhui K, et al. Bromelain inhibits COX-2 expression by blocking the activation of MAPK regulated NF-kappa B against skin tumor-initiation triggering mitochondrial death pathway. Cancer Lett. (2009)
29. ^ Majima M, et al. Determination of bradykinin-(1-5) in inflammatory exudate by a new ELISA as a reliable indicator of bradykinin generation. Inflamm Res. (1996)
30. ^ Ogino M, et al. Increased migration of neutrophils to granulocyte-colony stimulating factor in rat carrageenin-induced pleurisy: roles of complement, bradykinin, and inducible cyclooxygenase-2. Inflamm Res. (1996)
31. ^ Wittenborg A, et al. Comparative epidemiological study in patients with rheumatic diseases illustrated in a example of a treatment with non-steroidal anti- inflammatory drugs versus an oral enzyme combination preparation. Arzneimittelforschung. (2000)
32. ^ Masson M. Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice. Fortschr Med. (1995)
33. ^ Akhtar NM, et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee--a double-blind prospective randomized study. Clin Rheumatol. (2004)
34. ^ Inoue K, et al. Effect of etodolac on prostaglandin E2 biosynthesis, active oxygen generation and bradykinin formation. Prostaglandins Leukot Essent Fatty Acids. (1994)
35. ^ Buford TW, et al. Protease supplementation improves muscle function after eccentric exercise. Med Sci Sports Exerc. (2009)
36. ^ Miller PC, et al. The effects of protease supplementation on skeletal muscle function and DOMS following downhill running. J Sports Sci. (2004)
37. ^ Neumayer C, et al. Combined enzymatic and antioxidative treatment reduces ischemia-reperfusion injury in rabbit skeletal muscle. J Surg Res. (2006)
38. ^ Roep BO, et al. Modulation of autoimmunity to beta-cell antigens by proteases. Diabetologia. (2002)
39. ^ Kempf K, et al. Effect of combined oral proteases and flavonoid treatment in subjects at risk of Type 1 diabetes. Diabet Med. (2009)
40. ^ a b c Metzig C, et al. Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo. (1999)
41. ^ a b Heinicke RM, van der Wal L, Yokoyama M. Effect of bromelain (Ananase) on human platelet aggregation. Experientia. (1972)
42. ^ Felton GE. Fibrinolytic and antithrombotic action of bromelain may eliminate thrombosis in heart patients. Med Hypotheses. (1980)
43. ^ a b c d Ley CM, et al. A review of the use of bromelain in cardiovascular diseases. Zhong Xi Yi Jie He Xue Bao. (2011)
44. ^ Juhasz B, et al. Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium. Am J Physiol Heart Circ Physiol. (2008)
45. ^ Gaciong Z, et al. Beneficial effect of proteases on allograft arteriosclerosis in a rat aortic model. Nephrol Dial Transplant. (1996)
46. ^ a b Seligman B. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology. (1969)
47. ^ Gutfreund AE, Taussig SJ, Morris AK. Effect of oral bromelain on blood pressure and heart rate of hypertensive patients. Hawaii Med J. (1978)
48. ^ Seneviratne AN, Sivagurunathan B, Monaco C. Toll-like receptors and macrophage activation in atherosclerosis. Clin Chim Acta. (2012)
49. ^ Lauer D, Reichenbach A, Birkenmeier G. Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism. Exp Neurol. (2001)
50. ^ Baumhackl U, et al. A randomized, double-blind, placebo-controlled study of oral hydrolytic enzymes in relapsing multiple sclerosis. Mult Scler. (2005)
51. ^ a b c d e f g h Dave S, et al. Inhibition of adipogenesis and induction of apoptosis and lipolysis by stem bromelain in 3T3-L1 adipocytes. PLoS One. (2012)
52. ^ Seltzer AP. Adjunctive use of bromelains in sinusitis: a controlled study. Eye Ear Nose Throat Mon. (1967)
53. ^ Ryan RE. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache. (1967)
54. ^ Taub SJ. The use of bromelains in sinusitis: a double-blind clinical evaluation. Eye Ear Nose Throat Mon. (1967)
55. ^ A DOUBLE-BLIND CLINICAL EVALUATION OF BROMELAINS IN THE TREATMENT OF ACUTE SINUSITIS.
56. ^ Braun JM, Schneider B, Beuth HJ. Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS in children with acute sinusitis in Germany. In Vivo. (2005)
57. ^ NEUBAUER RA. A plant protease for potentiation of and possible replacement of antibiotics. Exp Med Surg. (1961)
58. ^ Grabovac V, Bernkop-Schnürch A. Improvement of the intestinal membrane permeability of low molecular weight heparin by complexation with stem bromelain. Int J Pharm. (2006)
59. ^ a b Guggi D, Bernkop-Schnürch A. Improved paracellular uptake by the combination of different types of permeation enhancers. Int J Pharm. (2005)
60. ^ Renzini G, Varengo M. Absorption of tetracycline in presence of bromelain after oral administration. Arzneimittelforschung. (1972)
61. ^ Bradbrook ID, Morrison PJ, Rogers HJ. The effect of bromelain on the absorption of orally administered tetracycline. Br J Clin Pharmacol. (1978)
62. ^ Volatile Components of Pineapple.
63. ^ Montero-Calderón M, Rojas-Graü MA, Martín-Belloso O. Aroma profile and volatiles odor activity along gold cultivar pineapple flesh. J Food Sci. (2010)
64. ^ a b c MOSS JN, FRAZIER CV, MARTIN GJ. BROMELAINS. THE PHARMACOLOGY OF THE ENZYMES. Arch Int Pharmacodyn Ther. (1963)
65. Klein G, et al. Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol. (2006)
66. Brien S, et al. Bromelain as an adjunctive treatment for moderate-to-severe osteoarthritis of the knee: a randomized placebo-controlled pilot study. QJM. (2006)
67. Stone MB, et al. Preliminary comparison of bromelain and Ibuprofen for delayed onset muscle soreness management. Clin J Sport Med. (2002)
68. Walker AF, et al. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine. (2002)
69. Tilwe GH, et al. Efficacy and tolerability of oral enzyme therapy as compared to diclofenac in active osteoarthrosis of knee joint: an open randomized controlled clinical trial. J Assoc Physicians India. (2001)