Digestive enzymes

Genestra: Digestive Enzymes by Dr. Aaron Hoo, NDJuly 2009

Digestive enzymes

In today’s processed and fast food culture, human digestion is often compromised manifesting itself in uncomfortable and sometimes embarrassing symptoms. These unfortunate experiences are exacerbated by the minimal intake of food enzymes found in raw fruits and vegetables which are further denatured when excessively cooked or pasteurized. To address the loss of enzymatic activity in the standard American diet, supplementation with digestive enzymes are not only recommended, they are a necessity.

Originally discovered in yeast1, digestive enzymes are the first step in the breakdown of food; enzymes are proteins that are produced by living organisms which facilitate biological activity such as hydrolyzing macronutrients – carbohydrates, fats, and proteins. Enzymes facilitate the process of digestion and thus are required for the absorption and assimilation of ingested food.

Indeed, the food we eat consists of large polymers that have to be broken down to monomers before they are absorbed and assimilated into cells. From food intake to the absorption of nutrients into systemic circulation, the process includes the following: the mechanical integration of food with the mixture of ingested solids and digestive juices from the GI tract; secretion of digestive enzymes that hydrolyze macromolecules to oligomers, dimers or monomers (eg. Carbohydrates are broken into monosaccharides like glucose and fructose, proteins into amino acids and lipids into glycerol and fatty acid); secretion of electrolytes, acid, or base to produce an appropriate mileau for optimal enzymatic digestion; secretion of bile acids to solubilize lipids and facilitate its absorption; hydrolysis of nutrient oligomers and dimers by enzymes on the surface of the intestinal wall, and absorption of nutrient molecules and electrolytes from the intestinal lumen by intestinal epithelial cells. 27

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(Illustration by Hans & Cassady)

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Enzymatic activity begins in the oral cavity where salivary glands produce salivary amylase, lingual lipase and ptyalin for starch and fat digestion. Aside from salivary secretion, a number of cells within the gastrointestinal system contain specific glands and surface epithelia, chief among which are those of the pancreas and small intestine with the former making the greatest contribution to digestive processes.

In the stomach, hydrochloric acid produced by parietal cells convert pepsinogen to pepsin which breaks down proteins while gastric lipase begins the hydrolysis of fats. Rennin, an enzyme present in the stomach acts on milk protein caesinogen and converts it to insoluble casein. While the secretion of bile from the liver and the presence of bile acids are necessary for optimal fat digestion and absorption, the digestion of food in the stomach is nonessential for adequate nutrition, as loss of this function is compensated for by the pancreas and small intestine. In light of this however, normal gastric digestion amplify the efficiency of the total digestive process. Essentially, peptides, amino acids and fatty acids when liberated in the stomach stimulate the coordinated release of pancreatic juice and bile into the lumen of the small intestine, thus ensuring efficient digestion of food. 27

Upon leaving the stomach, a bolus of food is subjected to pancreatic juices, intestinal juices and bile which are released into the lumen of the distal aspect of the duodenum,

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with most of the intra-luminal digestion occurring distal to this site. 27 Bile is a brownish green alkaline secretion from the liver; it consists of water, inorganic salts, cholesterol and bile salts which emulsify fats and aids in the activity of lipase. Pancreatic juice is also an alkaline fluid with pH of 7-8. It is carried to the duodenum via the pancreatic duct; it contains inactive proenzymes such as trypsinogen and chymotrypsinogen, both of which are activated by enterokinases (enteropeptidases) within intestinal juices, into trypsin and chymotrypsin respectively. Trypsin preferentially cleaves basic amino acids (eg. arginine and lysine) while chymotrypsin cleaves larger hydrophobic amino acids like tyrosine and phynylalanine and tryptophan. 27

Different enzymes are required to function within different pH environments which are a function of the primary amino acid sequences of the enzymes. For example, within the stomach, enzymes which facilitate protein denaturation and hydrolysis function optimally in an acidic environment with a pH < 2. In contrast, within the small intestine, enzymes such as enteropeptidases, disacchridases and phosphatases function optimally within a relatively alkaline environment with a pH >7 in order to facilitate the hydrolysis of starch, proteins and lipids. 27

Oral enzyme supplementation may be accomplished with digestive enzymes derived from animal, plant or microbial sources with the first being derived primarily from porcine (pork) or bovine (cattle) pancreas (eg. trypsin, chymotrypsin) for its protease, amylase and lipase activity; the second from bromelain or papain, and lastly from the fermentation of the Aspergillus oryzae or Rhizopus arrhizus. 22

In the case of oral supplementation with animal derived pancreatic enzymes, much discussion revolves around the need for enteric-coated preparations to ensure stability within the stomach and ultimate efficacy within the small intestine. Pancreatic lipase for example, is inactivated in an acidic environment, with pH of 4.0 or less. Some enzyme preparations provide a pH sensitive enteric coating to dissolve above pH of 5.5-6.0 in an attempt to protect them from stomach acid, however, some studies indicate enteric-coated tablets were less effective than the uncoated tablets with some even failing to dissolve in the small intestine. 21

To address this issue, French investigators studied the dissolution profile, acid stability and active enzyme release of different pancreatic enzyme preparations (two were enteric-coated and one was not). Dissolution experiments were examined at pH values of 4.0 to 5.8 with lipase, chymotrypsin and amylase activities measured in the solution as a function of time. Aside from a difference in the enzyme release activity of both enteric-coated tablets (one being released at pH 5.0 and the other at 5.4), the authors found that unlike chymotrypsin, lipase and amylase were highly fragile in acidic conditions at the lowest pH value (4.0) and were susceptible to proteolytic inactivation at pH 5.8. The uncoated tablet however, was the only one able to release high levels of chymotrypsin and lipase at low pH of 4.5. As a result of the study, the authors suggested that enteric-coated pancreatin containing similar amounts of enzymes were not “bioequivalent” depending on the milieu or pH of the duodenum and ultimately throughout the intestinal tract. 2

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Unlike pancreatic enzymes, bromelain remains stable and effective in a pH of 4.5-9.8 providing enzymatic activity from the stomach to the small intestine (9). Bromelain is an endopeptidase obtained from the fruit and stem of Ananas comosus/bracteatus (pineapple), but rather than being a single enzyme, it is comprised of macromolecules such as protease inhibitors, peroxidases, and acid phosphatase; as a whole, bromelain has been shown to breaks peptide bonds formed by lycine, alanine, tyrosine and glycine while remaining intact and proteolytically active within the gastrointestinal tract. 13

In contrast to bromelain, papain is a mixture of proteolytic enzymes derived from latex of the unripe fruit Carica papaya (papaya). Papain contains proteolytic, amylolytic and some lipolytic activity 7, splitting polypeptide bonds of arginine, phenylalanine and lysine. The latex derived from laticifers (the dense network of vessels from aerial parts of papayas) contains potent enzymes to aid in digestion; aside from papain, it includes other cysteine proteinases such as chymopapain, caricain and glycyl endopeptidases among others. Among the cysteine proteinases, papain has been most extensively studied since its molecular structure was fully identified in 1970 by x-ray crystallography. 7

Enzymes from non-animal sources are unique in that they can function synergistically with animal derived enzymes or as an alternative for vegetarians or vegans. These enzymes provide broad spectrum enzymatic activity in that they’re effective in providing protease, lipase, amylase, lactase, maltase, invertase and cellulase activity. Furthermore, non-animal derived enzymes possess greater stability throughout the pH range from 2-10, allowing them to be more active and effective throughout the whole gastrointestinal tract. 21

Understanding Enzyme Activity Units:The measurement of enzymatic activity involves an assay performed according to strict specification; these assays have been classified in the Food

Chemical Codex (FCC) and the United States Pharmacopoeia (USP). The following units and enzymatic activity are described and outlined below: 22, 29

Enzyme Potency or Activity UnitsAlpha amylase (fungal) DU (dextrinizing unit)Alpha amylase (bacterial) BAU (bacterial amylase unit)Amylase SKB (digestion of starch over time) (29)Cellulase CU (cellulose activity) Alpha-Galactosidase (fungal) GaIU (galactosidase unit)Beta-Glucanase (fungal) BGU (beta-glucanase unit)Glucoamylase (amyloglucosidase)(fungal) Glucoamylase unitHemicellulase (fungal) HCU (hemicellulase unit)Invertase (sucrase) (fungal) INVU (invertase unit)Lipase (fungal) FIP (fungal lipase international) or LU

(lipase unit, FCC), lipolytic activity Lysozyme (animal or microbial) Lysozyme unitPhytase FTU (phytase unit)Protease (plant) PU (papain unit)Protease (bacterial) PC (bacterial protease unit)

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Protease (acid) (fungal) SAP(spectrophotometric acid protease unit)Protease (neutral/alkaline) (fungal) HUT (hemoglobin unit on tyrosine basis)Pullulanase (bacterial) PU (pullulanase unit)Lactase (beta-galactosidase) (fungal) ALU (acid lactase unit)Lactase FCC units; based on liberation of

o-nitrophenol

Clinical Considerations:The use of digestive enzyme therapy began with the publications of Beard and Cutfield over a hundred years ago; these investigators outlined the anti-cancer effects of digestive enzymes in animal and human studies. 4, 5

Today, the broad application of enzyme therapy in clinical settings extend from its use as digestive aids to its application as proteolytic enzymes in wound debridement and healing as in ulcerated lesions 8, 26 to soft tissue injuries such as contusions, sprains, and general muscle injuries. For example, the therapeutic effects of bromelain have been identified and proven in a number of inflammatory diseases in both animal and human studies, including arthritis and inflammatory bowel disease. 12

Studies investigating the anti-inflammatory effects of bromelain suggest its efficacy in its ability to decrease the migration of neutrophils to the site of acute inflammation 9 as well as decrease the secretion of cytokines and chemokines such as interferon-gamma, interleukins and tumor necrosis factor (TNF) in inflammatory bowel disease. 17 For example, an animal study showed significant reductions in prostaglandin E2 (PGE2) and substance P (both key mediators of inflammation) in rodents with subcutaneous carrageenin-induced inflammation. 10

The use of bromelain also extends to the field of dermatology where oral bromelain was shown to be effective in the treatment of Pityriasis lichenoides chronica (PLC) a skin condition of unknown etiology. The authors concluded the treatment efficacy might be due to bromelain’s “anti-inflammatory, immunomodulatory and/or anti-viral properties”16

ultimately modulating normal inflammatory processes within the body via its effects on cellular adhesion (which affect intercellular communication amongst immune cells) and up-regulating the hepatic phagocytosis of inflammatory cytokines.

In everyday clinical settings, common symptoms which may be addressed with digestive enzymes include indigestion, bloating, excessive flatulence, abdominal cramping, and constipation alone or alternating with diarrhea as in irritable bowel syndrome.Furthermore, clinicians use digestive enzymes for the management of food allergies/sensitivities, functional dyspepsia, as well as leaky gut syndromes or hyper-permeability. Studies have shown its efficacy in lactose intolerance, pancreatic insufficiency, steatorrhea, and celiac disease among others. 21

Factors which contribute to the development of digestive complaints include poor eating habits such as improper mastication, eating late at night which may contribute to inadequate enzyme production, poor dietary and lifestyle choices (eg. consuming high

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amounts of alcohol, refined carbohydrates and fat). Aging also naturally affects digestion with inadequate production of hydrochloric acid by the parietal cells in the stomach.

Hypolactasia:One of the most widely recognized enzyme deficiency is that of hypolactasia, commonly known as lactose intolerance. Those who suffer from hypolactasia do not possess the enzyme lactase and as such, are incapable of appropriately digesting lactose (the sugar in dairy), leading to symptoms such as diarrhea, flatulence, bloating, abdominal cramping and pain.

Pre-hydrolyzed milk incubated with an enzyme from Kluyveromyces lactis yeast have been used effectively to treat those with lactose intolerance; furthermore, lactose maldigestion has also been shown to improve with the addition of lactase derived from the Aspergillus oryzae.21 This was confirmed by a recent 2008 study investigating the effect of oral intake of beta-D-galactosidase from Aspergillus oryzae in 134 patients with hypolactasia as diagnosed with the lactose H(2)-breath test. The authors found a highly significant reduction in the symptoms of hypolactasia with subsequent hydrogen excretion assessed by the breath test. 19

Exocrine pancreatic insufficiency:Exocrine pancreatic insufficiency is caused by chronic pancreatitis with the main clinical manifestations of fat malabsorption (steatorrhea) defined as fecal excretion of greater than 6 grams of fat per day, abdominal distension and discomfort. Fat malabsorption results in subsequent nutritional deficits primarily fat soluble vitamins (A, D, E, and K) with its sequellae. Researchers encourage the use of pancreatic enzymes, probiotics and bile acids to reduce intestinal inflammation in these patients. 18

Those with fat malsorption may be supported with oral intake of porcine derived pancreatic enzymes or acid-stable lipase from Aspergillus. In a placebo- controlled randomized cross- over animal study by Griffin et al., enzymatic preparation from Aspergillus oryzae (potency of 4,800 lipase units/LU and stable at a wide range of pH from 2-10), was shown to digest dietary fat within the stomach and into the small intestine. Results from this study indicated reductions in both fecal fat and stool volume; more striking however, was the finding that 4,800 LU of acid stable lipase from A. oryzae was as effective as 60,000 LU of conventional pancreatin. 21

A human cross over study examined the efficacy of acid stable microbial lipase, enteric coated pancreatin and conventional pancreatin in subjects with chronic pancreatitis, exocrine pancreatic insufficiency and severe steatorrhea. All three study groups showed significant improvement with almost complete resolution of symptoms. The authors reported that 75,000 LU per day of acid stable microbial lipase was as effective as lipase from enteric coated pancreatin (100,000 LU) and conventional pancreatin (360,000 LU) taken daily. 24

Cystic Fibrosis:

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Cystic fibrosis is the second most common childhood-onset single-gene disorder in North America. It is an autosomal recessive disorder caused by mutations in one gene on of

chromosome 7. This crux of cystic fibrosis is a defect in electrolyte transport system, resulting in thick, sticky mucus. Subsequently, abnormally viscous mucus affects the airways, resulting in pulmonary obstruction and chronic infections. Of note, it also occludes the flow of pancreatic juice from the pancreas into the small intestine, resulting in malabsorption of nutrients. 15

Administration of oral pancreatin in these patients is the cornerstone of digestive therapy in order to prevent the primary cause of death in patients with cystic fibrosis. Essentially, pancreatic enzymes are prescribed in the form of pancreatin or pancrelipase with the latter being preferred for its higher lipase activity which is especially beneficial in cystic fibrosis. 23

Intestinal hyperpermeability:

Intestinal hyperpermeability or “leaky gut” pertains to instances when intact large macromolecules pass through the intestinal mucosa into the bloodstream after oral ingestion. These macromolecules are perceived as antigens by the immune system resulting in mast cells transmitting a stress signal via the brain gut axis. This ultimately triggers proinflammatory mediators which stimulate nerve endings that affect intestinal motility and exacerbate intestinal hyperpermeability with possible implications in the pathogenesis of inflammatory bowel disease, IBS, enterocolitis 3 as well as eczema, arthritis and food allergies. 21 Macromolecules which may trigger an inflammatory response include lactalbumin, ovalbumin, globulin, ferritin, plant and animal enzymes such as bromelain and chymotrypsinogen, some whole viruses as well as protease enzymes from Aspergillus oryzae. The oral administration of enzymes at mealtime may facilitate and improve the digestion of dietary proteins, thus decreasing the amount of antigenic macromolecules leaking into systemic circulation. It has been hypothesized that intact protease from Aspergillus may hydrolyze any antigenic dietary proteins it encounters along the way, thereby decreasing the allergic response. 21

Celiac disease:Patients with celiac disease are subjected to the abnormal activation of their immune system by gluten (a component of the grain endosperm), and more specifically, the gliadin portion of wheat protein, the prolamine that is also found in rye, barley and oats.20

Celiac disease involves the destruction of mucosal villi which line the small intestine (small intestine enteropathy) which is mediated by the cellular and humoral-mediated immune reactions to gliadin. Damage to intestinal villi severely compromises the ability of the small intestine to absorb nutrients, manifesting in systemic conditions involving the dermatological, musculoskeletal, hematological, mucosal, neurological as well as psychological systems.20

Within the last decade, researchers have identified proline-glutamine rich epitopes from a-gliadin as being resistant to enzymatic breakdown and the dominant contributor to the

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stimulatory effects of dietary gluten on intestinal and peripheral T-lymphocytes in patients with celiac sprue. Thus, the a-gliadin protein fragment is implicated as the primary fraction that is most responsible for the symptomatic and pathogenic response seen in patients with celiac disease.

The 2002 study by Hausch et al. revealed that supplementation with bacterial prolyl

endopeptidases facilitate the rapid disintegration of the immunodominant epitopes found in a-gliadin fractions. Additionally, the authors identified dipeptidyl peptidase IV and dipeptidyl carboxypeptidase I as the rate-limiting enzymes in the breakdown of the immunodominant epitopes in gliadin. This landmark study provides evidence for the profound impact of proteolytic enzymes in the therapeutic strategy in the treatment of celiac sprue. 14

A more recent study published in 2009 evaluated the clearance of gluten with enzymes derived from aspergillopepsin from Aspergillus niger, and dipeptidyl peptidase IV from Aspergillus oryzae. Each enzyme was tested for its ability to hydrolyze gluten protein with reaction products analyzed by mass spectrometry, HPLC, ELISA and a T-cell proliferation assay. The authors describe marked enhancement in the hydrolysis of gluten relative to pepsin, and supplementation with enzymes from both Aspergillus niger and A. oryzae enabled the detoxification of gluten in whole wheat bread, and especially in the presence of casein (a competing protein from dairy). 6

GENESTRA FAMILY OF DIGESTIVE AND PROTEOLYTIC ENZYMES:

1. Digest Gluten Plus2. Digest Dairy Plus3. V-Enzymes4. Digest Plus5. Bio Enzymes

Digest Gluten Plus

Ingredients Per Capsule Gluten-specific protease (373P)

(providing 1.5 glutaminase BC units & 10 endo-proteinase BC units).......50 mg

Gluten-specific protease (223P) (providing 31.5 proteinase BC units).......350 mg

Digest Gluten Plus is specifically positioned for those with gluten intolerance. This formulation is suitable for vegetarians and contains endoproteases and exopeptidases; the former is designed to cleave protein bonds into peptide units while the latter cleaves peptides into individual amino acids. In this manner, Digest Gluten Plus is formulated to facilitate the digestion of gluten containing grains as it cleaves gliadin into shorter chain peptides and amino acids with the end result of significantly reducing the immuno-pathological impact of gliadin.

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Digest Gluten Plus is of clinical benefit in the following: patients who have an intolerance toward wheat and gluten containing foods; those who are diagnosed with celiac disease; those suffering from dyspepsia or irritable bowel syndrome secondary to the consumption of gluten-containing foods; and patients diagnosed with autism or attention-deficit-hyperactivity disorder where gluten is implicated.

Digest Dairy Plus

Ingredients Per Capsule Lactase 250 mg / 3750 FCC Vegetable protease 60 mg / 8 protease BCU Lipase 50 mg / 900 esterase BCU & 450 lipase BCU Bromelain 50 mg / 60 GDU Vegetable rennin 0.1 mg / 0.22 IMCU

Digest Dairy Plus is positioned specifically for those with lactose intolerance. It is appropriate for vegetarians, containing lactase, protease and lipase to hydrolyze all components of dairy products such as lactose, casein and triglycerides respectively. In this manner, Digest Dairy Plus hydrolyzes casein and non-casein proteins into shorter peptides and amino acids, digests lactose as well as converts triglycerides into monoglycerides and free fatty acids thereby ensuring symptomatic relief for patients with dairy intolerance. Furthermore, Digest Dairy Plus contains rennin, a protease that converts caseinogens into insoluble casein allowing for the coagulation of milk proteins in the stomach and facilitating its digestion.

V-Enzymes

Ingredients Per 2 Capsules Amylase (from Aspergillus oryzae) 600 mg / 18 000 AU Protease (from Bacillus subtilis) 300 mg / 42 CPU Cellulase (from Trichoderma sp.) 80 mg / 240 CU Bromelain (from Ananas comosus stem) 60 mg / 120 GDU Lactase (from Aspergillus oryzae) 40 mg / 2600 ALU Lipase (from Rhizopus oryzae) 30 mg / 1050 LU Acid Active Protease (from Aspergillus oryzae) 20 mg / 1.4 CPU Alkaline Active Protease (from Aspergillus oryzae) 20 mg / 4 CPU

V-Enzymes is an excellent digestive formula designed specifically with the vegetarian and vegan patient in mind. Sourced from microbial fermentation and pineapples, these enzymes provide a broad spectrum of digestive support throughout the gastrointestinal system with varying pH stability ranging from 3.5-9.0. As an added feature, V-Enzymes also contain lactase to support vegetarians who are lactose intolerant.

Digest Plus

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Ingredients Per Capsule Protease Activity 390 000 USP Amylase Activity 6500 USP Lipase Activity 520 USP Betaine Hydrochloride 162.5 mg Glutamic Acid 162.5 mg Pepsin 25 mg Papain (Papaya) 65 mg Pancreatin 6X Conc. 65 mg

Digest Plus is a powerful broad spectrum digestive enzyme formulation designed for the optimal digestion of macronutrients within the small intestine. It may be utilized for patients suffering from digestive complaints such as flatulence, bloating, indigestion, constipation and heartburn. In addition, the presence of potent proteases allow for optimal proteolytic activity in inflammatory conditions such as physical or soft tissue injuries.

The inclusion of Betaine Hydrocloride addresses digestive upset secondary to hypochlorhydria, especially in the elderly and in those who are chronically in a state of sympathetic dominance. Glutamic acid is aminated to form glutamine, the primary source of fuel for enterocytes necessary for gut healing; in addition, glutamic acid provide the precursors necessary for healthy glutathione and folic acid formation, essential for antioxidant and cellular maturation.

Digest Plus is also unique in that it includes pancreatin (from exocrine cells of porcine pancreas) in a 6X concentration thereby facilitating amylase, lipase and protease activity. In accordance with FDA Good Manufacturing Practice regulations, pancreatin 6X, active in neutral or slightly alkaline media, hydrolyzes fats to glycerol and fatty acids, modifies protein into proteoses and its derivatives and converts starches into dextrins and sugar, ultimately facilitating the breakdown of macromolecules for optimal absorption and assimilation by the body. 25

Bio-Enzymes

Ingredients Per Tablet

Protease Activity 20125 USP Lipase Activity 50 USP Amylase Activity 150 USP Carica papaya fruit (Papaya) 50 mg Papain (Papaya) 10 mg / 20 000 FCC- PU Bromelain (Pineapple) 200 MCU 10 mg Amylase (Aspergillus oryzae) 200 SKB 2 mg Pepsin 20 000 FCC 2 mg Pancrelipase 2 mg

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Genestra’s Bio-Enzymes is positioned for children and adults with digestive disturbances and malabsorption. Natural chlorophyll and peppermint flavors as well as fructose make this product especially popular with children.

The blend of animal and plant derived enzymes with the inclusion of Carica papaya fruit, papain and bromelain ensure optimal enzymatic activity throughout the pH range as food passes from the stomach to the small intestine.

Bio-Enzymes is unique in that it contains pancrealipase derived from porcine pancreas in accordance with U.S. Phamacopoeia (USP) standards. Pancrealipase lends itself to enzymatic activity that is approximately 30-50% greater than that of enzymes derived from bovine sources. While pancreatic enzymes from porcine sources are especially abundant in lipase and amylase, those from bovine pancreas are rich in proteolytic enzymes (proteases) but lacking in amylase and lipase. 22 Pancrealipase is processed in such a manner which preserves lipase enzyme activity and thus has a much higher lipase protease and amylase content compared to pancreatin. 23

References:

1) Achstetter, T., Ehmann, C., and Wolf, D. H. (1981) Arch. Biochem. Biophys. 207, 445-454

2) Aloulou A, Puccinelli D et al. In vitro comparative study of three pancreatic enzyme preparations: dissolution profiles, active enzyme release and acid stability. Aliment Pharmacol Ther. 2008 Feb 1; Vol. 27 (3), pp. 283-92

3) Ashkan F, Fields JZ., and Ali Keshavarzian. Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: Stress, intestinal hyperpermeability and inflammation. World J Gastroenterol 2007. June; Vol. 13(22): 3027-3030

4) Beard J. The action of trypsin upon the living cells of Jensen's mouse-tumour. Br Med J. 1906; 4 (Jan 20):140-1.

5) Cutfield A. Trypsin Treatment in Malignant Disease. Br Med J. 1907; 5: 525.

6) Ehren J, Moron B et al. A food-grade enzyme preparation with modest gluten detoxification properties. PLoS One 2009; Vol. 4 (7), pp. e6313

7) El Moussaoui, A., Nijs M et al. Review: Revisiting the enzymes stored in the laticifers of Carica papaya in the context of their possible participation in the plant defence mechanism. Cellular and Molecular Life Sciences. Vol. 58 (2001) p. 556-70

8) Falanga V. Wound Bed Preparation and the Role of Enzymes: A Case for Multiple Actions of Therapeutic Agents. Wounds. 2002

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9) Fitzhugh DJ, Shan S et al. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clinical Immunology. 2008 Jul; Vol. 128(1), pp. 66-74

10) Gaspani L, Limiroli E et al. In vivo and in vitro effects of bromelain on PGE(2) and SP concentrations in the inflammatory exudate in rats. Pharmacology. 2002 May; Vol. 65 (2), pp. 83-6.

11) Griffin SM et al. Acid resistant lipase as replacement therapy iin chronic pancreatic exocrine insufficiency: a study in dogs. Gut 1989; 30:1012-15

12) Hale LP, Greer PK et al. Proteinase activity and stability of natural bromelain

preparations. International Immunopharmacology. Vol. 5(4) 2005 pp.783-93

13) Hale LP. Proteolytic activity and immunogenicity of oral bromelain within the gastrointestinal tract of mice. International Immunopharmacology. 2004 Feb; Vol. 4(2), pp.255-64

14) Hausch F, Shan L et al. Intestinal Digestive Resistance of Immunodominant Gliadin

Peptides. Am J Physiol Gastrointest Liver Physiol. 2002 Oct; Vol. 283 (4)

15) Hendeles, L., Kuhn, R.J., and Milavetz, G. The role of pancreatic enzyme therapy in the treatment of cystic fibrosis. Pharmacy Today. 2006; Vol. 12 (9), pp.40–51

16) Massimiliano R., Pietro R et al. Role of bromelain in the treatment of patients with pityriasis lichenoides chronic. The Journal of Dermatological Treatment. 2007; Vol. 18 (4), pp. 219-22.

17) Onken JE, Greer PK et al. Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clinical Immunology. 2008 Mar; Vol. 126(3), pp. 345-52

18) Pezzilli R. Chronic pancreatitis: maldigestion, intestinal ecology and intestinal inflammation. World J Gastroenterol. 2009 Apr 14; Vol. 15 (14), pp. 1673-6

19) Portincasa P, Di Ciaula A et al. Beneficial effects of oral tilactase on patients with hypolactasia. Eur J Clin Invest 2008 Nov; Vol. 38 (11), pp. 835-44

20) Pruessner, H. Detecting Celiac Disease in Your Patients. American Family Physician. 1998 Mar; Vol. 57 (5)

21) Rachman, B. Unique Features and Application of Non-Animal Derived Enzymes. Clinical Nutrition Insights. 1997 Aug. Vol. 5 (10)

22) Roxas, M. The Role of Enzyme Supplementation in Digestive Disorders. Alternative Medicine Review. Vol. 13, No.4, 2008

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23) Scheindlin S. Clinical Enzymology: Enzymes as Medicine. Molecular Interventions. 2007; 7:4-8

24) Schneider MU et al. Pancreatic enzyme replacement therapy: comparative effects of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme preparations on steatorrhea in chronic pancreatitis. Hepato-gastroenterol 1985;332:97-102

25) Scientific Protein Laboratories LLC. Technical Data Sheet. Pancreatin 6X USP. 2005

26) Sinclair RD and Ryan TJ. Proteolytic Enzymes in Wound Healing: The Role of Enzymatic Debridement. Australian Journal of Dermatology. 2007 Jun; Vol. 35(1), pp.35-41

27) Thomas Devlin Ed. Textbook of Biochemistry With Clinical Correlations, 6th Ed. 2006. Wiley-Liss, John Wiley & Sons, Inc. Publication

28) Tyler VE, Brady LR, Robbers JE. Enzymes and other proteins. Pharmacognosy. 8th ed. Philadelphia, PA: Lea & Febiger; 1981:290-291

29) Wolfson D, Olmstead S et al. Making Sense of Digestive Enzymes: Technical Summary. ProThera Inc. 2008.

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