Article ID: WMC002495 2046-1690

Role of Systemic in Infections

Corresponding Author: Dr. Sukhbir Shahid, Consultant Pediatrician, Pediatrics - India

Submitting Author: Dr. Sukhbir Shahid, Consultant Pediatrician, Pediatrics - India

Article ID: WMC002495 Article Type: Review articles Submitted on:22-Nov-2011, 08:16:56 AM GMT Published on: 22-Nov-2011, 02:34:00 PM GMT Article URL: http://www.webmedcentral.com/article_view/2495 Subject Categories:COMPLEMENTARY MEDICINE Keywords:Enzymes, Systemic enzymes, Infections, Sepsis, Proteolytic, Supplementary How to cite the article:Shahid S . Role of Systemic Enzymes in Infections . WebmedCentral COMPLEMENTARY MEDICINE 2011;2(11):WMC002495 Source(s) of Funding: None

Competing Interests: None

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Role of Systemic Enzymes in Infections

Author(s): Shahid S

Abstract infections[4]. The ‘battle’ between the host’s immunity and organism leads to a lot of ‘molecular’morbidity and mortality. Anti-infective agents do help but at times benefit is marginal. These agents may sometimes Enzymes are complex macromolecules of amino-acids worsen the situation through release of immune which bio-catalyse various body processes. Adequate complexes and dead bacilli into the blood stream. concentrations of enzymes are essential for optimal They also fail to reverse the hemodynamic instability functioning of the immune system. During infections, and immune paralysis characteristic of these body’s enzymatic system is attacked and hence the infections[4]. Supplementation with drugs targeted immune system is also likely to derange. This may be against this ‘choatic’ or ‘dysfunctional’ immune detrimental for the host’s well-being and existence. response could be beneficial. Systemic enzymes Along with appropriate antimicrobial therapy, seem to aid tremendously in ‘taming’ this ‘wilderness’ administration of enzymes externally could plausibly and optimising the immune response[5]. help to stabilise this disturbed immune system and SYSTEMIC INFLAMMATORY RESPONSE thus assist the body to overcome the infections. This SYNDROME (SIRS) IN INFECTIONS would especially be useful in multi-drug resistant and SIRS is seen in an infective process [6]. It is in the severe nosocomial infections. Enzymes have been form of a cascade with counterregulation. It is initiated studied and found to play a supplementary role in by lipopolysaccharide (LPS), Lipid A, or endotoxin of control of these infections. They also seem to help in gram-negative bacteria, or lipoteichoic acid, control of difficult to manage viral infections. Besides, peptidoglycan, or exotoxin of gram-positive bacteria their use has been found to be beneficial in prevention (eg.), or similar components of virus, fungi or parasites. of various common infections such as flu and cold. In LPS binds to a specific plasma protein (LPS binding spite of their potential, they have remained largely protein) and this complex then binds to a membrane underestimated and underexploited. This review on receptor (CD14) on effector cells such as oral enzymes attempts to highlight the role and safety macrophages and endothelial cells. This initiates of enzymes as adjunctive therapy in infections. intracellular signal transduction via a specific receptor Introduction mechanism (Toll-like receptor, TLR) [3]. Complement system is also stimulated which assists in trigger and amplification of various components of the immune Infections of varying severity continue to scourge system[7, 8]. Mankind. Their incidence is on the rise. New infections Lymphocytes, monocytes and other immune cells are are emerging and old, conquered ones are making a attracted to site of infection and pro-inflammatory comeback[1, 2]. Also these infections are increasingly substances called cytokines are released. More than seen to be resistant to commonly used antibiotics and 120 different cytokines have been identified and though research into newer antibiotics is ongoing, it described. Monocytes produce nuclear factor-?B has failed to keep pace with the rising antimicrobial which also produces proinflammatory cytokines, α resistance. Alternative ways to manage these tumour necrosis factor alpha (TNF- ), interleukin-1 α ‘biological killers’ need to be delved into. Oral systemic (IL-1) and interleukin-6 (IL-6). TNF- and IL-1 in turn therapy seems to hold promise in control and generate toxic downstream mediators, such as elimination of certain of these infections. prostaglandins (by cycloxoygenase pathway), The outcome in an infection is dependent on a leukotrienes, platelet-activating factor, and multitude of factors such as genes, nutrional status of phospholipase A2 [9, 10]. These mediators damage host, virulence of infecting organism, time duration of endothelial lining and increase capillary leakage by infection etc[3]. A favourable outcome ensues when acting on a group of glycoproteins called selectins on host’s immune response is sufficient enough to arrest the endothelial cells (E-selectin and P-selectin) and the march of the infecting organism into it, whereas an leukocytes (L-selectin). Leukocytes marginate and inadequate immune response could prove detrimental. form strong bonds with the neighbouring cells. These Not only an hypo- but an hyper immune response has bonds are due to expression of adhesion molecules also been shown to be harmful. Such suboptimal on the cells. These adhesion molecules include responses characterize severe, advanced or resistant intercellular adhesion molecules 1 and 2 (ICAM-1 and

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2) on the endothelial cells, vascular adhesion ‘immunosuppression’ seen in infections and to salvage molecules (VCAM-1), and platelet-endothelial cell the host’s immune system. adhesion molecule 1 (PECAM-1). The receptors on ENZYME HISTORY leukocytes include members of the α2-integrin family During the Mayan civilization, wrapping papaya leaves of adhesion molecules such as CD11b and CD18 [11]. around wounds was supposed to aid healing. The Neutrophils are also chemoattracted to the site. Their juice of these leaves contains certain vital enzymes interaction with endothelial cells by means of adhesion which speeded healing. Pineapple has been used as a molecules causes further damage. Stimulated medicinal plant by folks of several tropical native neutrophils release and nitric oxide which cultures and its enzyme has been further aggravate the inflammation [12-15]. chemically known since 1876 [33]. Since 1950's, role TNF-α and IL-1 also cause expression of tissue factor of proteolytic enzymes such as bromelain, , on endothelial cells and monocytes. This initiates the , and chymotrypsin in anti-inflammation coagulation cascade; thrombin is produced which itself emerged. Due to their systemic action and oral is a proinflammatory substance. Fibrin clots form in the administration, they were called as oral systemic microvasculature. TNF-α and IL-1 also activate proteolytic enzymes. Gradually as more studies were plasminogen activator inhibitor-1 which inhibits carried out, utility of oral enzymes for treatment of fibrinolysis [16]. They also hamper activation of protein various infections came forth. Innumerable C and antithrombin; which are antithrombotic and also double-blind randomized and controlled trials were anti-inflammatory [17-19]. Cytokine production performed and oral enzymes were found to be useful continues. Thus an hyperinflammatory atmosphere is and safe adjuvant therapy in infections. Benefits of produced. This is counterproductive and enhances topical enzymes for wound debridement was mortality [20]. Blocking of these cytokines by specific discovered and their use in wound care gained antagonists has been shown to improve survival[21]. momentum. In some patients or later in the course of infection, PROPERTIES OF ENZYMES released stress hormones induce lymphocytes to Enzymes are albuminoid, complex macromolecules release anti-inflammatory cytokines such as IL-4, IL-10, made up of amino-acids. There can be digestive, and IL-13 [22]. These act to deactivate monocytes and metabolic or food enzymes. Digestive and metabolic decrease TNF-α, IL-1 and IL-6 production. Alpha2 enzymes are naturally produced in the body. They macroglobulin, the cytokine catcher is also converted tend to decline with age, inadequate and imbalanced into its ‘fast’ form. It mops up the excess cytokines and nutrition, and physical and mental strain[34]. An tries to keep inflammation under check [23-25]. But estimated 80 to 100 thousand enzymes are present in this inflammatory suppression leads to cellular human body; more than 3000 of these have been dysfunction and decrease in lymphocyte proliferation. identified to date[35]. Food enzymes come from plant Apoptosis (programmed cell death) of gut lymphocytes and animal sources. They are heat-labile and hence and endothelial cells takes place and anergy sets raw, fermented and lightly cooked foods are in[26-28]. enyme-rich[36]. However, neutophilic stimulation and consequent When first discovered, enzyme names ended with ‘in’ tissue damage continues unabated [29]. The released like pepsin or trypsin. But later, they were suffixed by nitric oxide, oxidases and proteases are main culprits ‘ase’ such as protease. An elaborate nomenclature by in this damage [30, 31]. Enzyme Commission (EC) of the International Union Thus the infective process is a complex process of of Biocemistry (IUB) classifies the proteolytic enzymes inflammation. No single into the class (class 3) which includes mediator/system/pathway/pathogen drives the peptid-hydrolase group (3.4) which comprises pathophysiology of sepsis, but it is a composite output. aminopeptidases (3.4.1), carboxypeptidases (3.4.2), Complex endothelial-leukocyte interactions are dipeptidases (3.4.3) and proteinases (3.4.4) [37]. essential for sustaining an inflammatory response. Enzymes for pharmaceutical uses are harnessed from Carefully timed sequence of molecular expression plants, fungi, bacteria and animals. They act after regulate these interactions. Simultaneous release of internal absorption and function best at specific pro- and anti-inflammatory elements is seen. The temperature and pH[35]. Hence processing, handling equilibrium between these two contrasting signals is and storage of the enzymes should be proper. The vital for recovery from infection[32]. This process is various enzymes known to be useful in infections are meant to be reparative, but there is always a risk for it as follows: Bromelain from pineapple stems ( Ananas to turn counterproductive. Systemic enzyme therapy comosus), catalase, chymotrypsin from ox bile, krillase has been shown to overcome the ‘cytokine storm’ or from Antarctic krill (E. superba), lysozyme, pancreatin,

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papain from unripe papayas (Carica papaya), pepsin, hampered and infectivity decreases. For example, protease, bioflavinoid rutin, serratiopeptidase or Bromelain can disrupt Enterotoxigenic Escherichia serrapeptase derived from nonpathogenic Coli (ETEC) receptors in vivo and protect against enterobacteria, Serratia E15, and trypsin. V-8 ETEC induced diarrhea[54, 55]. protease (from Staphylococcus aureus), pronase (from 3. They detoxify blood and remove viruses from Staphylococcus griseus), Subtilisin, ficin from Ficus circulation.They act as a "biological vacuum cleaners" tree latex have also been investigated in various eliminating impurities, foreign proteins, immune infections. complexes and harmful micro-organisms from the These enzymes are highly substrate specific. Hence blood stream and tissues. This greatly diminishes the combination of them has a better and synergistic inflammatory response and allows the normal immune effect[38]. Various enzyme combinations for infection functions to operate at a much healthier level. and inflammation exist in the market such as Vitalzym, 4. Enzymes cause enhancement of immune cells to Phlogenzym, Medizym, Wobenzym, Wobe-mugos, kill bacteria, viruses, molds and fungi[56]. Bromelain Chymotrypsin and trypsin combinations, increases proliferation of peripheral blood serratiopeptidase, and papain-urea skin creams with mononuclear cells. Production of IL-6, or without chlorophyllin. granulocyte-monocyte-colony stimulating factor α α ABSORPTION OF ENZYMES (GM-CSF), TNF- and type 1 cytokine IFN- The initial myth that enzymes are not absorbed by gut production, but not of type 2 cytokines IL-4 and IL-5 has been refuted by numerous animal and human are increased[57]. This induction is studies[39-46]. Absorption of intact enzymes into rest dose-dependent[58]. Macrophage activity is enhanced of body is possible by pinocytosis or by uptake by up to 700 percent with a combination of enzymes ‘roaming’ lymphocytes in the small intestinal lumen pancreatin, papain, bromelain, trypsin and which are again released into the gut wall. This is chymotrypsin[59]. Phagocytosis is also similar to the uptake of antibodies (gammaglobulins) accelerated[60]. into the child’s lymphatic system and blood stream 5. Enzymes break down immune complexes which from the mother’s milk. Substantial proportion of block the immune cells[35]. They dissolve immune bromelain is also absorbed[47]; highest concentration complex by removing Fc part of immunoglobulin and being present in blood 1 hour after administration[48]. eliminate immune complexes from circulation[61, 62]. Enzymes are likely to be destroyed by acidic gastric In the early phase, there may be worsening of the milieu and enteric-coating protects them from situation due to release of immune complexes fixed to annihilation and improves their bioavailability[49]. tissues into the blood (Jarisch-Herxheimer effect). Special blood factors such as the antiproteinase, α 6. They accelerate the volume and fluidity of blood ²-macroglobulin act as carrier for the enzymes and flow[63]. This facilitates elimination of inflammatory prevents them from digesting the blood proteins. Also products. Vascular endothelium is also stabilised[64]. these enzymes are protected from being acted upon 7. Enzymes such as bromelain modulate arachidonate by the blood proteases. They circulate in the body pathway in such a way that thromboxane production is acting on their appropriate substrates[50]. decreased with no effect on cyclooxygenase. This MECHANISM OF ACTION leads to a decrease in odema and inflammation and Enzymes are essential for each and every bodily reestablishment of balance between the 2 types of function. They act as ‘biocatalysts’ and produce big prostaglandins[33, 47]. effects with little efforts. They act at multiple sites of 8. Enzymes such as Serrapeptase enhance the the immune system to enhance it and diminish on bactericidal effect of antibiotics in cultures and inflammation. They normalize ‘a derailed immune prevents the formation of biofilms. This is valuable in system’ and hence aid in control and elimination of treating problematic prosthetic infections[65, 66]. infection. They are supposed to act in the following Papain has also been found to enhance ways: chemotherapeutic efficacy of antibiotics on an average 1. The enzymes cleave the antigenic surface protein of by 50% in mice with septicemia[67]. Bromelain also organisms and digest their outer coat. Thus they has been shown to increase blood and tissue levels of defunct the pathogens. The released enzyme-surface antibiotics[68-70]. This potentiation of antibiotics may protein complex is ingested by macrophages and be due to enhanced absorption, as well as increased dendritic cells and it induces higher antibody permeability of the diseased tissue which increases production [51-53]. access of antibiotics to site of infection. Bromelain 2. They reduce number and activity of receptors for might also provide a similar access to specific and pathogen on host cells. Thus pathogen attachment is non-specific components of immune system, therefore,

WebmedCentral > Review articles Page 4 of 13 WMC002495 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 07:57:46 AM enhancing the body's utilization of its own healing Preclinical and Clinical Studies resources. 9. Enzymes such as rutin are powerful anti-oxidants and effectively combat the harmful free radicals such Innumerable studies, controlled or otherwise, as nitric oxide, released during the inflammatory randomized or not, have been conducted to prove process[71, 72]. efficacy and safety of systemic enzymes in infections. 10. Enzymes block pro-inflammatory metabolites that Enzymes have been found useful in following propagate the inflammation. Evidence also suggests conditions- an immunomodulatory and hormone like activity acting 1. Airway infections and inflammations-Serrapeptase via intracellular signalling pathways for bromelain. It has been found to be effective in alleviating thick can inhibit induced T cell production of IL - 4 and to a infected respiratory secretions. Ninety-seven percent lesser degree of the IL-2 and induced IFN-α via of those taking serrapeptase reported good or modulation of the extracellular regulated kinase-2 excellent results compared to 22% in the control (ERK-2) intracellular signaling pathway[73]. Bromelain subjects. In a multi-center, double-blind, randomized significantly reduces CD4 T-lymphocytes of peyer’s study involving 193 participants, serratiapeptidase patches[74]. Hence it ameliorates exaggerated acted rapidly to reduce local inflammation and ease inflammation. Trypsin-chymotrypsin has also been symptoms in people suffering from ear, nose and shown to modulate cytokine levels in burns[75]. throat disorders[87]. Serrapeptase also is beneficial in 11. Cell surface receptors such as hyaluronan patients with bronchitis and other chronic lower airway receptor CD44 is reduced by bromelain. Hence diseases[88, 89]. Combination of trypsin and leukocyte migration and induction of proinflammatory chymotrypsin with antibiotics is effective for mediators declines[56, 76]. Enzymes down-regulate management of acute or chronic non-tubercular and degrade over-expressed inflammatory adhesion bronchopneumonias[90]. Bromelain is effective and molecules. In vitro chemotaxis assay has shown that safe in acute sinusitis. It decreases sinus pain and bromelain decreases chemokine receptor CD128 and throat pain. It changes the consistency of nasal mucus hence there is reduction in neutrophil migration in favourably[47, 70, 91-97]. response to IL-8[77]. 2. Sepsis and septic shock-Enzymes when used in 12. Enzymes activate alpha-2 macroglobulin, the conjunction with appropriate antibiotics can lead to cytokine catcher which usually exists in blood in an early recovery from sepsis in pediatric patients[71]. inactive form (slow form). This in turn promotes faster Papain has also been found to enhance the clearance of cytokine, TNF-α. Thus stimulus for chemotherapeutic efficacy of antibiotics on an average expression of the adhesion molecules is reduced. This by 50% in mice with septicemia[67]. Ishikawa et al assists in minimizing the heightened inflammatory has also shown that bromelain has a protective effect process[78]. when used with antibiotics in experimental infection in 13. Enzymes inhibit platelet aggregation and their mice produced by Streptococcus hemolyticus, adhesion to endothelial cells. Clot formation is Streptococcus pneumoniae and Pseudomonas reduced[63, 79-81]. Enzymes also break down fibrin aeruginosa[98]. deposits and also remove necrotic debris and excess 3. Oro-dental infections- Since 1960s, proteolytic fibrin from the bloodstream[82]. enzymes have been used in stomatology. 14. Enzymes possess anti-secretory and mucolytic Varney-Burch used peroral trypsin and chymotrypsin qualities. They act indirectly to decrease volume and in postdental surgery and found that these enzymes viscosity of infected secretions so that they can be reduced the healing time by 50%[99, 100]. Proteolytic easily coughed out[83-85]. Bromelain’s liquifing enzymes are also found to be useful in dental potential is greater than that of other enzymes. It acts infections. Used as a mouthwash, the enzymes help in by decreasing contents of acid glycoprotein and sialic combating gingivitis and reducing plaque formation in acid in sputum. children and young adults[101, 102]. 15. Enzymes decrease acute phase reactants[86]. 4. Skin and soft tissue infections- Adequate Systemic enzymes thus supplement antibiotics to debridement of wound and burn areas is essential for overcome infections. Enzymes reduce inflammation prevention and management of infections. and beneficially modulate the immune system. They Experimental runs of enzymes as wound debridement have no direct action on the organism per se but can agents have given positive results. Papain-urea, tame the host’s upset immune system in order to papain-urea-chlorophyllin, bromelain, ficin and harness its benefits. bacterial has been extensively

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investigated for use in wound bed HIV infections and found that they improved functional preparation[103-111]. A novel streaming technique ability and weight of patients and are also has been tried in order to improve efficiency of well-tolerated[126]. enzyme solutions to cause early wound debridement 11. Fungal infections- Bromelain has been found to and healing[112]. Bromelain scores over collagenase enhance the killing actity of human white cells against in efficacy and safety as a wound debridement candida albicans[60]. But no clinical studies of use of agent[113]. enzymes in fungal infections could be found. 5. Genito-urinary infections-Enzymes have been 12. Parasitic infections-There are very few studies on studied in urinary tract infections and found to play a role of enzymes in parasitic infections. Enzymes are favourable role. They can also help eradicate found to have a limited role in treatment of intestinal chlamydial infections of prostate[114]. helminthiasis[127-129]. More clinical studies are 6. Joint infections- Intraarticular serratiopeptidase needed to evaluate the role and safety of enzymes as enzyme has also been found useful in eradication of adjuvant therapy in intestinal worms. infection caused by biofilm-forming bacteria in DOSING experimental animal model. The serratiopeptidase The different enzyme preparations available in market group had significantly less persistence of infection as contain different enzyme combinations in different compared to the control group (5.6% s 37.5% strengths/potencies. The strengths are measured in respectively)[65]. grams or milligrams or in units of activity or 7. Viral hepatitis- Oral enzymes have been found to be international units. Food Chemical Codex (FCC) useful in hepatitis B infection. When administered, published by the National Academy Press is the they tended to lead to faster recovery, with early accepted standard for activity units. Plant based normalization of spleen and liver size, and restoration enzymes have more activity, more duration of action of liver function[115-117]. Enzymes are also superior and more pH stability compared with animal based to ribavarin and ?-interferon in hepatitis C patients[118, enzymes. The recommended dose varies according to 119]. the enzyme preparation and the type of disease for 8. Varicella-zoster infection- Various studies have which it is used. Usually 2-4 tablets are taken 2-3 shown that enzyme therapy is beneficial in herpes times a day. But even higher dosages are free of infections. Oral enzymes decreased significantly side-effects. For children, powder forms of enzymes ‘segmental pain’ on day 7 and 14 of the herpes zoster are also available. It is advisable to take enzymes 30 illness, as compared to the virostatic drug, acyclovir. minutes before meals or 2 hours after meals with a Global judgement of the drug by physicians was in sufficient amount of water. favour of the enzymes with similar tolerability in both SAFETY PROFILE groups. Hyperaesthesia and postzosteric neuralgia Enzymes are safe and well-tolerated in all age groups. was also less in enzyme group[120-122]. Billigmann et A lethal dose (LD50) could never be found. There are al in their study found no difference in segmental pain no undesirable adverse effects on bone marrow or in enzyme or acyclovir group, but adverse events were immunological system even with high or prolonged significantly less in enzyme group[123]. Mikazans enzyme administration[35]. Even consumption of 3700 used enzymes per os as well as locally in tablets per day produced only mild diarrhea[130]. herpes-zoster infection and observed that as Harmless alteration in the consistency, colour and compared to oral acyclovir, enzyme therapy reduced odour of stool may occur as a consequence of enzyme clinical symptoms and signs faster and also was free action. Nausea, vomiting, mild abdominal pain may be of any side-effects. Postherpetic neuralgia was also seen in some cases. Pancreatic enzyme may impair less in the enzyme group[124]. folic acid absorption and hence extra folate should be 9. Recurrent laryngeal papillomatosis- In an taken with long-term enzyme supplementation[131]. uncontrolled study, Mudrak et al found that after the High doses of serratippeptidase could cause surgical extirpation of the laryngeal papillomatosis, esophageal ulcers. Its use has also been associated subsequent application of peroral proteases caused a with acute eosinophilic pneumonia[132], subepidermal significant improvement in clinical and laboratory bullous dermatosis and inability to move. results in these patients. Also they were disease-free Serious allergic reaction, anaphylaxis or for 10-18 months[125]. But this result has not been hypersensitivity to enzymes are rare[133, 134]. Papain confirmed by means of a randomized controlled study. can cause problems only in those with papaya or latex 10. Human immunodeficiency virus (HIV)- allergy. Topical papain can cause eruption of painful Auto-antibodies and circulating immune complexes blisters and rashes in some patients. characterize HIV. Jaeger used hydrolytic enzymes in Bromelain has been found to potentiate the action of

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sedative drugs and antibiotics. It can cause changes in evidence-based. Hence future for enzyme therapy heart rate and blood pressure, especially in seems bright. They of course cannot replace hypertensive patients[135]. Seraapeptase also slows antimicrobials in infections but can play in pivotal heart rate and can lead to drowsiness. supportive role in overcoming the infections. More Enzymes can affect the coagulation system and hence randomized and controlled clinical trials on enzymes to it should not be used with blood thinning drugs such further elucidate its clinical potential would be as aspirin, warfarin, or coumadin. They are beneficial. More and widespread dissemination of contraindicated in hemophiliacs, pregnant or nursing knowledge on its clinical utility is required. As more mother, and in severe liver damage. forms and patents on enzymes are produced, and as Animal studies have demonstrated no teratogenic more studies are performed, its use in the day to day effect of enzyme mixtures. Dosages of 1.5 g/kg/day of management of infections would increase. It could bromelain administered to rats showed no play an important role in care of patients with carcinogenic or teratogenic effects. There is no nosocomial infections, especially in geriatric and development of tolerance on prolonged use of pediatric age groups, and in viral and resistant enzymes. infections. Its safety profile, lack of development of CURRENT STATUS resistance and inability to show tolerance would make Thus, enzymes are a useful adjunct to antibiotics in it a preferred supplementary option in elderly and both acute and chronic infections. Studies have shown pediatric population. It could serve as an effective, it to possess a useful role in correcting an ‘upset’ safe and cheap immunotherapeutic aid in infections. immune system. It may be of use in cases where modern pharmoactherapy has very limited role. It Conclusion could minimize morbidity and lead to early recovery from infections. It could enhance the actions of antimicrobials and assist in prompt and better control Systemic enzyme therapy has been shown to be of infections. useful for prevention and treatment of a variety of However, at present, enzymes are used mainly for infections. It holds promise for management of their digestive functions, for gut health, for general patients with infections which are unable to be treated well-being and for decreasing inflammation after with newer antibiotics and antiviral drugs. It could help surgery or trauma. It is being extensively used for where resistance to the antimirobials is high such as in sports injuries and in the orthopedic field. In spite of viral hepatitis and HIV. However, its benefits have not significant positive research on enzymes in infections, been harnessed enough. More clinical studies and its usefulness in infections remains underexploited. It improved awareness amongst the practicing has not been adequately used as supplementation in physicians would be one step forward in helping advanced infections, septic shock, resistant infections mankind overcome the curse of these terrifying and severe illnesses. This could possibly be due to infections. lack of awareness about its benefits amongst the practicing physicians. Research on enzymes has References remained mainly concentrated in Europe and Far East. Also not much literature in English has been published to highlight the efficacy and safety of enzymes in 1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont infections. Besides, since enzymes cannot be G, Carcillo J, Pinsky MR. Epidemiology of severe patented, they are of little interest to drug companies sepsis in the United States: Analysis of incidence, and there is a general unwillingness to use therapies outcome, and associated costs of care. Crit Care Med. not made by ‘big pharma’. There is also still skepticism 2001; 29: 1303-1310 in medical fraternity about findings that proteinases 2. Martin GS, Mannino DM, Eaton S, Moss M. The are absorbed from the gastrointestinal tract in a epidemiology of sepsis in the United States from 1979 functionally intact form, and consequently they deny through 2000 N Engl J Med. 2003; 348; 1546-1554 any efficacy of oral enzymes. 3. Snowden C, Kirkman E. The pathophysiology of FUTURE ROLE sepsis. British Journal of Anaesthesia ( CEPD There exists a remarkable list of clinical studies Reviews ) 2002; 2: 11-14. conforming to Good Clinical Practice(GCP) guidelines 4. Remick DJ. Pathophysiology of sepsis. Am J Path. and performed with polyenzyme drugs, which shows 2007; 170 (5): 1435-1444 that enzymes are beneficial in infections. The 5. Donelly PK. The role of protease in pharmacological efficacy of proteinases is immunoregulation. British Journal of Surgery 1983; 70:

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614-622 inflammation: a double-edged sword. J Leukoc Biol. 6. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein 1994; 56: 672–686 AM, Knaus WA, et al. Definitions for sepsis and organ 21. Watanabe S, Mukaida N, Ikeda N, Akiyama M, failure and guidelines for the use of innovative Harada A, Nakanishi I, et al. Prevention of endotoxin therapies in sepsis. The ACCP/SCCM Consensus shock by an antibody against leucocyte integrin beta 2 Conference Committee. American College of Chest through inhibiting production and action of TNF. Int Physicians/Society of Critical Care Medicine. Chest. Immunol 1995; 7: 1037-1046 1992; 101: 1644-1655 22. Rigato O, Salomao R. Impaired production of 7. Cooper NR. The classical complement pathway: interferon-gamma and tumor necrosis factor-alpha but activation and regulation of the first complement not of interleukin-10 in whole blood of patients with component. Adv Immunol 1985; 37: 151-216 sepsis. Shock. 2003; 19:113–116. 8. Riedemann NC, Guo RF, Neff TA, Laudes IJ, Keller 23. de Boer JP, Creasey AA, Chang A, Abbink JJ, KA, Sarma VJ, et al. Increased C5a receptor Roem D, Eerenberg AJ, Hack CE, Taylor FB. expression in sepsis. J Clin Invest 2002; 110:101-108 Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in 9. Remick DG, Kunkel RG, Larrick JW, Kunkel SL. sepsis: studies using a baboon model. Infect. Immun. Acute in vivo effects of human recombinant tumor 1993; 61 (12): 5035–5043. necrosis factor. Lab Invest. 1987; 56: 583–590. 24. Borth W, Teodorescu M. Inactivation of human 10. Tracey KJ, Beutler B, Lowry SF, Merryweather J, interleukin-2 (IL2) by alpha 2-macroglobulin-trypsin Wolpe S, Milsark IW, et al. Shock and tissue injury complexes. Immunology 1986; 57: 367-371 induced by recombinant human cachectin. Science. 25. James K, Milne I, Cunningham A, Elliot S-F. The 1986; 234: 470–474 effect of alpha2 macroglobulin in commercial cytokine 11. Aderem A, Ulevitch RJ. Toll-like receptors in the assays. Journal of Immunological Methods 1994; 168: induction of the innate immune response. Nature 33-37 2000; 406: 782-787 26. Reddy RC, Chen GH, Tekchandani PK, Standiford 12. Hatherill M, Tibby SM, Turner C, Ratnavel N, TJ. Sepsis-induced immunosuppression: From bad to Murdoch IA. Procalcitonin and cytokine levels: worse. Immunol Res. 2001; 24: 273-287 relationship to organ failure and mortality in pediatric 27. Hotchkiss RS, Karl IE. The Pathophysiology and septic shock Crit Care Med 2000; 28: 2591-2594 Treatment of Sepsis. NEJM. 2003; 348: 138-150 13. Waage A, Halstensen A, Espevik T. Association 28. Wesche DE, Lomas-Neira JL, Perl M, Chung CS, between tumour necrosis factor in serum and fatal Ayala A. Leukocyte apoptosis and its significance in outcome in patients with meningococcal disease. sepsis and shock. J Leukoc Biol. 2005; 78: 325–337 Lancet. 1987; 1:355–357 29. Brown KA, Brain SD, Pearson JD, Edgeworth JD, 14. Cobb AP, Danner RL. Nitric oxide and septic Lewis SM, Treacher DF. Neutrophils in development shock. JAMA. 1996; 275: 1192-1196. of multiple organ failure in sepsis. Lancet. 2006; 15. Fink MP, Heard SO. Laboratory models of sepsis 368:157–169 and septic shock. J Surg Res 1990; 49:186-196. 30. Hatherill M, Tibby SM, Turner C, Ratnavel N, 16. Vervloet MG, Thijs LG, Hack CE. Derangements of Murdoch IA. Procalcitonin and cytokine levels: coagulation and fibrinolysis in critically ill patients with relationship to organ failure and mortality in pediatric sepsis and septic shock. Semin Thromb Haemost. septic shock. Crit Care Med 2000; 28: 2591-2594 1998; 24: 33-44. 31. Waage A, Halstensen A, Espevik T. Association 17. Boehme MWJ, Deng Y, Raeth U, Bierhaus A, between tumour necrosis factor in serum and fatal Ziegler R, Stremmel W, et al. Release of outcome in patients with meningococcal disease. thrombomodulin from endothelial cells by concerted Lancet. 1987; 1:355–357 action of TNF-alpha and neutrophils: in vivo and in 32. Armstrong PB. Proteases and protease inhibitors: vitro studies. Immunology. 1996; 87: 134-140 a balance of activities in host-pathogen interaction. 18. Murakami K, Okajima K, Uchiba M, Johno M, Immunobiology. 2006; 211: 263-281 Nakagaki T, Okabe H, et al. Activated protein C 33. Taussig SJ, Batkin S. Bromelain, the enzyme prevents LPS-induced pulmonary vascular injury by complex of pineapple (Ananus comosus) and its inhibiting cytokine production. Am J Physiol. Lung Cell clinical application: An update. J. Ethnopharmacol Mol Physiol 1997; 272: L197-L202. 1988; 22: 191- 203. 19. Deitch EA. Animal models of sepsis and shock: a 34. Ji LL. Antioxidant enzyme response to exercise review and lessons learned. Shock 1998; 9: 1-11. and aging. Med. Sci. Sports Exerc. 1993; 25(2): 20. Smith JA. Neutrophils, host defense, and 225-231

WebmedCentral > Review articles Page 8 of 13 WMC002495 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 07:57:46 AM

35. Lopez DA, Williams RM, Miehlke M. Enzymes: The 51. Howenstine JA. How systemic enzymes work to Fountain of Life. Charleston SC: The Neville Press, cure diseases.(Clinical report) Original internsit Dec.1. Inc.; 1994 2006 (online format). 36. Prochaska LJ, Nguyen XT, Donat N, Piekutowski 52. Argyris BF. Role of macrophages in antibody WV. Effects of food processing on the thermodynamic production. Immune response to sheep red blood cells. and nutritive value of foods: literature and database The journal of immunology. 1967; 99: 744-750. survey. Med Hypotheses 2000; 54 (2): 254-262 53. Gallily R, Feldman M. The role of macrophages in 37. Stenesh J. Dictionary of Biochemistry and the induction of antibody in X-irradiated animals. Molecular Biology, 2nd Edition, John Wiley and Sons, Immunology 1967; 12 (2): 197-206 Inc: NJ.; 1989 (201): 748-6011 54. Chandlera DS, Mynott TL. Bromelain protects 38. Prochaska LJ; Piekutowski WV. On the synergistic piglets from diarrhoea caused by oral challenge with effects of enzymes in food with enzymes in the human K88 positive enterotoxigenic Escherichia coli. Gut body. A literature survey and analytical report. Med 1998; 43: 196-202 Hypotheses 1994; 42 (6): 355-362 55. Thomson AB, Keelan M, Thiesen A, Clandinin MT, 39. Smyth RD, Brennan R, Martin GJ. Studies Ropeleski M, Wild GE. Small bowel review: normal establishing the absorption of (proteolytic physiology. Part 1. Digestive Dis , Science 2001; 46: enzymes) from the gastrointestinal tract. Exp Med 2567-2587 Surg. 1964; 22: 46-59 56. Engwerda CR, Andrew D, Ladhams A, Mynott TL. 40. Castell JV, Friedrich G, Kuhn CS, Poppe GE. Bromelain modulates T cell and B cell immune Intestinal absorption of undegraded proteins in men: responses in vitro and in vivo. Cell Immunol 2001; 210 presence of bromelain in plasma after oral intake. Am (1): 66-75 J Physiol. 1997; 273: G139-G146 57. Barth H, Guseo A, Klein R. In vitro study on the 41. Ambrus JL, Lassman HB, DeMarchi EP. immunological effect of bromelain and trypsin on Absorption of exogenous and endogenous proteolytic mononuclear cells from humans. Eur J Med Res enzymes. Clin Pharmacol Therap 1967; 8: 362-368 2005; 10: 325-331 42. Kabacoff BL, Wohlman A, Umhey M, Avakian S. 58. Rose B, Herder C, Löffler H, Meierhoff G, Schloot Absorption of chymotrypsin from the intestinal tract. NC, Walz M, Martin S. Dose-dependent induction of Nature 1963; 199: 815-817 IL-6 by plant-derived proteases in vitro Clinical & 43. Martin GJ, Bogner RL, Edleman A. Further in vivo Experimental Immunology 2006; 143 (1): 85-92 observations with radioactive trypsin. Am J Pharm 59. Jordan FM. Enzymes-digestive and 1964; 129: 386-392 proteolytic-now an endangered species. Immunition 44. Avakian S. Further studies on the absorption of report. 2010; 5 (3) (online format). chymotrypsin. Clin Pharmacol Therap 1964; 5: 60. Brakebusch M, Wintergerst U, Petropoulou T, 712-715 Notheis G, Husfeld L, Belohradsky BH et al. Bromelain 45. Liebow C, Rothman SS: Enteropancreatic is an accelerator of phagocytosis, respiratory burst circulation of digestive enzymes. Science 1975; 189: and Killing of Candida albicans by human 472-474 granulocytes and monocytes. Eur J Med Res 2001; 6 46. White RR Bioavailability of 125I bromelain after (5): 193- 200 oral administration to rats. Biopharm Drug Dispos 61. Ekerot LK, Ohlsson K, Necking L. Elimination of 1988; 9(4): 397-403 protease-inhibitor complexes from the arthritic joint. Int 47. Taussig SJ. The mechanism of the physiological J Tissue React 1985; 7 (5): 391-395 action of bromelain. Medical hypotheses. 1980; 6(1): 62. Steffen C, Menzel J. Enzyme breakdown of 99-104 immune complexes. Rheumatol. 1983; 42: 249-255 48. White RR Bioavailability of 125I bromelain after 63. Kleine MW. Introduction to systemic enzyme oral administration to rats. Biopharm Drug Dispos therapy and results of experimental trials. In: Hermans 1988; 9(4): 397-403 GPH, Mosterd WL, editors. Sports, Medicine and 49. Nassif EG, Younoszai MK, Weinberger MM, Nassif Health. Amsterdam: Excerpta Medica; 1990: 1131 CM. Comparative effects of antacids, enteric coating, 64. Wilhelmi, G. Effect of and bile salts on the efficacy of oral pancreatic O-(beta-hydroxyelthyl)-rutiside on wound healing in enzyme therapy in cystic fibrosis. J Pediatr. 198; the rat. J Pharmacology 1979; 19(2): 82-85 98(2): 320-323 65. Mecikoglu M, Saygi B, Yildirim Y, Karadag-Saygi E, 50. Borth W. Alpha 2-macroglobulin, a multifunctional Ramadan SS, Esemenli T. The effect of proteolytic binding protein with targeting characteristics. The enzyme serratiopeptidase in the treatment of FASEB Journal 1992; 6: 3345-3353 experimental implant-related infection. J Bone Joint

WebmedCentral > Review articles Page 9 of 13 WMC002495 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 07:57:46 AM

Surg Am 2006; 88 (6): 1208-1214 16-22 66. Selan L, Berlutti F, Passariello C, Comodi-Ballanti 79. Heinicke RM, Van der Wal M, Yokoyama MM. MR, Thaller MC. Proteolytic enzymes: a new treatment Effect of bromelain on human platelet aggregation. strategy for prosthetic infections? Antimicrob Agents Experientia 1972; 28: 844-845 Chemother. 1993; 37(12): 2618-2621 80. Morita AH, Uchida DA, Taussig SJ. 67. Baskanchiladze GSh, Khurtsilava LA, Gelovani IA, Chromatographic fractionation and characterization of Asatiani MV, Rossinskii VI. Chemotherapeutic the active platelet aggregation inhibitory factor from effectiveness of antibiotics in combination with papain bromelain. Arch Inter Phar Ther 1979; 239: 340-350 in experimental septicemia. Antibiotiki. 1984; 29(1): 81. Metzig C, Grabowska E, Eckert K, Rehse K, 33-35 Maurer HR. Bromelain Proteases reduce human 68. Tinozzi S, Venegoni A. Effect of bromelain on platelet aggregation in vitro, adhesion to bovine serum and tissue levels of amoxycillin. Drugs Expt Clin endothelial cells and thrombus formation in rat vessels Res 1978; 4: 39-44. in vivo. In Vivo 1999; 13(1): 7-12 69. Luerti M, Vignali ML. Influence of bromelain on 82. Urano T, Ihara H, Umemura K, Suzuki Y, Oike M, penetration of antibiotics in uterus, salpinx and ovary. Akita S, et al. The profibrinolytic enzyme subtilisin NAT Drugs Expt Clin Res 1978; 4: 45-48. purified from Bacillus subtilis cleaves and inactivates 70. Neubauer RA. A plant protease for potentiation of plasminogen activator inhibitor type 1. J Biol Chem and possible replacement of antibiotics. Exp Med Surg 2001; 276 (27): 24690-24696 1961; 19: 143-160 83. Hunter RG, Henry GW, Heinicke RM. The action of 71. Shahid SK, Turakhia NH, Kundra M, Shanbag P, papain and bromelain on the uterus. Am J Ob Gyn Daftary GV, Schiess W. Efficacy and safety of 1957; 73: 867-873 Phlogenzym-A protease formulation, in sepsis in 84. Suzuki K, Niho T, Yamada H, Yamaguchi K, children. JAPI. 2002; 50: 527-531. Ohnishi H. Experimental study of the effects of 72. La Cassa C, Villegas I, Alacron de la Lastra C, bromelain on the sputum consistency in rabbits. Motilva V, Martin Calero MJ. Evidence for protective Nippon Yakurigaku Zasshi 1983; 81: 211-216 and antioxidant properties of rutin, a natural flavone, 85. Mynott TL, Guandalini S, Raimondi F, Fasano A. against ethanol induced gastric lesions. J Bromelain prevents secretion caused by Vibrio Ethnopharmacol. 2000; 71: 45-53 cholerae and Escherichia coli enterotoxins in rabbit 73. Mynott TL, Ladhams A, Scarmato P, Engwerda ileum in vitro. Gastroenterol. 1997; 113: 175-184 CR. Bromelain, from pineapple stems, proteolytically 86. Fisher JD, Weeks RL, Curry WM, Hrinda ME, blocks activation of extracellular regulated kinase-2 in Rosen LL. Effects of an oral enzyme preparation, T cells. J. Immunol. 1999; 163: 2568-2575 Chymoral, upon serum proteins associated with injury 74. Manhart N, Akomeah R, Bergmeister H, Spittler A, (acute phase reactants) in man. J Med 1974; 5(5): Ploner M, Roth E. Administration of proteolytic 258-273 enzymes bromelain and trypsin diminish the number of 87. Mazzone A, Catalani M, Constanzo M, Drusian A, CD4+ cells and interferon-gamma response in Peyer's Mandoli A, Russo S, et al. Evaluation of Serratia patches and spleen in endotoxemic balb/c mice. Cell. peptidase in acute or chronic inflammation of Immunol. 2002; 2: 113-119 otorhinolaryngolog pathology: a multicentre, 75. RaviKumar, T., Ramakrishnan, M., Jayaraman, V., double-blind, randomized trial versus placebo. J Int and Babu, M. Effect of trypsin-chymotrypsin (Chymoral Med Res 1990;18(5): 379-388 Forte D.S.) preparation on the modulation of cytokine 88. Nakamura S, Hashimoto Y, Mikami M, Yamanaka levels in burn patients. Burns 2001; 27(7): 709-716 E, Soma T, Hino M, et al. Effect of the proteolytic 76. Hale LP, Greer PK, Sempowski GD. Bromelain enzyme serrapeptase in patients with chronic airway treatment alters leukocyte expression of cell surface disease. Respirology 2003; 8 (3): 316-320 molecules involved in cellular adhesion and activation. 89. Braga PC, Moretti M, Piacenza A, Montoli CC, Clin. Immunol 2002; 104: 183-190 Guffanti EE. Effects of seaprose on the rheology of 77. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. bronchial mucus in patients with chronic bronchitis. A Bromelain treatment decreases neutrophil migration to double-blind study vs placebo. Int J Clin Pharmacol sites of inflammation. Clin Immunol. 2008; 128(1): Res 1993; 13 (3): 179-185 66-74 90. Rampazzo F. A new drug combination for the 78. Schaefer U, Brücker B, Elbers A, Neugebauer E. treatment of non-tubercular acute and chronic The capacity of ?2-macroglobulin to inhibit an bronchopneumopathies. Kango. 1966; 18 (1): 113. exogenous protease is significantly increased in 91. Kelly GS. Bromelain: a literature review and critically ill and septic patients. Shock. 2004; 22(1): discussion of its therapeutic applications. Alt Med

WebmedCentral > Review articles Page 10 of 13 WMC002495 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 07:57:46 AM

Review 1996; 1(4): 243-257 wounds using proteolytic enzymes derived from 92. Braun JM, Schneider B, Beuth HJ. Therapeutic Antarctic krill. Wound Repair Regen 1998; 6:50-57. use, efficiency and safety of the proteolytic pineapple 107. Falabella AF, Carson P, Eaglstein WH, Falanga enzyme Bromelain-POS in children with acute sinusitis V. The safety and efficacy of a proteolytic ointment in in Germany. In Vivo 2005; 19 (2): 417-421 the treatment of chronic ulcers of the lower extremity J 93. SeltzerAP. Adjunctive use of bromelains in Am Acad Dermatol 1998; 39:737-740 sinusitis. Eye Ear Nose Throat Monthly 1967; 108. Hebda PA, Flynn KJ, Dohar JE. Evaluation of the 46:1281-1288 efficacy of enzymatic debriding agents for removal of 94. Taub SJ. The use of Ananase in sinusitis-a study necrotic tissue and promotion of healing in porcine of 60 patients. Eye Ear Nose Throat Monthly 1966; 45: skin wounds Wounds 1998; 10: 83-96 96-98 109. Alvarez OM, Fernandez-Obregon A, Rogers RS, 95. Grossan M. Enhancing the Mucociliary System. Bergamo L, Masso J, Black M. Chemical debridement Advance for Respiratory Care Practitioners. 1995; 8: of pressure ulcers: A prospective, randomized, 12-13 comparative trial of collagenase and papain/urea 96. Grossan M. Nasal function: office measurement of formulations. Wounds 2000; 12: 15-25 nasal mucociliary clearance. In: English Grossan M, 110. Pullen R, Popp R, Volkers P, Fusgen I. ed. Otolaryngology. Vol 2. Chapter 7. Philadelphia, PA: Prospective randomized double-blind study of the Lippincott Williams & Wilkins; 1994 wound-debriding effects of collagenase and 97. Majima Y, Inagaki M. The effect of an orally fibrinolysin/ deoxyribonuclease in pressure ulcers. Age administered proteolytic enzyme on the elasticity and and Ageing 2002; 31: 126-130 viscosity of nasal mucus. Archives of 111. Taussig SJ. Bromelain: a proteolytic enzyme and Oto-Rhino-Laryngology 1988; 244: 335-359 its clinical application. Hiroshima J Med Sci 1975; 98. Ishikawa H, Oguro Y. Protective effect of 24:185-193 stem-bromelain in combination with antibiotics on 112. Yaakobi T, Roth D, Chen Y, Freeman A. experimental infection in mice induced by Streaming of Proteolytic Enzyme Solutions for Wound Streptococcus hemolyticus, Diplococcus pneumoniae, Debridement: A Feasibility Study. Wounds. 2004; or Pseudomonas aeruginosa. Jpn J Antibiot. 1974; 16(6): 201-205 27(2): 118-121 113. Maurer HR. Bromelain: biochemistry, 99. Varney-Burch M. An evaluation of an oral pharmacology and medical use. Cellular and anti-inflammatory enzyme in dental surgery. Dent. Molecular Life Sciences 2001; 58(9): 1234-1245 Mag. 1962; 2: 102–104 114. Mori S, Ojima Y, Hirose T, Sasaki T, Hashimoto 100. Forrest WI, Goodridge DL, Watson AM, Starkey Y. The clinical effect of proteolytic enzyme containing WE. Double-blind clinical trials of proteolytic enzyme bromelain and trypsin on urinary tract infection therapy in oral surgery. Br J Oral Surg. 1968; 6(1): evaluated by double blind method. Acta Obstet 7-10 Gynaecol Jpn. 1972; 19(3): 147-153 101. Formicola AJ, Grupe HE Jr., Bradley EL Jr., 115. Patney NL, Pachori S. A Study of Serum Weatherford TW III, Hunt DE. A clinical evaluation of a Glycolytic Enzymes and Serum B Hepatitis in Relation proteolytic enzyme mouthwash on plaque and to LIV.52 Therapy Medicine and Surgery 1986; 26 (4): gingivitis in children. NY State Dent J. 1972; 38(6): 9-16 334-340 116. Romanova SV, Shabunina EI, Pereslegina IA, 102. Robinson RJ, Stoller NH, Vilardi M, Cohen DW. Tolkacheva NI. Influence of WobenzymR therapy on Clinical evaluation of the effect of a proteolytic enzyme immune and metabolic parameters in children with mouthwash on plaque and gingivitis in young adults. chronic hepatitis B. Int J Immunother 1997; 13 (2-4): Community Dent Oral Epidemiol. 1975; 3(6): 271-275 99-100 103. Brett DW. Chlorophyllin--A Healer? A Hypothesis 117. Vassilenko AM, Fessenko VI, Schvets SV. for its Activity. Wounds 2005; 17(7): 190-195 Efficacy of systemic enzyme therapy in the treatment 104. Falanga V. Wound bed preparation and the role of patients with chronic hepatitis B. Int J of enzymes: A case for multiple actions of therapeutic Immunotherapy 2001; 17(2/3/4): 93-97 agents. Wounds 2002; 14: 47-57 118. Romanova SV, Shabunina EI, Pereslegina IA, 105. Klasen HJ. A review on the nonoperative removal Tolkacheva NI. Influence of WobenzymR therapy on of necrotic tissue from burn wounds. Burns 2000; 26: immune and metabolic parameters in children with 207-222. chronic hepatitis B. Int J Immunother 1997; 13 (2-4): 106. Mekkes JR, LePoole IC, Das PK, Bos JD, 99-100 Westerhof W. Efficient debridement of necrotic 119. Vassilenko AM, Fessenko VI, Schvets SV.

WebmedCentral > Review articles Page 11 of 13 WMC002495 Downloaded from http://www.webmedcentral.com on 23-Dec-2011, 07:57:46 AM

Efficacy of systemic enzyme therapy in the treatment (7): 540-544 of patients with chronic hepatitis B. Int J 133. Wuthrich B. Proteolytic enzymes: potential Immunotherapy 2001; 17(2/3/4): 93-97 allergens for the skin and respiratory tract? Hautarzt 120. Kleine MW. Comparison between an oral 1985; 36: 123-125 hydrolytic enzyme combination and oral acyclovir in 134. Gailhofer G, Wilders-Truschnig M, Smolle J, the treatment of acute zoster: a double-blind, Ludvan M. Asthma caused by bromelain: an controlled multicentre trial. Journal of the European occupational allergy. Clin Allergy 1988;18: 445-450 Academy of Dermatology and Venereology 2006; 2(4): 135. Gutfreund A, Taussig S, Morris A. Effect of oral 296 – 307 bromelain on blood pressure and heart rate of 121. Bartsch W. Proteolytic enzymes in the treatment hypertensive patients. Haw Med Jour 1978; 37: of herpes zoster. Der Informierte Arz 1974; 2(10): 1-7. 143-146 122. Kleine MW, Stauder GM, Beese EW: The intestinal absorption of orally administered hydrolytic enzymes and their effects in the treatment of acute herpes zoster as compared with those of oral acyclovir therapy. Phytomedicine 1995; 2: 7-15 123. Billigmann P. Enzyme therapy—an alternative in treatment of herpes zoster. A controlled study of 192 patients. Fortschritte der Medizin 1995; 113(4): 43-48 124. Mikazans I. Possibility to treat Herpes zoster using enzymes. Journal of Dermatology 1997; 38 (2):15-20 125. Mudrak J, Bobak L, Sebova I. Adjuvant therapy with hydrolytic enzymes in recurrent laryngeal papillomatosis. Acta Otolaryngol Suppl. 1997; 527: 128-130 126. Jaeger H. Hydrolytic Enzymes in the Treatment of HIV Infections. Allgemeinmedizin 1990; 19: 160-164 127. Stepek G, Buttle DJ, Duce IR, Lowe A, Behnke JM. Assessment of the anthelmintic effect of natural plant cysteine proteinases against the gastrointestinal nematode, Heligmosomoides polygyrus, in vitro. Parasitology 2005; 130 (Pt 2): 203-211. 128. Stepek G, Lowe AE, Buttle DJ, Duce IR, Behnke JM. In vitro and in vivo anthelmintic efficacy of plant cysteine proteinases against the rodent gastrointestinal nematode, Trichuris muris. Parasitology. 2006;132 (Pt 5):681-689 129. Bumbaloab TS, Gustinaab FJ, Oleksiakab RE. The treatment of pinworm infection (enterobiasis) with papain. The Journal of Pediatrics. 1953; 42 (5): 576-579 130. Friess H., Kleeff J., Malfertheiner P, Muller MW, Homuth K, Buchler MW. Influence of high-dose pancreatic enzyme treatment on pancreatic function in healthy volunteers. Int. J Pancreatol. 1998; 23 (2):115-123 131. Russell RM, Dutta SK, Oaks EV, Rosenberg IH, Giovetti AC. Impairment of folic acid absorption by oral pancreatic extracts. Dig Dis Sci. 1980; 25: 369-373 132. Sasaki S, Kawanami R, Motizuki Y, Nakahara Y, Kawamura T, Tanaka A et al. Serrapeptase-induced lung injury manifesting as acute eosiniphilic pneumonia. Nihon Kokyuki Gakkai Zasshi 2000; 38

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