Role of Systemic Enzymes in Infections

Article ID: WMC002504 ISSN 2046-1690

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

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

Previous Article Reference: http://www.webmedcentral.com/article_view/2495 Article ID: WMC002504 Article Type: Review articles Submitted on:12-Jan-2012, 05:47:48 PM GMT Published on: 13-Jan-2012, 06:15:10 PM GMT Article URL: http://www.webmedcentral.com/article_view/2504 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 2012;3(1):WMC002504 Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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 Κ 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 enzyme 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 on also been shown to be harmful. Such suboptimal 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 β2-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 proteases and nitric oxide which cultures and its enzyme bromelain 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, papain, on endothelial cells and monocytes. This initiates the protease, 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 mediator /system /pathway into the hydrolase class (class 3) which includes /pathogen drives the pathophysiology of sepsis, but it peptid-hydrolase group (3.4) which comprises is a composite output. Complex endothelial-leukocyte aminopeptidases (3.4.1), carboxypeptidases (3.4.2), interactions are essential for sustaining an dipeptidases (3.4.3) and proteinases (3.4.4) [37]. inflammatory response. Carefully timed sequence of Enzymes for pharmaceutical uses are harnessed from molecular expression regulate these interactions. plants, fungi, bacteria and animals. They act after Simultaneous release of pro- and anti-inflammatory internal absorption and function best at specific elements is seen. The equilibrium between these two temperature and pH[35]. Hence processing, handling contrasting signals is vital for recovery from and storage of the enzymes should be proper. The infection[32]. This process is meant to be reparative, various enzymes known to be useful in infections are but there is always a risk for it to turn as follows: Bromelain from pineapple stems ( Ananas counterproductive. Systemic enzyme therapy has comosus), catalase, chymotrypsin from ox bile, krillase 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, effects with little efforts. They act at multiple sites of protease, bioflavinoid rutin, serratiopeptidase or the immune system to enhance it and diminish on serrapeptase derived from nonpathogenic inflammation. They normalize ‘a derailed immune enterobacteria, Serratia E15, and trypsin. V-8 protease system’ and hence aid in control and elimination of (from Staphylococcus aureus), pronase (from infection. They are supposed to act in the following Staphylococcus griseus), Subtilisin, ficin from Ficus ways: tree latex have also been investigated in various 1. The enzymes cleave the antigenic surface protein of infections. organisms and digest their outer coat. Thus they These enzymes are highly substrate specific. Hence defunct the pathogens. The released enzyme-surface combination of them has a better and synergistic protein complex is ingested by macrophages and effect[38]. Various enzyme combinations for infection dendritic cells and it induces higher antibody and inflammation exist in the market such as Vitalzym, production [52-54]. Phlogenzym, Medizym, Wobenzym, Wobe-mugos, 2. They reduce number and activity of receptors for Chymotrypsin and trypsin combinations, pathogen on host cells. Thus pathogen attachment is serratiopeptidase, and papain-urea skin creams with hampered and infectivity decreases. For example, or without chlorophyllin. Bromelain can disrupt Enterotoxigenic Escherichia ABSORPTION OF ENZYMES Coli (ETEC) receptors in vivo and protect against The initial myth that enzymes are not absorbed by gut ETEC induced diarrhea[55, 56]. has been refuted by numerous animal and human 3. They detoxify blood and remove viruses from studies[39-46]. Absorption of intact enzymes into rest circulation.They act as a "biological vacuum cleaners" of body is possible by pinocytosis or by uptake by eliminating impurities, foreign proteins, immune ‘roaming’ lymphocytes in the small intestinal lumen complexes and harmful micro-organisms from the which are again released into the gut wall. This is blood stream and tissues. This greatly diminishes the similar to the uptake of antibodies (gammaglobulins) inflammatory response and allows the normal immune into the child’s lymphatic system and blood stream functions to operate at a much healthier level. from the mother’s milk. Substantial proportion of 4. Enzymes cause enhancement of immune cells to bromelain is also absorbed[47]; highest concentration kill bacteria, viruses, molds and fungi[57]. Bromelain being present in blood 1 hour after administration[46]. increases proliferation of peripheral blood Enzymes are likely to be destroyed by acidic gastric mononuclear cells. Production of IL-6, milieu and enteric-coating protects them from granulocyte-monocyte-colony stimulating factor annihilation and improves their bioavailability[48]. In (GM-CSF), TNF-α and type 1 cytokine IFN-γ the small intestine, the released enzymes are production, but not of type 2 cytokines IL-4 and IL-5 absorbed by above mechanisms into portal vein and are increased[58]. This induction is lymph. Studies have shown that brush border dose-dependent[59]. Macrophage activity is enhanced membrane bound enzymes do not degrade the up to 700 percent with a combination of enzymes therapeutically administered enzymes. Galenic pancreatin, papain, bromelain, trypsin and preparations of these enzymes with bioadhesive chymotrypsin[60]. Phagocytosis is also polymers such as hydroxyethylcellulose or slightly accelerated[61]. modified chitosan-EDTA further increases stability of 5. Enzymes break down immune complexes which them against proteolytic degradation [49]. Metabolic block the immune cells[35]. They dissolve immune transformation by liver cells (first pass metabolism) complex by removing Fc part of immunoglobulin and does decrease the enzyme concentration in blood but eliminate immune complexes from circulation[62, 63]. administration of larger doses per orally achieves In the early phase, there may be worsening of the optimal concentration of the enzyme in blood and situation due to release of immune complexes fixed to brings about the required actions [50]. Special blood tissues into the blood (Jarisch-Herxheimer effect). factors such as the antiproteinase, a2-macroglobulin 6. They accelerate the volume and fluidity of blood act as carrier for the enzymes and prevents them from flow[64]. This facilitates elimination of inflammatory digesting the blood proteins. Also these enzymes are products. Vascular endothelium is also stabilised[65]. protected from being acted upon by the blood 7. Enzymes such as bromelain modulate arachidonate proteases. They circulate in the body acting on their pathway in such a way that thromboxane production is appropriate substrates[51]. 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].

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8. Enzymes such as Serrapeptase enhance the qualities. They act indirectly to decrease volume and bactericidal effect of antibiotics in cultures and viscosity of infected secretions so that they can be prevents the formation of biofilms. This is valuable in easily coughed out[84-86]. Bromelain’s liquifing treating problematic prosthetic infections[66, 67]. potential is greater than that of other enzymes. It acts Papain has also been found to enhance by decreasing contents of acid glycoprotein and sialic chemotherapeutic efficacy of antibiotics on an average acid in sputum. by 50% in mice with septicemia[68]. Bromelain also 15. Enzymes decrease acute phase reactants[87]. has been shown to increase blood and tissue levels of Systemic enzymes thus supplement antibiotics to antibiotics[69-71]. This potentiation of antibiotics may overcome infections. Enzymes reduce inflammation be due to enhanced absorption, as well as increased and beneficially modulate the immune system. They permeability of the diseased tissue which increases have no direct action on the organism per se but can access of antibiotics to site of infection. Bromelain tame the host’s upset immune system in order to might also provide a similar access to specific and harness its benefits. non-specific components of immune system, therefore, 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[72, 73]. 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 via intracellular signalling pathways for bromelain. It -Serrapeptase has been found to be effective in can inhibit induced T cell production of IL - 4 and to a alleviating thick infected respiratory secretions. lesser degree of the IL-2 and induced IFN-γ via Ninety-seven percent of those taking serrapeptase modulation of the extracellular regulated kinase-2 reported good or excellent results compared to 22% in (ERK-2) intracellular signaling pathway[74]. Bromelain the control subjects. In a multi-center, double-blind, significantly reduces CD4 T-lymphocytes of peyer’s randomized study involving 193 participants, patches[75]. Hence it ameliorates exaggerated serratiapeptidase acted rapidly to reduce local inflammation. Trypsin-chymotrypsin has also been inflammation and ease symptoms in people suffering shown to modulate cytokine levels in burns[76]. from ear, nose and throat disorders[88]. Serrapeptase 11. Cell surface receptors such as hyaluronan also is beneficial in patients with bronchitis and other receptor CD44 is reduced by bromelain. Hence chronic lower airway diseases[89, 90]. Combination of leukocyte migration and induction of proinflammatory trypsin and chymotrypsin with antibiotics is effective mediators declines[57, 77]. Enzymes down-regulate for management of acute or chronic non-tubercular and degrade over-expressed inflammatory adhesion bronchopneumonias[91]. 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, 71, 92-98]. response to IL-8[78]. 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[72]. inactive form (slow form). This in turn promotes faster Papain has also been found to enhance the clearance of cytokine, TNF-a. Thus stimulus for chemotherapeutic efficacy of antibiotics on an average expression of the adhesion molecules is reduced. This by 50% in mice with septicemia[68]. Ishikawa et al has assists in minimizing the heightened inflammatory also shown that bromelain has a protective effect process[79]. 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[64, 80-82]. Enzymes also break down fibrin aeruginosa[99]. deposits and also remove necrotic debris and excess 3.Oro-dental infections- Since 1960s, proteolytic fibrin from the bloodstream[83]. enzymes have been used in stomatology. 14. Enzymes possess anti-secretory and mucolytic Varney-Burch used peroral trypsin and chymotrypsin

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in postdental surgery and found that these enzymes of any side-effects. Postherpetic neuralgia was also reduced the healing time by 50%[100, 101]. Proteolytic less in the enzyme group[125]. enzymes are also found to be useful in dental 9.Recurrent laryngeal papillomatosis- In an infections. Used as a mouthwash, the enzymes help in uncontrolled study, Mudrak et al found that after the combating gingivitis and reducing plaque formation in surgical extirpation of the laryngeal papillomatosis, children and young adults[102, 103]. subsequent application of peroral proteases caused a 4.Skin and soft tissue infections- Adequate significant improvement in clinical and laboratory debridement of wound and burn areas is essential for results in these patients. Also they were disease-free prevention and management of infections. for 10-18 months[126]. But this result has not been Experimental runs of enzymes as wound debridement confirmed by means of a randomized controlled study. agents have given positive results. Papain-urea, 10.Human immunodeficiency virus (HIV)- papain-urea-chlorophyllin, bromelain, ficin and Auto-antibodies and circulating immune complexes bacterial collagenase has been extensively characterize HIV. Jaeger used hydrolytic enzymes in investigated for use in wound bed HIV infections and found that they improved functional preparation[104-112]. A novel streaming technique ability and weight of patients and are also has been tried in order to improve efficiency of well-tolerated[127]. enzyme solutions to cause early wound debridement 11.Fungal infections- Bromelain has been found to and healing[113]. Bromelain scores over collagenase enhance the killing actity of human white cells against in efficacy and safety as a wound debridement candida albicans[61]. But no clinical studies of use of agent[114]. 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[115]. helminthiasis[128-130]. 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)[66]. grams or milligrams or in units of activity or 7.Viral hepatitis- Oral enzymes have been found to international units. Food Chemical Codex (FCC) be 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[116-118]. Enzymes are also superior and more pH stability compared with animal based to ribavarin and a-interferon in hepatitis C patients[119, enzymes. The recommended dose varies according to 120]. 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[121-123]. 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[124]. Mikazans enzyme administration[35]. Even consumption of 3700 used enzymes per os as well as locally in tablets per day produced only mild diarrhea[131]. 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

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seen in some cases. Pancreatic enzyme may impair patented, they are of little interest to drug companies folic acid absorption and hence extra folate should be and there is a general unwillingness to use therapies taken with long-term enzyme supplementation[132]. not made by ‘big pharma’. There is also still skepticism High doses of serratippeptidase could cause in medical fraternity about findings that proteinases esophageal ulcers. Its use has also been associated are absorbed from the gastrointestinal tract in a with acute eosinophilic pneumonia[133], subepidermal functionally intact form, and consequently they deny bullous dermatosis and inability to move. any efficacy of oral enzymes. Serious allergic reaction, anaphylaxis or FUTURE ROLE hypersensitivity to enzymes are rare[134, 135]. Papain There exists a remarkable list of clinical studies can cause problems only in those with papaya or latex conforming to Good Clinical Practice(GCP) guidelines allergy. Topical papain can cause eruption of painful and performed with polyenzyme drugs, which shows blisters and rashes in some patients. that enzymes are beneficial in infections. The Bromelain has been found to potentiate the action of pharmacological efficacy of proteinases is 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[136]. 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 andFar 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

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Reviews Review 1

Review Title: Enzymes in infections

Posted by Dr. bhumika desai on 21 Feb 2012 01:46:10 PM GMT

1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Yes 3 Is this a new and original contribution? Yes 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase No the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? No 8 Is the quality of the diction satisfactory? Yes 9 Are the illustrations and tables necessary and acceptable? Yes 10 Are the references adequate and are they all necessary? Yes 11 Are the keywords and abstract or summary informative? Yes

Rating: 9 Comment: An excellent review on role of enzymes in infections. It could serve as an harbinger for further research in the field.

Competing interests: none Invited by the author to make a review on this article? : Yes Experience and credentials in the specific area of science: alternative medicine

Publications in the same or a related area of science: No How to cite: desai b.Enzymes in infections[Review of the article 'Role of Systemic Enzymes in Infections ' by ].WebmedCentral 1970;3(2):WMCRW001514

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Review 2

Review Title: Enzymes in infections

Posted by Dr. jaspal mehta on 19 Jan 2012 12:49:13 PM GMT

Rating: 9 Comment: The article is an excellent review highlighting the various positive benefits of enzymes in treatment of infectious diseases. Usage of enzymes as supplementary aids in infections needs to be propagated. More studies with various enzyme combinations would be fruitful.

Invited by the author to make a review on this article? : Yes Experience and credentials in the specific area of science: supports enzymes and alternative modes of treatment

Publications in the same or a related area of science: No How to cite: mehta j.Enzymes in infections[Review of the article 'Role of Systemic Enzymes in Infections ' by ].WebmedCentral 1970;3(1):WMCRW001404

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Review 3

Review Title: Role of Enzymes Reduces Infection Severity

Posted by Dr. Bill Misner on 13 Jan 2012 10:35:53 PM GMT

1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Yes 3 Is this a new and original contribution? No 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase Yes the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? No 8 Is the quality of the diction satisfactory? Yes 9 Are the illustrations and tables necessary and acceptable? Yes 10 Are the references adequate and are they all necessary? Yes 11 Are the keywords and abstract or summary informative? Yes

Rating: 8 Comment: This paper is a brilliant review discussing a variety of pathways systemic enzymes reduce the severity of infection. The author posed serious comments supporting a real adjunct supporting pharmacology resolution of infections. The problem for Enzyme dose is transtion beyond first pass metabolism, which the author addressed proposing enteric-coating protocols.

As a WMC lead faculty, I salute Dr. Sukhbir Shahid 's manuscript, an excellent review of a seldom-discussed/neglected treatment regimen.

Well-done!

Dr. Bill Misner PhD {Emeritus}

Competing interests: None. Invited by the author to make a review on this article? : No Experience and credentials in the specific area of science: American Alternative Medical Association Commission on Certification {Board Certified Alternative Medicine Practitioner}

Ph.D. Holistic Nutrition

M.S. Holistic Nutrition

Publications in the same or a related area of science: Yes References: Misner B., & Cranton E., Endurance Performance Gains Following Intravenous EDTA Chelation Therapy In A Healthy 60-year Old Athlete. CLINICAL PRACTICE OF ALTERNATIVE MEDICINE, Volume 2, Number 2, Summer 2001: Pages 135 & 136. Bagchi D, Misner B, Bagchi M, Kothari SC, Downs BW, Fafard RD, Preuss HG. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a

Webmedcentral > Review articles Page 15 of 17 WMC002504 Downloaded from http://www.webmedcentral.com on 21-Feb-2012, 02:00:01 PM mechanistic exploration. Int J Clin Pharmacol Res. 2002;22(3-4):101-10. PMID: 12837047 [PubMed - indexed for MEDLINE] Misner, B. Food alone may not provide sufficient micronutrients for preventing deficiency. Journal of the International Society of Sports Nutrition. 3(1):51-55, 2006. How to cite: Misner B.Role of Enzymes Reduces Infection Severity[Review of the article 'Role of Systemic Enzymes in Infections ' by ].WebmedCentral 1970;3(1):WMCRW001377

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