Review articles
 

By Dr. Sukhbir Shahid
Corresponding Author Dr. Sukhbir Shahid
Pediatrics, - India
Submitting Author Dr. Sukhbir Shahid
COMPLEMENTARY MEDICINE

Enzymes, Systemic enzymes, Infections, Sepsis, Proteolytic, Supplementary

Shahid S. Role of Systemic Enzymes in Infections. WebmedCentral COMPLEMENTARY MEDICINE 2011;2(11):WMC002495
doi: 10.9754/journal.wmc.2011.002495
No
Click here
Submitted on: 22 Nov 2011 08:16:56 AM GMT
Published on: 22 Nov 2011 02:34:00 PM GMT

Abstract


Enzymes are complex macromolecules of amino-acids which bio-catalyse various body processes. Adequate concentrations of enzymes are essential for optimal functioning of the immune system. During infections, body’s enzymatic system is attacked and hence the immune system is also likely to derange. This may be detrimental for the host’s well-being and existence. Along with appropriate antimicrobial therapy, administration of enzymes externally could plausibly help to stabilise this disturbed immune system and thus assist the body to overcome the infections. This would especially be useful in multi-drug resistant and severe nosocomial infections. Enzymes have been studied and found to play a supplementary role in control of these infections. They also seem to help in control of difficult to manage viral infections. Besides, their use has been found to be beneficial in prevention of various common infections such as flu and cold. In spite of their potential, they have remained largely underestimated and underexploited. This review on oral enzymes attempts to highlight the role and safety of enzymes as adjunctive therapy in infections.

Introduction


Infections of varying severity continue to scourge Mankind. Their incidence is on the rise. New infections are emerging and old, conquered ones are making a comeback[1, 2]. Also these infections are increasingly seen to be resistant to commonly used antibiotics and though research into newer antibiotics is ongoing, it has failed to keep pace with the rising antimicrobial resistance. Alternative ways to manage these ‘biological killers’ need to be delved into. Oral systemic enzyme therapy seems to hold promise in control and elimination of certain of these infections.
The outcome in an infection is dependent on a multitude of factors such as genes, nutrional status of host, virulence of infecting organism,  time duration of infection etc[3]. A favourable outcome ensues when host’s immune response is sufficient enough to arrest the march of the infecting organism into it, whereas an inadequate immune response could prove detrimental. Not only an hypo- but an hyper immune response has also been shown to be harmful. Such suboptimal responses characterize severe, advanced or resistant 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 worsen the situation through release of immune complexes and dead bacilli into the blood stream. They also fail to reverse the hemodynamic instability and immune paralysis characteristic of these infections[4]. Supplementation with drugs targeted against this ‘choatic’ or ‘dysfunctional’ immune response could be beneficial. Systemic enzymes seem to aid tremendously in ‘taming’ this ‘wilderness’ and optimising the immune response[5].
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS) IN INFECTIONS
SIRS is seen in an infective process [6]. It is in the form of a cascade with counterregulation. It is initiated by  lipopolysaccharide (LPS), Lipid A, or endotoxin of gram-negative bacteria, or lipoteichoic acid, peptidoglycan, or exotoxin of gram-positive bacteria (eg.), or similar components of virus, fungi or parasites. LPS binds to a specific plasma protein (LPS binding protein) and this complex then binds to a membrane receptor (CD14) on effector cells such as macrophages and endothelial cells. This initiates intracellular signal transduction via a specific receptor mechanism (Toll-like receptor, TLR) [3]. Complement system is also stimulated which assists in trigger and amplification of various components of the immune system[7, 8].  
Lymphocytes, monocytes and other immune cells are attracted to site of infection and pro-inflammatory substances called cytokines are released. More than 120 different cytokines have been identified and described. Monocytes produce nuclear factor-?B which also produces proinflammatory cytokines, tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). TNF-α and IL-1 in turn generate toxic downstream mediators, such as  prostaglandins (by cycloxoygenase pathway), leukotrienes, platelet-activating factor, and phospholipase A2  [9, 10]. These mediators damage endothelial lining and increase capillary leakage by acting on a group of glycoproteins called selectins on the endothelial cells (E-selectin and P-selectin) and leukocytes (L-selectin). Leukocytes marginate and form strong bonds with the neighbouring cells. These bonds are due to expression  of adhesion molecules on the cells. These adhesion molecules include intercellular adhesion molecules 1 and 2 (ICAM-1 and 2) on the endothelial cells, vascular adhesion molecules (VCAM-1),  and platelet-endothelial cell adhesion molecule 1 (PECAM-1). The receptors on leukocytes include members of the α2-integrin family of adhesion molecules such as CD11b and CD18 [11].
Neutrophils are also chemoattracted to the site. Their interaction with endothelial cells by means of adhesion molecules causes further damage. Stimulated neutrophils release proteases and nitric oxide which further aggravate the inflammation [12-15].
TNF-α and IL-1 also cause expression of tissue factor on endothelial cells and monocytes. This initiates the coagulation cascade; thrombin is produced which itself is a proinflammatory substance. Fibrin clots form in the microvasculature. TNF-α and IL-1 also activate plasminogen activator inhibitor-1 which inhibits fibrinolysis [16]. They also hamper activation of protein C and antithrombin; which are antithrombotic and also anti-inflammatory [17-19]. Cytokine production continues. Thus an hyperinflammatory atmosphere is produced. This is counterproductive and enhances mortality [20]. Blocking of these cytokines by specific antagonists has been shown to improve survival[21].  
In some patients or later in the course of infection, released stress hormones induce lymphocytes to release anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 [22]. These act to deactivate monocytes and decrease TNF-α, IL-1 and IL-6 production. Alpha2 macroglobulin, the cytokine catcher is also converted into its ‘fast’ form. It mops up the excess cytokines and tries to keep inflammation under check [23-25]. But this inflammatory suppression leads to cellular dysfunction and decrease in lymphocyte proliferation. Apoptosis (programmed cell death) of gut lymphocytes and endothelial cells takes place and anergy sets in[26-28].
However, neutophilic stimulation  and consequent tissue damage continues unabated [29]. The released nitric oxide, oxidases and proteases are main culprits in this damage [30, 31].
Thus the infective process is a complex process of inflammation. No single mediator/system/pathway/pathogen drives the pathophysiology of sepsis, but it is a composite output. Complex endothelial-leukocyte interactions are essential for sustaining an inflammatory response. Carefully timed sequence of molecular expression regulate these interactions. Simultaneous release of pro- and anti-inflammatory elements is seen. The equilibrium  between these two contrasting signals is vital for recovery from infection[32]. This process is meant to be reparative, but there is always a risk for it to turn counterproductive. Systemic enzyme therapy has been shown to overcome the ‘cytokine storm’ or ‘immunosuppression’ seen in infections and to salvage the host’s immune system.
ENZYME HISTORY
During the Mayan civilization, wrapping papaya leaves around wounds was supposed to aid healing. The juice of these leaves contains certain vital enzymes which speeded healing. Pineapple has been used as a medicinal plant by folks of several tropical native cultures and its enzyme bromelain has been chemically known since 1876 [33]. Since 1950's, role of proteolytic enzymes such as bromelain, papain, protease, and chymotrypsin in anti-inflammation emerged. Due to their systemic action and oral administration, they were called as oral systemic proteolytic enzymes. Gradually as more studies were carried out, utility of oral enzymes for treatment of various infections came forth. Innumerable double-blind randomized and controlled trials were performed and oral enzymes were found to be useful and safe adjuvant therapy in infections.  Benefits of topical enzymes for wound debridement was discovered and their use in wound care gained momentum.  
PROPERTIES OF ENZYMES
Enzymes are albuminoid, complex macromolecules made up of amino-acids. There can be digestive, metabolic or food enzymes. Digestive and metabolic enzymes are naturally produced in the body. They tend to decline with age, inadequate and imbalanced nutrition, and physical and mental strain[34]. An estimated 80 to 100 thousand enzymes are present in human body; more than 3000 of these have been identified to date[35]. Food enzymes come from plant and animal sources. They are heat-labile and hence raw, fermented and lightly cooked foods are enyme-rich[36].
When first discovered, enzyme names ended with ‘in’ like pepsin or trypsin. But later, they were suffixed by ‘ase’ such as protease. An elaborate nomenclature by Enzyme Commission (EC) of the International Union of Biocemistry (IUB) classifies the proteolytic enzymes into the hydrolase class (class 3) which includes peptid-hydrolase group (3.4) which comprises aminopeptidases (3.4.1), carboxypeptidases (3.4.2), dipeptidases (3.4.3) and proteinases (3.4.4) [37].
Enzymes for pharmaceutical uses are harnessed from plants, fungi, bacteria and animals. They act after internal absorption and function best at specific temperature and pH[35]. Hence processing, handling and storage of the enzymes should be proper. The various enzymes known to be useful in infections are as follows: Bromelain from pineapple stems ( Ananas comosus), catalase, chymotrypsin from ox bile, krillase from Antarctic krill (E. superba), lysozyme, pancreatin, papain from unripe papayas (Carica papaya), pepsin, protease, bioflavinoid rutin, serratiopeptidase or serrapeptase derived from nonpathogenic enterobacteria, Serratia E15, and trypsin.  V-8 protease (from Staphylococcus aureus), pronase (from Staphylococcus griseus), Subtilisin, ficin from Ficus tree latex have also been investigated in various infections.
These enzymes are highly substrate specific. Hence combination of them has a better and synergistic effect[38]. Various enzyme combinations for infection and inflammation exist in the market such as Vitalzym, Phlogenzym, Medizym, Wobenzym, Wobe-mugos, Chymotrypsin and trypsin combinations, serratiopeptidase, and papain-urea skin creams with or without chlorophyllin.

ABSORPTION OF ENZYMES
The initial myth that enzymes are not absorbed by gut has been refuted by numerous animal and human studies[39-46]. Absorption of intact enzymes into rest of body is possible by pinocytosis or by uptake by ‘roaming’ lymphocytes in the small intestinal lumen which are again released into the gut wall. This is similar to the uptake of antibodies (gammaglobulins) into the child’s lymphatic system and blood stream from the mother’s milk. Substantial proportion of bromelain is also absorbed[47]; highest concentration being present in blood 1 hour after administration[48]. Enzymes are likely to be destroyed by acidic gastric milieu and enteric-coating protects them from annihilation and improves their bioavailability[49]. Special blood factors such as the antiproteinase, α²-macroglobulin act as carrier for the enzymes and  prevents them from digesting the blood proteins. Also these enzymes are protected from being acted upon by the blood proteases. They circulate in the body acting on their appropriate substrates[50].
MECHANISM OF ACTION
Enzymes are essential for each and every bodily function. They act as ‘biocatalysts’ and produce big effects with little efforts. They act at multiple sites of the immune system to enhance it and diminish on inflammation. They normalize ‘a derailed immune system’ and hence aid in control and elimination of infection. They are supposed to act in the following ways:
1. The enzymes cleave the antigenic surface protein of organisms and digest their outer coat. Thus they defunct the pathogens. The released enzyme-surface protein complex is ingested by macrophages and dendritic cells and it induces higher antibody production [51-53].
2. They reduce number and activity of receptors for pathogen on host cells. Thus pathogen attachment is hampered and infectivity decreases. For example, Bromelain can disrupt Enterotoxigenic Escherichia Coli (ETEC) receptors in vivo and protect against ETEC induced diarrhea[54, 55].
3. They detoxify blood and remove viruses from circulation.They act as a "biological vacuum cleaners" eliminating impurities, foreign proteins, immune complexes and harmful micro-organisms from the blood stream and tissues. This greatly diminishes the inflammatory response and allows the normal immune functions to operate at a much healthier level.
4. Enzymes cause enhancement of immune cells to kill bacteria, viruses, molds and fungi[56]. Bromelain increases proliferation of peripheral blood mononuclear cells. Production of IL-6, granulocyte-monocyte-colony stimulating factor (GM-CSF), TNF-α and type 1 cytokine IFN-α production, but not of type 2 cytokines IL-4 and IL-5 are increased[57]. This induction is dose-dependent[58]. Macrophage activity is enhanced up to 700 percent with a combination of enzymes pancreatin, papain, bromelain, trypsin and chymotrypsin[59].  Phagocytosis is also accelerated[60].
5. Enzymes break down immune complexes which block the immune cells[35]. They dissolve immune complex by removing Fc part of immunoglobulin and eliminate immune complexes from circulation[61, 62]. In the early phase, there may be worsening of the situation due to release of immune complexes fixed to tissues into the blood (Jarisch-Herxheimer effect).
6. They accelerate the volume and fluidity of blood flow[63]. This facilitates elimination of inflammatory products. Vascular endothelium is also stabilised[64].
7. Enzymes such as bromelain modulate arachidonate pathway in such a way that thromboxane production is decreased with no effect on cyclooxygenase. This leads to a decrease in odema and inflammation and reestablishment of balance between the 2 types of prostaglandins[33, 47].
8. Enzymes such as Serrapeptase enhance the bactericidal effect of antibiotics in cultures and prevents the formation of biofilms. This is valuable in treating problematic prosthetic infections[65, 66]. Papain has also been found to enhance chemotherapeutic efficacy of antibiotics on an average by 50% in mice with septicemia[67]. Bromelain also has been shown to increase blood and tissue levels of antibiotics[68-70].  This potentiation of antibiotics may be due to enhanced absorption, as well as increased permeability of the diseased tissue which increases access of antibiotics to site of infection. Bromelain might also provide a similar access to specific and non-specific components of immune system, therefore, enhancing the body's utilization of its own healing resources.
9. Enzymes such as rutin are powerful anti-oxidants and effectively combat the harmful free radicals such as nitric oxide, released during the inflammatory process[71, 72].
10. Enzymes block pro-inflammatory metabolites that propagate the inflammation. Evidence also suggests an immunomodulatory and hormone like activity acting via intracellular signalling pathways for bromelain. It can inhibit induced T cell production of  IL - 4 and to a lesser degree of the IL-2 and induced  IFN-α via modulation of the extracellular regulated kinase-2 (ERK-2) intracellular signaling pathway[73].  Bromelain significantly reduces CD4 T-lymphocytes of peyer’s patches[74]. Hence it ameliorates exaggerated inflammation. Trypsin-chymotrypsin has also been shown to modulate cytokine levels in burns[75].
11. Cell surface receptors such as hyaluronan receptor CD44 is reduced by bromelain. Hence leukocyte migration and induction of proinflammatory mediators declines[56, 76]. Enzymes down-regulate and degrade over-expressed inflammatory adhesion molecules. In vitro chemotaxis assay has shown that bromelain decreases chemokine receptor CD128 and hence there is reduction in neutrophil migration in response to IL-8[77].  
12. Enzymes activate alpha-2 macroglobulin, the cytokine catcher which usually exists in blood in an inactive form (slow form). This in turn promotes  faster clearance of cytokine, TNF-α. Thus stimulus for expression of the adhesion molecules is reduced. This assists in minimizing the heightened inflammatory process[78].  
13. Enzymes inhibit platelet aggregation and their adhesion to endothelial cells. Clot formation is reduced[63, 79-81]. Enzymes also break down fibrin deposits and also remove necrotic debris and excess fibrin from the bloodstream[82].
14. Enzymes possess anti-secretory and mucolytic qualities. They act indirectly to decrease volume and viscosity of infected secretions so that they can be easily coughed out[83-85]. Bromelain’s liquifing potential is  greater than that of other enzymes. It acts by decreasing contents of acid glycoprotein and sialic acid in sputum.
15. Enzymes decrease acute phase reactants[86].
Systemic enzymes thus supplement antibiotics to overcome infections. Enzymes reduce inflammation and beneficially modulate the immune system. They have no direct action on the organism per se but can tame the host’s upset immune system in order to harness its benefits.

Preclinical and Clinical Studies


Innumerable studies, controlled or otherwise, randomized or not, have been conducted to prove efficacy and safety of systemic enzymes in infections. Enzymes have been found useful in following conditions-
1. Airway infections and inflammations-Serrapeptase has been found to be effective in alleviating thick infected respiratory secretions. Ninety-seven percent of those taking serrapeptase reported good or excellent results compared to 22% in the control subjects. In a multi-center, double-blind, randomized study involving 193 participants, serratiapeptidase acted rapidly to reduce local inflammation and ease symptoms in people suffering from ear, nose and throat disorders[87].  Serrapeptase also is beneficial in patients with bronchitis and other chronic lower airway diseases[88, 89]. Combination of trypsin and chymotrypsin with antibiotics is effective for management of acute or chronic non-tubercular bronchopneumonias[90]. Bromelain is effective and safe in acute sinusitis. It decreases sinus pain and throat pain. It changes the consistency of nasal mucus favourably[47, 70, 91-97].  
2. Sepsis and septic shock-Enzymes when used in conjunction with appropriate antibiotics can lead to early recovery from sepsis in pediatric patients[71]. Papain has also been found to enhance the chemotherapeutic efficacy of antibiotics on an average by 50% in mice with septicemia[67].  Ishikawa et al has also shown that bromelain has a protective effect when used with antibiotics in experimental infection in mice produced by Streptococcus hemolyticus, Streptococcus pneumoniae and  Pseudomonas aeruginosa[98].
3. Oro-dental infections- Since 1960s, proteolytic enzymes have been used in stomatology. Varney-Burch used peroral trypsin and chymotrypsin in postdental surgery and found that these enzymes reduced the healing time by 50%[99, 100]. Proteolytic enzymes are also found to be useful in dental infections. Used as a mouthwash, the enzymes help in combating gingivitis and reducing plaque formation in children and young adults[101, 102].  
4. Skin and soft tissue infections- Adequate debridement of wound and burn areas is essential for prevention and management of infections. Experimental runs of enzymes as wound debridement agents have given positive results. Papain-urea, papain-urea-chlorophyllin, bromelain, ficin and bacterial collagenase has been extensively investigated for use in wound bed preparation[103-111]. A novel streaming technique has been tried in order to improve efficiency of enzyme solutions to cause early wound debridement and healing[112].  Bromelain scores over collagenase in efficacy and safety as a wound debridement agent[113].  
5. Genito-urinary infections-Enzymes have been studied in urinary tract infections and found to play a favourable role. They can also help eradicate chlamydial infections of prostate[114].
6. Joint infections- Intraarticular serratiopeptidase enzyme has also been found useful in eradication of infection caused by biofilm-forming bacteria in experimental animal model. The serratiopeptidase group had significantly less persistence of infection as compared to the control group (5.6% s 37.5% respectively)[65].
7. Viral hepatitis- Oral enzymes have been found to be useful in hepatitis B infection. When administered, they tended to lead to faster recovery, with early normalization of spleen and liver size, and restoration of liver function[115-117]. Enzymes are also superior to ribavarin and ?-interferon in hepatitis C patients[118, 119].
8. Varicella-zoster infection- Various studies have shown that enzyme therapy is beneficial in herpes infections. Oral enzymes decreased significantly ‘segmental pain’ on day 7 and 14 of the herpes zoster illness, as compared to the virostatic drug, acyclovir. Global judgement of the drug by physicians was in favour of the enzymes with similar tolerability in both groups. Hyperaesthesia and postzosteric neuralgia was also less in enzyme group[120-122]. Billigmann et al in their study found no difference in segmental pain in enzyme or acyclovir group, but adverse events were significantly less in enzyme group[123].  Mikazans used enzymes per os as well as locally in herpes-zoster infection and observed that as compared to oral acyclovir, enzyme therapy reduced clinical symptoms and signs faster and also was free of any side-effects. Postherpetic neuralgia was also less in the enzyme group[124].  
9. Recurrent laryngeal papillomatosis- In an uncontrolled study, Mudrak et al found that after the surgical extirpation of the laryngeal papillomatosis, subsequent application of peroral proteases caused a significant improvement in clinical and laboratory results in these patients. Also they were disease-free for 10-18 months[125]. But this result has not been confirmed by means of a randomized controlled study.
10. Human immunodeficiency virus (HIV)- Auto-antibodies and circulating immune complexes characterize HIV. Jaeger used hydrolytic enzymes in HIV infections and found that they improved functional ability and weight of patients and are also well-tolerated[126].
11. Fungal infections- Bromelain has been found to enhance the killing actity of human white cells against candida albicans[60]. But no clinical studies of use of enzymes in fungal infections could be found.
12. Parasitic infections-There are very few studies on role of enzymes in parasitic infections. Enzymes are found to have a limited role in treatment of intestinal helminthiasis[127-129]. More clinical studies are needed to evaluate the role and safety of enzymes as adjuvant therapy in intestinal worms.
DOSING
The different enzyme preparations available in market contain different enzyme combinations in different strengths/potencies. The strengths are measured in grams or milligrams or in units of activity or international units.  Food Chemical Codex (FCC) published by the National Academy Press is the accepted standard for activity units. Plant based enzymes have more activity, more duration of action and more pH stability compared with animal based enzymes. The recommended dose varies according to the enzyme preparation and the type of disease for which it is used.  Usually 2-4 tablets are taken 2-3 times a day. But even higher dosages are free of side-effects. For children, powder forms of enzymes are also available. It is advisable to take enzymes 30 minutes before meals or 2 hours after meals with a sufficient amount of water.
SAFETY PROFILE
Enzymes are safe and well-tolerated in all age groups. A lethal dose (LD50) could never be found. There are no undesirable adverse effects on bone marrow or immunological system even with high or prolonged enzyme administration[35]. Even consumption of 3700 tablets per day produced only mild diarrhea[130].  Harmless alteration in the consistency, colour and odour of stool may occur as a consequence of enzyme action.  Nausea, vomiting, mild abdominal pain may be seen in some cases. Pancreatic enzyme may impair folic acid absorption and hence extra folate should be taken with long-term enzyme supplementation[131].  High doses of serratippeptidase could cause esophageal ulcers. Its use has also been associated with acute eosinophilic pneumonia[132], subepidermal bullous dermatosis and inability to move.
Serious allergic reaction, anaphylaxis or hypersensitivity to enzymes are rare[133, 134]. Papain can cause problems only in those with papaya or latex allergy. Topical papain can cause eruption of painful blisters and rashes in some patients.  
Bromelain has been found to potentiate the action of sedative drugs and antibiotics. It can cause changes in heart rate and blood pressure, especially in hypertensive patients[135]. Seraapeptase also slows heart rate and can lead to drowsiness.
Enzymes can affect the coagulation system and hence it should not be used with blood thinning drugs such as aspirin, warfarin, or coumadin. They  are contraindicated in hemophiliacs, pregnant or nursing mother, and in severe liver damage.
 Animal studies have demonstrated no teratogenic effect of enzyme mixtures. Dosages of 1.5 g/kg/day of  bromelain administered to rats showed no carcinogenic or teratogenic effects.  There is no development of tolerance on prolonged use of enzymes.
CURRENT STATUS
Thus, enzymes are a useful adjunct to antibiotics in both acute and chronic infections. Studies have shown it to possess a useful role in correcting an ‘upset’ immune system. It may be of use in cases where modern pharmoactherapy has very limited role. It could minimize morbidity and lead to early recovery from infections. It could enhance the actions of antimicrobials and assist in prompt and better control of infections.  
However, at present, enzymes are used mainly for their digestive functions, for gut health, for general well-being and for decreasing inflammation after surgery or trauma. It is being extensively used for sports injuries and in the orthopedic field. In spite of significant positive research on enzymes in infections, its usefulness in infections remains underexploited. It has not been adequately used as supplementation in advanced infections, septic shock, resistant infections and severe illnesses. This could possibly be due to lack of awareness about its benefits amongst the practicing physicians. Research on enzymes has 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 infections. Besides, since enzymes cannot be patented, they are of little interest to drug companies and there is a general unwillingness to use therapies not made by ‘big pharma’. There is also still skepticism in medical fraternity about findings that proteinases are absorbed from the gastrointestinal tract in a functionally intact form, and consequently they deny any efficacy of oral enzymes.
FUTURE ROLE
There exists a remarkable list of clinical studies conforming to Good Clinical Practice(GCP) guidelines and performed with polyenzyme drugs, which shows that enzymes are beneficial in infections. The pharmacological efficacy of proteinases is evidence-based. Hence future for enzyme therapy seems bright. They of course cannot replace antimicrobials in infections but can play in pivotal supportive role in overcoming the infections. More randomized and controlled clinical trials on enzymes to further elucidate its clinical potential would be beneficial. More and widespread dissemination of knowledge on its clinical utility is required. As more forms and patents on enzymes are produced, and as more studies are performed, its use in the day to day management of infections would increase. It could play an important role in care of patients with nosocomial infections, especially in geriatric and pediatric age groups, and in viral and resistant infections. Its safety profile, lack of development of resistance and inability to show tolerance would make it a preferred supplementary option in elderly and pediatric population. It could serve as an effective, safe and cheap immunotherapeutic aid in infections.

Conclusion


Systemic enzyme therapy has been shown to be useful for prevention and treatment of a variety of infections. It holds promise for management of patients with infections which are unable to be treated with newer antibiotics and antiviral drugs. It could help where resistance to the antimirobials is high such as in viral hepatitis and HIV. However, its benefits have not been harnessed enough. More clinical studies and improved awareness amongst the practicing physicians would be one step forward in helping mankind overcome the curse of these terrifying infections.

References


1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29: 1303-1310
2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000 N Engl J Med. 2003; 348; 1546-1554
3. Snowden C, Kirkman E. The pathophysiology of sepsis. British Journal of Anaesthesia ( CEPD Reviews ) 2002; 2: 11-14.
4. Remick DJ. Pathophysiology of sepsis. Am J Path. 2007; 170 (5): 1435-1444
5. Donelly PK. The role of protease in immunoregulation. British Journal of Surgery 1983;  70: 614-622
6. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992; 101: 1644-1655
7. Cooper NR. The classical complement pathway: activation and regulation of the first complement component. Adv Immunol 1985; 37: 151-216
8. Riedemann NC, Guo RF, Neff TA, Laudes IJ, Keller KA, Sarma VJ, et al. Increased C5a receptor expression in sepsis. J Clin Invest 2002; 110:101-108   
9. Remick DG, Kunkel RG, Larrick JW, Kunkel SL. Acute in vivo effects of human recombinant tumor necrosis factor. Lab Invest. 1987; 56: 583–590.
10. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, et al. Shock and tissue injury induced by recombinant human cachectin. Science. 1986; 234: 470–474
11. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000;  406: 782-787
12. Hatherill M, Tibby SM, Turner C, Ratnavel N, Murdoch IA. Procalcitonin and cytokine levels: relationship to organ failure and mortality in pediatric septic shock Crit Care Med 2000; 28: 2591-2594
13. Waage A, Halstensen A, Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987; 1:355–357
14. Cobb AP, Danner RL. Nitric oxide and septic shock. JAMA. 1996; 275: 1192-1196.
15. Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J Surg Res 1990; 49:186-196.
16. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Haemost. 1998; 24: 33-44.
17. Boehme MWJ, Deng Y, Raeth U, Bierhaus A, Ziegler R, Stremmel W, et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology. 1996; 87: 134-140
18. Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, et al. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol. Lung Cell Mol Physiol 1997; 272: L197-L202.
19. Deitch EA. Animal models of sepsis and shock: a review and lessons learned. Shock 1998; 9: 1-11.
20. Smith JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol. 1994; 56: 672–686  
21. Watanabe S, Mukaida N, Ikeda N, Akiyama M, Harada A, Nakanishi I, et al. Prevention of endotoxin shock by an antibody against leucocyte integrin beta 2 through inhibiting production and action of TNF. Int Immunol 1995; 7: 1037-1046
22. Rigato O, Salomao R. Impaired production of interferon-gamma and tumor necrosis factor-alpha but not of interleukin-10 in whole blood of patients with sepsis. Shock. 2003; 19:113–116.
23. de Boer JP, Creasey AA, Chang A, Abbink JJ, Roem D, Eerenberg AJ, Hack CE, Taylor FB. Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: studies using a baboon model. Infect. Immun. 1993; 61 (12): 5035–5043.
24. Borth W, Teodorescu M. Inactivation of human interleukin-2 (IL2) by alpha 2-macroglobulin-trypsin complexes. Immunology 1986; 57: 367-371
25. James K, Milne I, Cunningham A, Elliot S-F. The effect of alpha2 macroglobulin in commercial cytokine assays. Journal of Immunological Methods 1994; 168: 33-37
26. Reddy RC, Chen GH, Tekchandani PK, Standiford TJ. Sepsis-induced immunosuppression: From bad to worse. Immunol Res. 2001; 24: 273-287
27. Hotchkiss RS, Karl IE. The Pathophysiology and Treatment of Sepsis. NEJM. 2003; 348: 138-150
28. Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A. Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol. 2005; 78: 325–337
29. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006; 368:157–169
30. Hatherill M, Tibby SM, Turner C, Ratnavel N, Murdoch IA. Procalcitonin and cytokine levels: relationship to organ failure and mortality in pediatric septic shock. Crit Care Med 2000; 28: 2591-2594
31. Waage A, Halstensen A, Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987; 1:355–357
32. Armstrong PB. Proteases and protease inhibitors: a balance of activities in host-pathogen interaction. Immunobiology. 2006; 211: 263-281
33. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananus comosus) and its clinical application: An update. J. Ethnopharmacol 1988; 22: 191- 203.
34. Ji LL. Antioxidant enzyme response to exercise and aging. Med. Sci. Sports Exerc. 1993; 25(2): 225-231
35. Lopez DA, Williams RM, Miehlke M. Enzymes: The Fountain of Life. Charleston SC:  The Neville Press, Inc.; 1994
36. Prochaska LJ, Nguyen XT, Donat N, Piekutowski WV. Effects of food processing on the thermodynamic and nutritive value of foods: literature and database survey. Med Hypotheses 2000; 54 (2): 254-262
37. Stenesh J. Dictionary of Biochemistry and Molecular Biology, 2nd Edition, John Wiley and Sons, Inc:  NJ.; 1989 (201): 748-6011
38. Prochaska LJ; Piekutowski WV. On the synergistic effects of enzymes in food with enzymes in the human body. A literature survey and analytical report. Med Hypotheses 1994; 42 (6): 355-362
39. Smyth RD, Brennan R, Martin GJ. Studies establishing the absorption of bromelains (proteolytic enzymes) from the gastrointestinal tract. Exp Med Surg. 1964; 22: 46-59
40. Castell JV, Friedrich G, Kuhn CS, Poppe GE. Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Am J Physiol. 1997; 273: G139-G146
41. Ambrus JL, Lassman HB, DeMarchi EP. Absorption of exogenous and endogenous proteolytic enzymes. Clin Pharmacol Therap 1967; 8: 362-368
42. Kabacoff BL, Wohlman A, Umhey M, Avakian S. Absorption of chymotrypsin from the intestinal tract. Nature 1963; 199: 815-817
43. Martin GJ, Bogner RL, Edleman A. Further in vivo observations with radioactive trypsin. Am J Pharm 1964; 129: 386-392
44. Avakian S. Further studies on the absorption of chymotrypsin. Clin Pharmacol Therap 1964; 5: 712-715
45. Liebow C, Rothman SS: Enteropancreatic circulation of digestive enzymes. Science 1975; 189: 472-474
46. White RR Bioavailability of 125I bromelain after oral administration to rats. Biopharm Drug Dispos 1988; 9(4): 397-403
47. Taussig SJ. The mechanism of the physiological action of bromelain. Medical hypotheses. 1980; 6(1): 99-104
48. White RR Bioavailability of 125I bromelain after oral administration to rats. Biopharm Drug Dispos 1988; 9(4): 397-403
49. Nassif EG, Younoszai MK, Weinberger MM, Nassif CM. Comparative effects of antacids, enteric coating, and bile salts on the efficacy of oral pancreatic enzyme therapy in cystic fibrosis. J Pediatr. 198; 98(2): 320-323
50. Borth W. Alpha 2-macroglobulin, a multifunctional binding protein with targeting characteristics. The FASEB Journal 1992; 6: 3345-3353
51. Howenstine JA. How systemic enzymes work to cure diseases.(Clinical report) Original internsit Dec.1. 2006 (online format).
52. Argyris BF. Role of macrophages in antibody production. Immune response to sheep red blood cells. The journal of immunology. 1967; 99: 744-750.
53. Gallily R, Feldman M. The role of macrophages in the induction of antibody in X-irradiated animals. Immunology 1967; 12 (2): 197-206
54. Chandlera DS, Mynott TL. Bromelain protects piglets from diarrhoea caused by oral challenge with K88 positive enterotoxigenic Escherichia coli. Gut 1998; 43: 196-202
55. Thomson AB, Keelan M, Thiesen A, Clandinin MT, Ropeleski M, Wild GE. Small bowel review: normal physiology. Part 1. Digestive Dis , Science 2001; 46: 2567-2587
56. Engwerda CR, Andrew D, Ladhams A, Mynott TL. Bromelain modulates T cell and B cell immune responses in vitro and in vivo. Cell Immunol 2001; 210 (1): 66-75
57. Barth H, Guseo A, Klein R. In vitro study on the immunological effect of bromelain and trypsin on mononuclear cells from humans. Eur J Med Res 2005;  10: 325-331
58. Rose B, Herder C, Löffler H, Meierhoff G, Schloot NC, Walz M, Martin S.  Dose-dependent induction of IL-6 by plant-derived proteases in vitro Clinical & Experimental Immunology 2006; 143 (1): 85-92
59. Jordan FM. Enzymes-digestive and proteolytic-now an endangered species. Immunition report. 2010; 5 (3) (online format).
60. Brakebusch M, Wintergerst U, Petropoulou T, Notheis G, Husfeld L, Belohradsky BH et al. Bromelain is an accelerator of phagocytosis, respiratory burst and Killing of Candida albicans by human granulocytes and monocytes. Eur J Med Res 2001; 6 (5): 193- 200
61. Ekerot LK, Ohlsson K, Necking L. Elimination of protease-inhibitor complexes from the arthritic joint. Int J Tissue React 1985; 7 (5): 391-395
62. Steffen C, Menzel J. Enzyme breakdown of immune complexes.  Rheumatol. 1983; 42: 249-255
63. Kleine MW. Introduction to systemic enzyme therapy and results of experimental trials. In: Hermans GPH, Mosterd WL, editors. Sports, Medicine and Health. Amsterdam: Excerpta Medica; 1990: 1131
64. Wilhelmi, G. Effect of O-(beta-hydroxyelthyl)-rutiside on wound healing in the rat. J Pharmacology 1979; 19(2): 82-85
65. Mecikoglu M, Saygi B, Yildirim Y, Karadag-Saygi E, Ramadan SS, Esemenli T. The effect of proteolytic enzyme serratiopeptidase in the treatment of experimental implant-related infection. J Bone Joint Surg Am 2006; 88 (6): 1208-1214
66. Selan L, Berlutti F, Passariello C, Comodi-Ballanti MR, Thaller MC. Proteolytic enzymes: a new treatment strategy for prosthetic infections? Antimicrob Agents Chemother. 1993; 37(12): 2618-2621
67. Baskanchiladze GSh, Khurtsilava LA, Gelovani IA, Asatiani MV, Rossinskii VI. Chemotherapeutic effectiveness of antibiotics in combination with papain in experimental septicemia. Antibiotiki. 1984; 29(1): 33-35
68. Tinozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxycillin. Drugs Expt Clin Res 1978; 4: 39-44.
69. Luerti M, Vignali ML. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Expt Clin Res 1978; 4: 45-48.
70. Neubauer RA. A plant protease for potentiation of and possible replacement of antibiotics. Exp Med Surg 1961; 19: 143-160
71. Shahid SK, Turakhia NH, Kundra M, Shanbag P, Daftary GV, Schiess W. Efficacy and safety of Phlogenzym-A protease formulation, in sepsis in children. JAPI. 2002; 50: 527-531.
72. La Cassa C, Villegas I, Alacron de la Lastra C, Motilva V, Martin Calero MJ. Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions. J Ethnopharmacol. 2000; 71: 45-53
73. Mynott TL, Ladhams A, Scarmato P, Engwerda CR. Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells. J. Immunol. 1999; 163: 2568-2575
74. Manhart N, Akomeah R, Bergmeister H, Spittler A, Ploner M, Roth E. Administration of proteolytic enzymes bromelain and trypsin diminish the number of CD4+ cells and interferon-gamma response in Peyer's patches and spleen in endotoxemic balb/c mice. Cell. Immunol. 2002; 2: 113-119
75. RaviKumar, T., Ramakrishnan, M., Jayaraman, V., and Babu, M. Effect of trypsin-chymotrypsin (Chymoral Forte D.S.) preparation on the modulation of cytokine levels in burn patients. Burns 2001; 27(7): 709-716
76. Hale LP, Greer PK, Sempowski GD.  Bromelain treatment alters leukocyte expression of cell surface molecules involved in cellular adhesion and activation. Clin. Immunol 2002; 104: 183-190
77. Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol.  2008; 128(1): 66-74
78. Schaefer U, Brücker B, Elbers A, Neugebauer E. The capacity of ?2-macroglobulin to inhibit an exogenous protease is significantly increased in critically ill and septic patients. Shock. 2004; 22(1): 16-22
79. Heinicke RM, Van der Wal M, Yokoyama MM. Effect of bromelain on human platelet aggregation. Experientia 1972; 28: 844-845
80. Morita AH, Uchida DA, Taussig SJ. Chromatographic fractionation and characterization of the active platelet aggregation inhibitory factor from bromelain. Arch Inter Phar Ther 1979; 239: 340-350
81. Metzig C, Grabowska E, Eckert K, Rehse K, Maurer HR. Bromelain Proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo 1999; 13(1): 7-12
82. Urano T, Ihara H, Umemura K, Suzuki Y, Oike M, Akita S, et al. The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type 1. J Biol Chem 2001; 276 (27): 24690-24696
83. Hunter RG, Henry GW, Heinicke RM. The action of papain and bromelain on the uterus. Am J Ob Gyn 1957; 73: 867-873
84. Suzuki K, Niho T, Yamada H, Yamaguchi K, Ohnishi H. Experimental study of the effects of bromelain on the sputum consistency in rabbits. Nippon Yakurigaku Zasshi 1983; 81: 211-216
85. Mynott TL, Guandalini S, Raimondi F, Fasano A. Bromelain prevents secretion caused by Vibrio cholerae and Escherichia coli enterotoxins in rabbit ileum in vitro. Gastroenterol. 1997; 113: 175-184
86. Fisher JD, Weeks RL, Curry WM, Hrinda ME, Rosen LL. Effects of an oral enzyme preparation, Chymoral, upon serum proteins associated with injury (acute phase reactants) in man. J Med 1974; 5(5): 258-273
87. Mazzone A, Catalani M, Constanzo M, Drusian A, Mandoli A, Russo S, et al. Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngolog pathology: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res 1990;18(5): 379-388
88. Nakamura S, Hashimoto Y, Mikami M, Yamanaka E, Soma T, Hino M, et al. Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease. Respirology 2003; 8 (3): 316-320
89. Braga PC, Moretti M, Piacenza A, Montoli CC, Guffanti EE. Effects of seaprose on the rheology of bronchial mucus in patients with chronic bronchitis. A double-blind study vs placebo. Int J Clin Pharmacol Res 1993; 13 (3): 179-185
90. Rampazzo F. A new drug combination for the treatment of non-tubercular acute and chronic bronchopneumopathies. Kango. 1966; 18 (1): 113.
91. Kelly GS. Bromelain: a literature review and discussion of its therapeutic applications. Alt Med Review 1996; 1(4): 243-257
92. Braun JM, Schneider B, Beuth HJ. Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS in children with acute sinusitis in Germany. In Vivo 2005; 19 (2): 417-421
93. SeltzerAP. Adjunctive use of bromelains in sinusitis. Eye Ear Nose Throat Monthly 1967; 46:1281-1288
94. Taub SJ. The use of Ananase in sinusitis-a study of 60 patients. Eye Ear Nose Throat Monthly 1966; 45: 96-98
95. Grossan M. Enhancing the Mucociliary System. Advance for Respiratory Care Practitioners. 1995; 8: 12-13
96. Grossan M. Nasal function: office measurement of nasal mucociliary clearance. In: English Grossan M, ed. Otolaryngology. Vol 2. Chapter 7. Philadelphia, PA: Lippincott Williams & Wilkins; 1994
97. Majima Y, Inagaki M. The effect of an orally administered proteolytic enzyme on the elasticity and viscosity of nasal mucus. Archives of Oto-Rhino-Laryngology 1988; 244: 335-359
98. Ishikawa H, Oguro Y. Protective effect of stem-bromelain in combination with antibiotics on experimental infection in mice induced by Streptococcus hemolyticus, Diplococcus pneumoniae, or Pseudomonas aeruginosa.  Jpn J Antibiot. 1974; 27(2): 118-121
99. Varney-Burch M. An evaluation of an oral anti-inflammatory enzyme in dental surgery. Dent. Mag. 1962; 2: 102–104
100. Forrest WI, Goodridge DL, Watson AM, Starkey WE. Double-blind clinical trials of proteolytic enzyme therapy in oral surgery. Br J Oral Surg. 1968; 6(1): 7-10
101. Formicola AJ, Grupe HE Jr., Bradley EL Jr., Weatherford TW III, Hunt DE. A clinical evaluation of a proteolytic enzyme mouthwash on plaque and gingivitis in children. NY State Dent J. 1972; 38(6): 334-340
102. Robinson RJ, Stoller NH, Vilardi M, Cohen DW. Clinical evaluation of the effect of a proteolytic enzyme mouthwash on plaque and gingivitis in young adults. Community Dent Oral Epidemiol. 1975; 3(6): 271-275
103. Brett DW. Chlorophyllin--A Healer? A Hypothesis for its Activity. Wounds 2005; 17(7): 190-195
104. Falanga V. Wound bed preparation and the role of enzymes: A case for multiple actions of therapeutic agents. Wounds 2002; 14: 47-57  
105. Klasen HJ. A review on the nonoperative removal of necrotic tissue from burn wounds. Burns 2000; 26: 207-222.  
106. Mekkes JR, LePoole IC, Das PK, Bos JD, Westerhof W. Efficient debridement of necrotic wounds using proteolytic enzymes derived from Antarctic krill. Wound Repair Regen 1998; 6:50-57.
107. Falabella AF, Carson P, Eaglstein WH, Falanga V. The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity J Am Acad Dermatol 1998; 39:737-740  
108. Hebda PA, Flynn KJ, Dohar JE. Evaluation of the efficacy of enzymatic debriding agents for removal of necrotic tissue and promotion of healing in porcine skin wounds Wounds 1998; 10: 83-96
109. Alvarez OM, Fernandez-Obregon A, Rogers RS, Bergamo L, Masso J, Black M. Chemical debridement of pressure ulcers: A prospective, randomized, comparative trial of collagenase and papain/urea formulations. Wounds 2000; 12: 15-25
110. Pullen R, Popp R, Volkers P, Fusgen I. Prospective randomized double-blind study of the wound-debriding effects of collagenase and fibrinolysin/ deoxyribonuclease in pressure ulcers. Age and Ageing 2002; 31: 126-130
111. Taussig SJ. Bromelain: a proteolytic enzyme and its clinical application. Hiroshima J Med Sci 1975; 24:185-193
112. Yaakobi T, Roth D, Chen Y, Freeman A. Streaming of Proteolytic Enzyme Solutions for Wound Debridement: A Feasibility Study. Wounds. 2004; 16(6): 201-205
113. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cellular and Molecular Life Sciences 2001; 58(9): 1234-1245
114. Mori S, Ojima Y, Hirose T, Sasaki T, Hashimoto Y. The clinical effect of proteolytic enzyme containing bromelain and trypsin on urinary tract infection evaluated by double blind method. Acta Obstet Gynaecol Jpn. 1972; 19(3): 147-153
115. Patney NL, Pachori S. A Study of Serum Glycolytic Enzymes and Serum B Hepatitis in Relation to LIV.52 Therapy  Medicine and Surgery 1986; 26 (4): 9-16
116. Romanova SV, Shabunina EI, Pereslegina IA, Tolkacheva NI. Influence of WobenzymR therapy on immune and metabolic parameters in children with chronic hepatitis B. Int J Immunother 1997; 13 (2-4): 99-100
117. Vassilenko AM, Fessenko VI, Schvets SV. Efficacy of systemic enzyme therapy in the treatment of patients with chronic hepatitis B. Int J Immunotherapy 2001; 17(2/3/4): 93-97
118. Romanova SV, Shabunina EI, Pereslegina IA, Tolkacheva NI. Influence of WobenzymR therapy on immune and metabolic parameters in children with chronic hepatitis B. Int J Immunother 1997; 13 (2-4): 99-100
119. Vassilenko AM, Fessenko VI, Schvets SV. Efficacy of systemic enzyme therapy in the treatment of patients with chronic hepatitis B. Int J Immunotherapy 2001; 17(2/3/4): 93-97
120. Kleine MW. Comparison between an oral hydrolytic enzyme combination and oral acyclovir in the treatment of acute zoster: a double-blind, controlled multicentre trial. Journal of the European Academy of Dermatology and Venereology 2006; 2(4): 296 – 307
121. Bartsch W. Proteolytic enzymes in the treatment of herpes zoster. Der Informierte Arz 1974; 2(10): 1-7.
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 (7): 540-544
133. Wuthrich B. Proteolytic enzymes: potential allergens for the skin and respiratory tract? Hautarzt 1985; 36: 123-125
134. Gailhofer G, Wilders-Truschnig M, Smolle J, Ludvan M. Asthma caused by bromelain: an occupational allergy. Clin Allergy 1988;18: 445-450
135. Gutfreund A, Taussig S, Morris A. Effect of oral bromelain on blood pressure and heart rate of hypertensive patients. Haw Med Jour 1978; 37: 143-146

Source(s) of Funding


None

Competing Interests


None

Disclaimer


This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

Reviews
6 reviews posted so far

Dear Dr. Jamalul, Thank u so much for sparing time to review my article. The comments and suggestions will be incorporated in the revised version. But as a matter of fact as u mentioned, more randomiz... View more
Responded by Dr. Sukhbir Shahid on 14 Jun 2012 05:55:16 AM GMT

review of enzymes in infections
Posted by Dr. Imel Rustogi on 22 Jan 2012 03:04:58 PM GMT

Thanks for the review and comments. Increasing resistance to antibiotics calls for research into alternative ways of controlling the various emerging, reemerging and resistant infections and its chall... View more
Responded by Dr. Sukhbir Shahid on 23 Jan 2012 03:40:59 PM GMT

enzymes in infections-peer review
Posted by Dr. jaspal s mehta on 23 Dec 2011 05:27:09 PM GMT

Dear Dr. Mehta, Thanks for your review of my article. The suggestions given have been noted and the same shall be incorporated in the revised version. Thank you Dr. Shahid SK... View more
Responded by Dr. Sukhbir Shahid on 24 Dec 2011 05:32:27 AM GMT

review on role of enzymes in infection
Posted by Dr. bhumika s desai on 23 Dec 2011 06:23:30 AM GMT

Dear Dr. Bhumika, Thank you for your valuable comments on my ms. More studies on usefulness of polyforms of enzymes would aid to enhance the role of enzymes in infections. With mounting drug-resistant... View more
Responded by Dr. Sukhbir Shahid on 23 Dec 2011 03:18:29 PM GMT

Thanks for review of my article and the comments. They are highly appreciated. They would be useful for revising my article and the comments would be incorporated in the revised version. ... View more
Responded by Dr. Sukhbir Shahid on 07 Dec 2011 01:25:42 PM GMT

A Review of Enzymes Reducing Infection
Posted by Dr. Bill Misner on 24 Nov 2011 05:40:50 AM GMT

Dear Dr. Bill Misner, Thank you for your review and the comments on my paper. They are extremely valuable for me and would help for revising my paper. I have noted the points raised and would add it i... View more
Responded by Dr. Sukhbir Shahid on 24 Nov 2011 05:47:17 AM GMT

Comments
0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.

 

Author Comments
0 comments posted so far

 

What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
Where
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)