View source for Proteases (medical and related uses)

[[Proteases]] (also sometimes referred to as ''proteolytic enzymes'' or ''peptidases'') are in use, or have been proposed or tried, for a number of purposes related to medicine or surgery.  Some preparations involving protease have undergone successful clinical trials and have regulatory authorization;<ref>See [[Tissue plasminogen activator]] and [[Maggot therapy]].</ref> and some further ones have shown apparently useful effects in experimental medical studies.<ref name = "Mecikoglu_2006" />  Proteases have also been used by proponents of alternative therapies, or identified in materials of traditional or folk medicine.<ref>Examples include Serratia E-15 protease ([[Serratiopeptidase]]) (see also separate references in this list); [[Wobenzym]] (a mixture of [[bromelain]] and [[papain]]);  and [[Maggot therapy]].</ref> A [[serine protease]] of human origin, activated [[protein C]], was produced in recombinant form and marketed as [[Drotrecogin alfa]] (also known as Xigris (TM)) and licensed for intensive-care treatment of severe sepsis.  It was voluntarily withdrawn by the manufacturer in 2011 after being shown to be ineffective.<ref>{{cite web
| title = Xigris (drotrecogin alfa (activated)) to be withdrawn due to lack of efficacy
| work = Press release
| publisher = European Medicines Agency
| location = London, UK
| url = http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2011%2F10%2Fnews_detail_001373.jsp&mid=WC0b01ac058004d5c1
| archive-url = https://web.archive.org/web/20111028112048/http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/10/news_detail_001373.jsp&mid=WC0b01ac058004d5c1
| archive-date = 28 October 2011
| url-status = live
| date = 25 October 2011
| access-date = 26 October 2011
}}</ref><ref>{{cite web |url=http://www.businessweek.com/news/2011-10-25/lilly-pulls-xigris-off-markets-after-sepsis-drug-fails-study.html |title=Lilly Pulls Xigris Off Markets After Sepsis Drug Fails Study - Businessweek |website=www.businessweek.com |url-status=dead |archive-url=https://web.archive.org/web/20111029155823/http://www.businessweek.com/news/2011-10-25/lilly-pulls-xigris-off-markets-after-sepsis-drug-fails-study.html |archive-date=2011-10-29}} </ref>

Some of these uses rely directly on the proteolytic activity:  others rely on observations of anti-inflammatory activity.

==Medical and surgical applications==

===Treatment of blood clots in ischemic stroke===
{{main|Thrombolysis#Agents}}
[[Tissue plasminogen activator]] (TPA) is a [[serine protease]] occurring in animals including humans.  Human-identical TPA (produced industrially by genetically recombinant microorganisms) has an established medical use in the treatment of ischemic stroke: by its proteolytic activity it enables the action of another enzyme (plasmin), which breaks down the protein (fibrin) of blood clots.<ref name="Rivera-Bou">{{cite journal|url=http://emedicine.medscape.com/article/811234-overview+eMedicine+Specialties|title=Thrombolytic Therapy|date=2008-11-20|website=Medscape|vauthors=Rivera-Bou WL, Cabanas JG, Villanueva SE}}</ref><ref name="pmid22632907">{{cite journal | vauthors = Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, Cohen G | title = Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis | journal = Lancet | volume = 379 | issue = 9834 | pages = 2364–72 | date = June 2012 | pmid = 22632907 | pmc = 3386494 | doi = 10.1016/S0140-6736(12)60738-7 }}</ref>

[[Venombin A]] from snake venom were used in stokes to deplete [[fibrinogen]] by forming very weak clots that can be easily dissolved. Available evidence does not support any benefit in such usage.<ref name=Cochrane2012>{{cite journal | vauthors = Hao Z, Liu M, Counsell C, Wardlaw JM, Lin S, Zhao X | title = Fibrinogen depleting agents for acute ischaemic stroke | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD000091 | date = March 2012 | pmid = 22419274 | doi = 10.1002/14651858.CD000091.pub2 }}</ref>

===Wound debridement===

[[Debridement]] involves the removal of dead or damaged tissue from wounds
in order to assist healing.  Much of the debris to be removed is proteinaceous, and proteolytic enzymes have been applied to this purpose.

[[Papain]] is a protease obtained from the latex of the fruit of the papaya tree.  It has been used (without regulation) for wound debridement for many years, but in the US in 2008 it was [[Papain#Action by the FDA to restrict marketing of all topical drug products containing papain|brought under regulation]] by the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] and removed from sale for this purpose, following reports of adverse effects.  On the other hand, recent research has been exploring new ways of administering papain for wound debridement.<ref>{{cite journal |first1=Tali |last1=Yaakobi |first2=Dalit |last2=Roth |first3=Yoram |last3=Chen |first4=Amihay |last4=Freeman |title=Streaming of Proteolytic Enzyme Solutions for Wound Debridement: A Feasibility Study |url=http://www.woundsresearch.com/article/7499 |journal=Wounds |volume=19 |issue=7 |date=July 2007}}</ref>

Papain as well as other proteases, including [[bromelain (pharmacology)|bromelain]], collagenase, trypsin and thermolysin, have also been tried or used according to other reports on the use of proteases for debridement of wounds and burns without damaging healthy tissue.<ref>{{cite journal | vauthors = Klasen HJ | title = A review on the nonoperative removal of necrotic tissue from burn wounds | journal = Burns | volume = 26 | issue = 3 | pages = 207–22 | date = May 2000 | pmid = 10741585 | doi = 10.1016/S0305-4179(99)00117-5 }}</ref>

[[Maggot therapy]] for wound debridement is a traditional therapy which was in recent years approved by the FDA.<ref>See article [[Maggot therapy#Regulation|Maggot therapy -- Regulation]] and references cited therein.</ref> It has been identified that the maggots produce proteolytic enzymes which take part in the debridement process.<ref>{{cite journal | vauthors = Reames MK, Christensen C, Luce EA | title = The use of maggots in wound debridement | journal = Annals of Plastic Surgery | volume = 21 | issue = 4 | pages = 388–91 | date = October 1988 | pmid = 3232928 | doi = 10.1097/00000637-198810000-00017 }}</ref>

===Applications of proteases auxiliary to antibiotic therapy===

Some pathogenic bacteria produce [[biofilm]]s or [[exudate]]s containing protein, which in some degree help the bacteria adhere to host tissue, or in some degree physically shield the bacteria or hinder the penetration of substances such as antibiotics administered with the intent that they contact the bacteria.  Accordingly, proteolytic enzymes have been tried in conjunction with antibiotics.  Thus, it has been reported that ''Serratia'' sp. E-15 protease (also known as [[serratiopeptidase]]; {{UniProt|P07268}})<ref name=ATCC21074>Serratia E-15 protease, otherwise known as serratiopeptidase, first prepared in the late 1960s, is obtained from ''Serratia'' sp. E-15,  which was isolated from silkworm ''Bombyx mori'' L. (intestine), and deposited with the [[American Type Culture Collection]] as strain ATCC 21074 (enter 21074 on [http://www.lgcstandards-atcc.org/LGCAdvancedCatalogueSearch/tabid/961/Default.aspx?CollectionID=103 ATCC/LGC search page] for information). Within the ATCC the micro-organism is alternatively named ''[[Serratia marcescens]]'' Bizio.  The preparation and some uses of the protease are described in [http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=3,792,160.PN.&OS=PN/3,792,160&RS=PN/3,792,160 US Patent 3,792,160], issued 12 Feb 1974:  M Isono, et al., for ''Method of treating inflammation and composition therefor''.  The material is also described in {{cite journal | vauthors = Miyata K, Maejima K, Tomoda K, Isono M | title = Serratia protease: Part I. Purification and general properties of the enzyme. | journal = Agricultural and Biological Chemistry | date = February 1970 | volume = 34 | issue = 2 | pages = 310–8 }}</ref> was effective for eradicating infection caused by biofilm-forming bacteria in an experimental animal model (which involved carrying out experimental limb surgery on rats, at the same time experimentally introducing Staphylococcus infection). The authors considered that "The antibiofilm property of the enzyme may enhance antibiotic efficacy in the treatment of staphylococcal infections."<ref name = "Mecikoglu_2006">{{cite journal | vauthors = Mecikoglu M, Saygi B, Yildirim Y, Karadag-Saygi E, Ramadan SS, Esemenli T | title = The effect of proteolytic enzyme serratiopeptidase in the treatment of experimental implant-related infection | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 88 | issue = 6 | pages = 1208–14 | date = June 2006 | pmid = 16757752 | doi = 10.2106/JBJS.E.00007 }}</ref>

The same enzyme, when used concomitantly with an antibiotic, was also reported to increase antibiotic concentration at a target site.<ref>{{cite journal | vauthors = Okumura H, Watanabe R, Kotoura Y, Nakane Y, Tangiku O | title = [Effects of a proteolytic-enzyme preparation used concomitantly with an antibiotic in osteoarticular infections (author's transl)] | language = ja | journal = The Japanese Journal of Antibiotics | volume = 30 | issue = 3 | pages = 223–7 | date = March 1977 | pmid = 853579 }}</ref>

===Applications of protease for enzyme therapy===

[[Protease]] is also capable of medical applications. It is one of the enzymes in [[Sollpura (Liprotamase)]], a [[pancreatic enzyme replacement therapy]] (PERT). It assists in the breakdown of [[proteins]] into [[amino acids]] and [[polypeptides]].<ref>"Anthera Pharmaceuticals - Sollpura." Anthera Pharmaceuticals - Sollpura. N.p., n.d. Web. 21 July 2015. <http://www.anthera.com/pipeline/science/sollpura.html {{Webarchive|url=https://web.archive.org/web/20150718042137/http://www.anthera.com/pipeline/science/sollpura.html |date=2015-07-18 }}>.</ref>

==Applications of protease based on anti-inflammatory activity==

[[Bromelain]] is a protease usually obtained from pineapple stem tissue, which has been medically used for its anti-inflammatory effects (see [[Bromelain#Medical uses|Bromelain - medical uses]]).

Serratia E-15 protease (also known as [[serratiopeptidase]]<ref name="ATCC21074"/> or serrapeptidase<ref>{{cite web|title=Serratiopeptidase and Its Effectiveness|url=http://www.serrapeptase.org/blog/serrapeptase-efficacy|publisher=Serrapeptase.org|access-date=4 February 2015}}</ref>) is another protease that has been proposed as an anti-inflammatory agent.<ref>See US Patent 3,792,160, issued 12 Feb 1974:  M Isono, et al., for ''Method of treating inflammation and composition therefor''.  The material is also described in {{cite journal | vauthors = Miyata K, Maejima K, Tomoda K, Isono M | title = Serratia protease: Part I. Purification and general properties of the enzyme. | journal = Agricultural and Biological Chemistry | date = February 1970 | volume = 34 | issue = 2 | pages = 310–8 }}</ref>  Anti-inflammatory effects of this protease have been reported again more recently,<ref name="pmid2647603">{{cite journal | vauthors = Esch PM, Gerngross H, Fabian A | title = [Reduction of postoperative swelling. Objective measurement of swelling of the upper ankle joint in treatment with serrapeptase-- a prospective study] | language = de | journal = Fortschritte der Medizin | volume = 107 | issue = 4 | pages = 67–8, 71–2 | date = February 1989 | pmid = 2647603 }}</ref> and the material has come into some use in alternative or complementary medicine.  On the other hand, it does not appear that there are positive clinical trial results for this material of a kind that would be needed to gain regulatory approval for controlled pharmaceutical uses.<ref>"[http://www.medicine.ox.ac.uk/bandolier/booth/alternat/serrapep.html ''Serratiopeptidase - finding the evidence'']", an article available at [[Bandolier (journal)|Bandolier (online journal)]].</ref>

== See also ==
* [[Nattokinase]]

== References ==
{{reflist}}

{{Proteases}}
{{Enzymes}}
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[[Category:Hydrolases]]
[[Category:EC 3.4|*]]
[[Category:Medical treatments]]
[[Category:Proteases| ]]