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'''Serum-derived bovine immunoglobulin/protein isolate''' ('''SBI'''), sold under the brand name '''EnteraGam''' among others, is a derived product from the [[blood]] of adult cows.
'''Serum-derived bovine immunoglobulin/protein isolate''' ('''SBI'''), sold only under the brand name '''EnteraGam<sup>®</sup>''', is a medical food product derived from bovine serum obtained from adult cows in the United States.


EnteraGam'''<sup>®</sup>''' is a medical food product intended for the dietary management of chronic diarrhea and loose stools. EnteraGam'''<sup>®</sup>''' must be administered under medical supervision. It is used to manage chronic loose or frequent stools in any condition or disease where diarrhea is chronically present such as in patients with [[diarrhea]]-predominant [[irritable bowel syndrome]] (IBS-D), [[inflammatory bowel disease]] (IBD), small intestine bacterial overgrowth (SIBO), recurrent ''Clostridium difficile''-infection associated diarrhea, microscopic colitis or [[HIV]]-related enteropathy as well as many other diseases and conditions resulting in chronic diarrhea.<ref name=":0"><nowiki>http://enteragam.com/assets/lib/EnteraGam_Product_Information.pdf</nowiki>, Retrieved July 2018. </ref> EnteraGam'''<sup>®</sup>''' is manufactured by Entera Health, Inc. Ankeny, IA and promoted by RedHill Biopharma, Inc. Raleigh, NC to gastroenterologists and other healthcare providers in the United States.
It is primarily used to manage [[enteropathy]] in people whose ability to digest is impaired. It can also be used to manage chronic loose or frequent stools like those commonly associated with [[diarrhea]]-predominant [[irritable bowel syndrome]] (IBS-D), [[inflammatory bowel disease]] (IBD) or [[HIV]]-related enteropathy.<ref name="WJG">{{cite journal |last=Petschow |first=Bryon W. |last2=Blikslager |first2=Anthony T.|last3=Weaver|first3=Eric M. |last4=Campbell |first4=Joy M. |last5=Polo| first5=Javier| last6=Shaw| first6=Audrey L.| last7=Burnett| first7=Bruce P.| last8=Klein |first8=Gerald L. |last9=Rhoads |first9 =J. Marc| date=September 2014 |title=Bovine immunoglobulin protein isolates for the nutritional management of enteropathy |journal= [[World Journal of Gastroenterology]]|publisher= |volume=20 |issue=33 |pages= 11713–26|doi=10.3748/wjg.v20.i33.11713 | pmid=25206275 | pmc=4155361}}</ref>


== Mechanism of Action ==
⚫
==Medical uses==
Unlike common dietary proteins, SBI contains a concentrated source of immunoglobulin that may aid in the management of chronic diarrhea or loose and frequent stools. Immunoglobulins found in SBI have been shown to bind to microbial components with immune-activating potential from a variety of bacteria, fungi and viruses, including those implicated in human disease.<ref>{{Cite journal|last=Horgan|first=A|date=April 26-30, 2014|title=Serum-derived bovine immunoglobulin/protein isolate binds to pathogen associated molecular patterns.|url=http://www.fasebj.org/content/28/1_Supplement/836.6|journal=FASEB|volume=|pages=|via=}}</ref> The putative mechanism of action features, this binding of inflammatory antigens may prevent their passage into the lamina propria of the bowel wall, presumably due steric exclusion.<ref>{{Cite journal|last=Detzel|first=CJ|date=April 2015|title=Bovine immunoglobulin/protein isolate binds pro-inflammatory bacterial compounds and prevents immune activation in an intestinal co-culture model|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382133/pdf/pone.0120278.pdf|journal=PLOS One|volume=10(4)|pages=|via=}}</ref> The resultant dampening of immune response in the gut-associated lymphoid tissue (GALT) is believed to allow for restoration of intestinal homeostasis, leading to resumption of normal gut function and nutrient absorption.<ref name=":1">{{Cite journal|last=Petschow|first=Bryon W.|date=May 2014|title=Serum-derived bovine immunoglobulin/protein isolate: postulated mechanism of action for management of enteropathy|url=|journal=Clinical and Experimental Gastroenterology|volume=7|pages=181–90|via=}}</ref>


The therapeutic effect of SBI’s action on various GI conditions with chronic diarrhea provides a specific nutritional benefit that cannot be provided by normal dietary proteins alone or by increased intake of foods which contain immunoglobulin (i.e., milk).<ref name=":0" /><ref name=":2">{{Cite journal|last=Petschow|first=Bryon W|date=January 2015|title=Dietary Requirement for Serum-Derived Bovine Immunoglobulins in the Clinical Management of Patients with Enteropathy|url=|journal=Digestive Diseases and Sciences|volume=|pages=|via=}}</ref>
Serum-derived bovine immunoglobulin/protein isolate is most often used in the fat loss prevention of post-weaning piglets. Due to dietary change post-weaning piglets often develop [[diarrhea]] and it has been shown to have some efficacy in preventing this fat loss related to diarrhea in this animal population.<ref name="Immunoglobulins and Early weaned pigs">{{cite journal|last1=Pierce|first1=JL|title=Effects of spray dried animal plasma and immunoglobulins on performance of early weaned pigs|journal=J Animal Science|pmid=16282627|volume=83|year=2005|pages=2876–85|doi=10.2527/2005.83122876x}}</ref>


⚫
==Medical uses==
Oral immunoglobulins may improve function in the [[Human gastrointestinal tract|gastrointestinal (GI) tract]].<ref name="WJG"/><ref name="Dietary">{{cite journal |last=Petschow |first=Bryon W. |last2=Burnett |first2=Bruce P.|last3=Shaw|first3=Audrey L.|last4=Weaver|first4=Eric M. |last5=Klein| first5=Gerald L.| last6=| first6=| last7=| first7=| last8= |first8= |last9= |first9 =| date=January 2015 |title=Dietary Requirement for Serum-Derived Bovine Immunoglobulins in the Clinical Management of Patients with Enteropathy|url=https://link.springer.com/article/10.1007/s10620-014-3322-0 |journal= [[Digestive Diseases and Sciences]]|publisher= |volume=60 |issue=1 |pages= 13–23|doi=10.1007/s10620-014-3322-0 |access-date=7 June 2015}}</ref> Conditions like HIV often limit or impair the body's ability to digest select nutrients. Studies have indicated that serum-derived bovine immunoglobulin/protein may help restore the ability of the GI tract to properly absorb and utilize those nutrients.<ref name="CEG">{{cite journal |last=Petschow |first=Bryon W. |last2=Burnett |first2=Bruce|last3=Shaw|first3=Audrey L. |last4=Weaver |first4=Eric M. |last5=Klein| first5=Gerald L.| last6=| first6=| last7=| first7=| last8= |first8= |last9= |first9 =| date=May 2014 |title=Serum-derived bovine immunoglobulin/protein isolate: postulated mechanism of action for management of enteropathy |journal= [[Clinical and Experimental Gastroenterology]]|publisher= |volume=7 |issue= |pages= 181–90|doi=10.2147/CEG.S62823 | pmid=24904221 | pmc=4041178}}</ref>

In humans, oral immunoglobulins may improve function in the [[Human gastrointestinal tract|gastrointestinal (GI) tract]].<ref name=":0" /><ref name=":2" /> Conditions like HIV-enteropathy, IBS-D (irritable bowel syndrome with diarrhea) , SIBO (small intestine bacterial overgrowth), recurrent C. difficile infection-associated diarrhea and post-infectious IBS-D often limit or impair the body's ability to absorb and digest select nutrients including water.<ref name=":1" /> Clinical studies have indicated that serum-derived bovine immunoglobulin/protein isolate may help to reduce diarrhea and to restore the ability of the GI tract to properly absorb and utilize those nutrients.<ref>{{Cite journal|last=Wilson|first=Dale|date=|title=Evaluation of Serum-Derived Bovine Immunoglobulin Protein Isolate in Subjects with Diarrhea-Predominant Irritable Bowel Syndrome|url=|journal=Clinical Medicine Insights: Gastroenterology|volume=6|pages=49–60|via=}}</ref><ref>{{Cite journal|last=Arrouk|first=R|date=2017|title=Serum-derived bovine immunoglobulin (SBI) for children with diarrhea predominant irritable bowel syndrome (d-IBS)|url=|journal=NASPGHAN|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Rana|first=A|date=2017 Apr|title=Tolerability, and efficacy of serum-derived bovine immunoglobulin in children with diarrhea-predominant irritable bowel syndrome|url=http://www.gastrojournal.org/article/S0016-5085(17)32299-0/abstract|journal=Gastroenterol|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Crawford|first=C|date=2015|title=Post-infectious irritable bowel syndrome with functional diarrhea following C. difficile infections: Case studies of responses using serum-derived bovine immunoglobulin|url=http://www.ghrnet.org/index.php/joghr/article/view/900|journal=Gastro and Hepatology Res.|volume=4(4)|pages=1577-81|via=}}</ref><ref>{{Cite journal|last=Good|first=L|date=2017|title=SBI Retrospective Study Group. Oral serum bovine immunoglobulin improves IBS-D symptoms analyzed from patient medical charts|url=http://www.alliedacademies.org/articles/oral-serum-bovine-immunoglobulin-improves-ibsd-symptoms-analyzed-from-patient-medical-charts.pdf|journal=Biol Med Case Rep.|volume=1(1)|pages=16-23|via=}}</ref><ref>{{Cite journal|last=Shaw|first=AL|date=2017|title=Impact of serum-derived bovine immunoglobulin/protein isolate therapy on irritable bowel syndrome and inflammatory bowel disease: A survey of patient perspective|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460652/pdf/ppa-11-1001.pdf|journal=Patient Prefer Adherence|volume=11(1001)|pages=1-7|via=}}</ref><ref>{{Cite journal|last=Valentin|first=N|date=2017|title=A. Potential mechanisms of effects of serum-derived bovine immunoglobulin/protein isolate therapy in patients with diarrhea-predominant irritable bowel syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350178/pdf/PHY2-5-e13170.pdf|journal=Physiol Rep.|volume=5(5)|pages=|via=}}</ref><ref>{{Cite journal|last=Weinstock|first=LB|date=2014|title=Serum-derived bovine immunoglobulin/protein isolate therapy for patients with refractory irritable bowel syndrome|url=http://file.scirp.org/pdf/OJGas_2014102311124814.pdf|journal=Open J Gastroenterology|volume=4|pages=329-334|via=}}</ref><ref>{{Cite journal|last=Beaurele|first=BD|date=2015|title=Successful management of refractory ulcerative colitis with orally administered serum-derived bovine immunoglobulin therapy|url=http://www.oatext.com/pdf/CCRR-1-130.pdf|journal=Clin Case Rep Rev.|volume=1(4)|pages=90-92|via=}}</ref><ref>{{Cite journal|last=Shafran|first=I|date=2015|title=Management of inflammatory bowel disease patients with oral serum-derived bovine immunoglobulin|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622288/pdf/10.1177_1756283X15593693.pdf|journal=Thera Adv Gastroenterol.|volume=|pages=1-9|via=}}</ref><ref>{{Cite journal|last=Soriano|first=RA|date=2017|title=Clinical and pathologic remission of pediatric ulcerative colitis with serum-derived bovine immunoglobulin added to standard treatment regimen|url=https://www.karger.com/Article/Pdf/475923|journal=Case Rep Gastroenterol.|volume=11(2)|pages=335-343|via=}}</ref><ref>{{Cite journal|last=Ferm|first=S|date=2017|title=Serum-derived bovine immunoglobulin as novel adjunct in complicated Clostridium difficile colitis treatmen|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425282/pdf/CG-CGCR170030.pdf|journal=ACG Case Rep J.|volume=|pages=|via=nih.gov}}</ref><ref>{{Cite journal|last=Gelfand|first=MS|date=2017|title=Oral serum-derived bovine immunoglobulin for management of infectious diarrhea due to norovirus and cryptosporidiosis in solid organ transplant patients|url=|journal=Infect Dis Clin Practice|volume=25(4)|pages=218-220|via=}}</ref><ref>{{Cite journal|last=Arikapudi|first=S|date=2017|title=Serum bovine immunoglobulin for chemotherapy-induced gastrointestinal mucositis|url=|journal=Amer J Hospice and Palliative Med.|volume=|pages=|via=}}</ref><ref>''Iduru S, Burnett BP.  Management of celiac disease and non-celiac gluten sensitivity with serum-derived bovine immunoglobulin/protein isolate. Poster presented (#1343) at 2015 ACG Annual Scientific Meeting, Honolulu, HI.  October 19, 2015.''</ref><ref>''Kumar V, Zhou E, Yuliya A, Mansoor MS, Sharma P, Feuerstadt P. Serum-derived bovine immunoglobulin (SBI) is safe and well tolerated in patients with recurrent C. difficile infection (RCDI) treated medically. Poster (P100) Presented at American College of Gastroenterology Annual Meeting, Orlando, FL. October 15, 2017.''</ref>


==History==
==History==


Research into serum-derived bovine immunoglobulin/protein isolate (SBI) and other bovine-associated sources began in the field of [[Veterinary medicine|animal health]].<ref name="Journal1998">{{cite journal |last=van Beers-Schreurs |first=Hetty M.G. |last2=Nabuurs |first2=Marius J.A.|last3=Vellenga |first3=Liebe |last4=Kalsbeek-van der Valk |first4=Hilda J. |last5=Wensing| first5=Theo| last6=Breukink| first6=Hendrik J.| last7=| first7=| last8= |first8= |last9=|first9 =| date=June 1998 |title=Weaning and the Weanling Diet Influence the Villous Height and Crypt Depth in the Small Intestine of Pigs and Alter the Concentrations of Short-Chain Fatty Acids in the Large Intestine and Blood|url=http://jn.nutrition.org/content/128/6/947.short |journal= [[Journal of Nutrition]]|publisher= |volume=128 |issue=6 |pages= |doi=|access-date=7 June 2015}}</ref> Early studies examined the health effects of SBI on early weaned [[Domestic pig|piglets]] that had developed intestinal inflammation, intestinal barrier dysfunction, and general enteropathy. These issues often manifested in diarrhea, [[dehydration]], and death for young piglets.<ref name="Peace">{{cite journal |last=Peace |first=Ralph Michael |last2=Campbell |first2=Joy|last3=Polo|first3=Javier |last4=Crenshaw |first4=Joe |last5=Russell| first5=Louis| last6=Moeser| first6=Adam| last7=| first7=| last8= |first8=|last9=|first9 =| date=July 2011 |title=Spray-Dried Porcine Plasma Influences Intestinal Barrier Function, Inflammation, and Diarrhea in Weaned Pigs|url=http://jn.nutrition.org/content/141/7/1312.short |journal= [[Journal of Nutrition]]|publisher= |volume=141 |issue=7 |pages= |doi=|access-date=7 June 2015}}</ref><ref name="Pierce">{{cite journal |last=Pierce |first=JL |last2=Cromwell |first2=GL|last3=Lindemann|first3=MD |last4=Russell |first4=LE |last5=Weaver| first5=EM| last6=| first6=| last7=| first7=| last8= |first8=|last9=|first9 =| date=December 2005 |title=Effects of spray-dried animal plasma and immunoglobulins on performance of early weaned pigs.|journal= [[Journal of Animal Science]]|publisher= |volume=83 |issue=12 |pages= 2876–85|doi= 10.2527/2005.83122876x| pmid=16282627}}</ref> SBI and other [[Antibody|immunoglobulin]]-rich substances in piglets improved [[digestion]], [[metabolism]], and feed intake, increasing lean muscle mass and protein utilization. Gastric infection and diarrhea were also reduced in the post-[[weaning]] phase.<ref name="SBIReview">{{cite journal |last=Torralladorna|first=David | date=2010 |title=Spray Dried Animal Plasma as an Alternative to Antibiotics in Weanling Pigs - A Review |url=http://www.koreascience.or.kr/article/ArticleFullRecord.jsp?cn=E1DMBP_2010_v23n1_131|journal=Asian-Australasian Journal of Animal Sciences|publisher= |volume=23 |issue=1 |pages= |doi=|access-date=7 June 2015}}</ref>
Research into bovine- and porcine-associated sources of immunoglobulin began in the field of [[Veterinary medicine|animal health]].<ref>{{Cite journal|last=Pierce|first=JL|date=December 2005|title=Effects of spray-dried animal plasma and immunoglobulins on performance of early weaned pigs|url=|journal=Journal of Animal Science|volume=83 (12)|pages=2876–85|via=}}</ref><ref>{{Cite journal|last=Peace|first=Ralph Michael|date=July 2011|title=Spray-Dried Porcine Plasma Influences Intestinal Barrier Function, Inflammation, and Diarrhea in Weaned Pigs|url=|journal=Journal of Nutrition|volume=141 (7)|pages=|via=}}</ref> Studies examined the health effects of adding immunoglobulins to the feed of  early-weaned [[Domestic pig|piglets]] that had developed intestinal inflammation, intestinal barrier dysfunction, and general malnutrition causing the piglets not to thrive.<ref>{{Cite journal|last=van Beers-Schreurs|first=Hetty M.G|date=June 1998|title=Weaning and the Weanling Diet Influence the Villous Height and Crypt Depth in the Small Intestine of Pigs and Alter the Concentrations of Short-Chain Fatty Acids in the Large Intestine and Blood|url=|journal=Journal of Nutrition|volume=128 (6)|pages=|via=}}</ref> These issues often manifested in diarrhea, [[dehydration]], and death for young piglets. The addition of [[Antibody|immunoglobulin]]-rich protein isolates  to the piglets’ food improved [[digestion]], [[metabolism]], and feed intake, increasing lean muscle mass and protein utilization.<ref>{{Cite journal|last=Torralladorna|first=David|date=2010|title=Spray Dried Animal Plasma as an Alternative to Antibiotics in Weanling Pigs - A Review|url=|journal=Asian-Australasian Journal of Animal Sciences|volume=23 (1)|pages=|via=}}</ref><ref>{{Cite journal|last=Kuchibhatla|first=R|date=2015|title=Nutritional impact of dietary plasma proteins in animals undergoing experimental challenge and implications for patients with inflammatory bowel disorders. A meta-analysis.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561828/pdf/an007930.pdf)|journal=Adv Nutr.|volume=6(5)|pages=541-51|via=nih.gov}}</ref>Gastric infection and diarrhea were also reduced in the post-[[weaning]] phase.


Based on the benefits of immunoglobulins in swine, EnteraGam'''<sup>®</sup>''', a formulation for humans , was developed and introduced into the US market in 2013 as a [[medical food]]. Medical foods have become a mainstay in the management of gastrointestinal disorders.<ref>{{Cite journal|last=Ciampa|first=BP|date=2017|title=The emerging therapeutic role of medical Foods for gastrointestinal disorders|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402682/pdf/GH_13_104.pdf|journal=Gastroenterol Hepatol.|volume=13(2)|pages=104-115|via=nih.gov}}</ref> It is estimated that nearly 8 million doses of EnteraGam'''<sup>®</sup>''' have been administered to over 32,000 patients in the United States since 2013. The overall AE rate (Adverse Events rate) is less than 0.4%. The most common AEs reported by patients administered EnteraGam'''<sup>®</sup>''' include mild constipation (23), headache (13), mild diarrhea (11), nausea (8), abdominal pain (8), abdominal distention (7) and hives (7). No serious AEs have been attributed to EnteraGam'''<sup>®</sup>''' during post-marketing surveillance.
EnteraGam, a formulation for people, was introduced into the US market in 2013 as a [[medical food]].<ref name="GEBTN">{{cite journal |last=Dutton |first=Gail | date=1 August 2013 |title=Big Need in IBD: Drugs to Slow Progression|url=http://www.genengnews.com/gen-articles/big-need-in-ibd-drugs-to-slow-progression/4941/ |journal= [[Genetic Engineering & Biotechnology News]]|publisher= |volume=33 |issue=14 |pages= |doi=|access-date=7 June 2015}}</ref><ref name="Market">{{cite news | last=| first=| title =New Prescription Medical Food Product For Dietary Management of IBS-D| newspaper =| location = | pages = | language = | publisher =[[MarketWatch]]| date =20 August 2013 | url =http://www.marketwatch.com/story/new-prescription-medical-food-product-for-dietary-management-of-ibs-d-2013-08-20| accessdate =7 June 2015}}</ref>


==Composition==
==Composition==


Immunoglobulin from beef protein constitutes greater than 50% of the composition of EnteraGam. The product comes in a powder that, in addition to the serum-derived bovine immunoglobulin/protein isolate (SBI), is composed of around 5 grams of [[dextrose]] which aids in the product's ability to mix well into liquid and soft foods as well as trace amounts of [[sunflower]] [[lecithin]] which helps in spray drying the protein and dextrose to a powder. EnteraGam contains no milk products like [[whey protein]], [[casein]], or [[lactose]]. The product also contains no [[gluten]], dye, or [[soy]]. Patients with a beef allergy or any other allergy to SBI components are advised to avoid using EnteraGam.<ref name="WJG"/><ref name="Market"/><ref name="Wilson">{{cite journal |last=Wilson |first=Dale|last2=Evans |first2=Malkanthi|last3=Weaver|first3=Eric |last4=Shaw|first4=Audrey L.|last5=Klein| first5=Gerald L.| last6=| first6=| last7=| first7=| last8= |first8=|last9=|first9 =| date=December 2013 |title=Evaluation of Serum-Derived Bovine Immunoglobulin Protein Isolate in Subjects with Diarrhea-Predominant Irritable Bowel Syndrome|journal=Clinical Medicine Insights: Gastroenterology|publisher= |volume=6 |issue= |pages= 49–60|doi=10.4137/CGast.S13200 | pmid=24833942 | pmc=4020402}}</ref><ref name="EG">{{cite news | last=| first=| title =EnteraGam Available for IBS-D Dietary Management| newspaper =| location = | pages = | language = | publisher =''[[Monthly Prescribing Reference]]''| date =20 August 2013 | url =http://www.empr.com/news/enteragam-available-for-ibs-d-dietary-management/article/308025/| accessdate =7 June 2015}}</ref>
Immunoglobulin from beef protein constitutes greater than 50% of the composition of EnteraGam'''<sup>®</sup>'''. This product is made from the serum of cows after the red cells have been filtered out and the product sprayed on a surface and dried. Each dose of powder that results, in addition to the serum-derived bovine immunoglobulin/protein isolate (SBI), contains 5 grams of [[dextrose]] (pure glucose) which aids in the product's ability to mix well into liquid and soft foods as well as trace amounts of [[sunflower]] [[lecithin]] which helps in spray drying the protein to a powder. EnteraGam'''<sup>®</sup>''' contains no milk products like [[whey protein]], [[casein]], or [[lactose]]. The product also contains no [[gluten]], dye, or [[soy]]. Patients with a beef allergy or any other allergy to SBI components are advised to avoid using EnteraGam'''<sup>®</sup>'''<ref name=":0" /><sup> </sup> Cow plasma and serum are also commonly used in various foods like prepared meat and poultry products. Cow milk contains lower levels (~1%) of the same immunoglobulin.

== Medical Foods ==
'''EnteraGam<sup>®</sup> is a medical food as defined by the Orphan Drug Act of 1988  Medical supervision is required.'''

The term medical food, as defined by the Orphan Drug Act (21 U.S.C. 360ee[b][3]) of 1988, is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” Ingredients in medical foods must be generally recognized as safe (GRAS) and/or approved food additives.

EnteraGam'''<sup>®</sup>''' is manufactured in compliance with current Good Manufacturing Practice (cGMP) for medical foods.


==References==
==References==

Revision as of 19:23, 29 September 2018

Serum-derived bovine immunoglobulin/protein isolate (SBI), sold only under the brand name EnteraGam®, is a medical food product derived from bovine serum obtained from adult cows in the United States.

EnteraGam® is a medical food product intended for the dietary management of chronic diarrhea and loose stools. EnteraGam® must be administered under medical supervision. It is used to manage chronic loose or frequent stools in any condition or disease where diarrhea is chronically present such as in patients with diarrhea-predominant irritable bowel syndrome (IBS-D), inflammatory bowel disease (IBD), small intestine bacterial overgrowth (SIBO), recurrent Clostridium difficile-infection associated diarrhea, microscopic colitis or HIV-related enteropathy as well as many other diseases and conditions resulting in chronic diarrhea.[1] EnteraGam® is manufactured by Entera Health, Inc. Ankeny, IA and promoted by RedHill Biopharma, Inc. Raleigh, NC to gastroenterologists and other healthcare providers in the United States.

Mechanism of Action

Unlike common dietary proteins, SBI contains a concentrated source of immunoglobulin that may aid in the management of chronic diarrhea or loose and frequent stools. Immunoglobulins found in SBI have been shown to bind to microbial components with immune-activating potential from a variety of bacteria, fungi and viruses, including those implicated in human disease.[2] The putative mechanism of action features, this binding of inflammatory antigens may prevent their passage into the lamina propria of the bowel wall, presumably due steric exclusion.[3] The resultant dampening of immune response in the gut-associated lymphoid tissue (GALT) is believed to allow for restoration of intestinal homeostasis, leading to resumption of normal gut function and nutrient absorption.[4]

The therapeutic effect of SBI’s action on various GI conditions with chronic diarrhea provides a specific nutritional benefit that cannot be provided by normal dietary proteins alone or by increased intake of foods which contain immunoglobulin (i.e., milk).[1][5]

Medical uses

In humans, oral immunoglobulins may improve function in the gastrointestinal (GI) tract.[1][5] Conditions like HIV-enteropathy, IBS-D (irritable bowel syndrome with diarrhea) , SIBO (small intestine bacterial overgrowth), recurrent C. difficile infection-associated diarrhea and post-infectious IBS-D often limit or impair the body's ability to absorb and digest select nutrients including water.[4] Clinical studies have indicated that serum-derived bovine immunoglobulin/protein isolate may help to reduce diarrhea and to restore the ability of the GI tract to properly absorb and utilize those nutrients.[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]

History

Research into bovine- and porcine-associated sources of immunoglobulin began in the field of animal health.[22][23] Studies examined the health effects of adding immunoglobulins to the feed of  early-weaned piglets that had developed intestinal inflammation, intestinal barrier dysfunction, and general malnutrition causing the piglets not to thrive.[24] These issues often manifested in diarrhea, dehydration, and death for young piglets. The addition of immunoglobulin-rich protein isolates  to the piglets’ food improved digestion, metabolism, and feed intake, increasing lean muscle mass and protein utilization.[25][26]Gastric infection and diarrhea were also reduced in the post-weaning phase.

Based on the benefits of immunoglobulins in swine, EnteraGam®, a formulation for humans , was developed and introduced into the US market in 2013 as a medical food. Medical foods have become a mainstay in the management of gastrointestinal disorders.[27] It is estimated that nearly 8 million doses of EnteraGam® have been administered to over 32,000 patients in the United States since 2013. The overall AE rate (Adverse Events rate) is less than 0.4%. The most common AEs reported by patients administered EnteraGam® include mild constipation (23), headache (13), mild diarrhea (11), nausea (8), abdominal pain (8), abdominal distention (7) and hives (7). No serious AEs have been attributed to EnteraGam® during post-marketing surveillance.

Composition

Immunoglobulin from beef protein constitutes greater than 50% of the composition of EnteraGam®. This product is made from the serum of cows after the red cells have been filtered out and the product sprayed on a surface and dried. Each dose of powder that results, in addition to the serum-derived bovine immunoglobulin/protein isolate (SBI), contains 5 grams of dextrose (pure glucose) which aids in the product's ability to mix well into liquid and soft foods as well as trace amounts of sunflower lecithin which helps in spray drying the protein to a powder. EnteraGam® contains no milk products like whey protein, casein, or lactose. The product also contains no gluten, dye, or soy. Patients with a beef allergy or any other allergy to SBI components are advised to avoid using EnteraGam®[1]  Cow plasma and serum are also commonly used in various foods like prepared meat and poultry products. Cow milk contains lower levels (~1%) of the same immunoglobulin.

Medical Foods

EnteraGam® is a medical food as defined by the Orphan Drug Act of 1988  Medical supervision is required.

The term medical food, as defined by the Orphan Drug Act (21 U.S.C. 360ee[b][3]) of 1988, is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” Ingredients in medical foods must be generally recognized as safe (GRAS) and/or approved food additives.

EnteraGam® is manufactured in compliance with current Good Manufacturing Practice (cGMP) for medical foods.

References

  1. ^ a b c d http://enteragam.com/assets/lib/EnteraGam_Product_Information.pdf, Retrieved July 2018.
  2. ^ Horgan, A (April 26–30, 2014). "Serum-derived bovine immunoglobulin/protein isolate binds to pathogen associated molecular patterns". FASEB.{{cite journal}}: CS1 maint: date format (link)
  3. ^ Detzel, CJ (April 2015). "Bovine immunoglobulin/protein isolate binds pro-inflammatory bacterial compounds and prevents immune activation in an intestinal co-culture model" (PDF). PLOS One. 10(4).
  4. ^ a b Petschow, Bryon W. (May 2014). "Serum-derived bovine immunoglobulin/protein isolate: postulated mechanism of action for management of enteropathy". Clinical and Experimental Gastroenterology. 7: 181–90.
  5. ^ a b Petschow, Bryon W (January 2015). "Dietary Requirement for Serum-Derived Bovine Immunoglobulins in the Clinical Management of Patients with Enteropathy". Digestive Diseases and Sciences.
  6. ^ Wilson, Dale. "Evaluation of Serum-Derived Bovine Immunoglobulin Protein Isolate in Subjects with Diarrhea-Predominant Irritable Bowel Syndrome". Clinical Medicine Insights: Gastroenterology. 6: 49–60.
  7. ^ Arrouk, R (2017). "Serum-derived bovine immunoglobulin (SBI) for children with diarrhea predominant irritable bowel syndrome (d-IBS)". NASPGHAN.
  8. ^ Rana, A (2017 Apr). "Tolerability, and efficacy of serum-derived bovine immunoglobulin in children with diarrhea-predominant irritable bowel syndrome". Gastroenterol. {{cite journal}}: Check date values in: |date= (help)
  9. ^ Crawford, C (2015). "Post-infectious irritable bowel syndrome with functional diarrhea following C. difficile infections: Case studies of responses using serum-derived bovine immunoglobulin". Gastro and Hepatology Res. 4(4): 1577–81.
  10. ^ Good, L (2017). "SBI Retrospective Study Group. Oral serum bovine immunoglobulin improves IBS-D symptoms analyzed from patient medical charts" (PDF). Biol Med Case Rep. 1(1): 16–23.
  11. ^ Shaw, AL (2017). "Impact of serum-derived bovine immunoglobulin/protein isolate therapy on irritable bowel syndrome and inflammatory bowel disease: A survey of patient perspective" (PDF). Patient Prefer Adherence. 11(1001): 1–7.
  12. ^ Valentin, N (2017). "A. Potential mechanisms of effects of serum-derived bovine immunoglobulin/protein isolate therapy in patients with diarrhea-predominant irritable bowel syndrome" (PDF). Physiol Rep. 5(5).
  13. ^ Weinstock, LB (2014). "Serum-derived bovine immunoglobulin/protein isolate therapy for patients with refractory irritable bowel syndrome" (PDF). Open J Gastroenterology. 4: 329–334.
  14. ^ Beaurele, BD (2015). "Successful management of refractory ulcerative colitis with orally administered serum-derived bovine immunoglobulin therapy" (PDF). Clin Case Rep Rev. 1(4): 90–92.
  15. ^ Shafran, I (2015). "Management of inflammatory bowel disease patients with oral serum-derived bovine immunoglobulin" (PDF). Thera Adv Gastroenterol.: 1–9.
  16. ^ Soriano, RA (2017). "Clinical and pathologic remission of pediatric ulcerative colitis with serum-derived bovine immunoglobulin added to standard treatment regimen". Case Rep Gastroenterol. 11(2): 335–343.
  17. ^ Ferm, S (2017). "Serum-derived bovine immunoglobulin as novel adjunct in complicated Clostridium difficile colitis treatmen" (PDF). ACG Case Rep J. – via nih.gov.
  18. ^ Gelfand, MS (2017). "Oral serum-derived bovine immunoglobulin for management of infectious diarrhea due to norovirus and cryptosporidiosis in solid organ transplant patients". Infect Dis Clin Practice. 25(4): 218–220.
  19. ^ Arikapudi, S (2017). "Serum bovine immunoglobulin for chemotherapy-induced gastrointestinal mucositis". Amer J Hospice and Palliative Med.
  20. ^ Iduru S, Burnett BP.  Management of celiac disease and non-celiac gluten sensitivity with serum-derived bovine immunoglobulin/protein isolate. Poster presented (#1343) at 2015 ACG Annual Scientific Meeting, Honolulu, HI.  October 19, 2015.
  21. ^ Kumar V, Zhou E, Yuliya A, Mansoor MS, Sharma P, Feuerstadt P. Serum-derived bovine immunoglobulin (SBI) is safe and well tolerated in patients with recurrent C. difficile infection (RCDI) treated medically. Poster (P100) Presented at American College of Gastroenterology Annual Meeting, Orlando, FL. October 15, 2017.
  22. ^ Pierce, JL (December 2005). "Effects of spray-dried animal plasma and immunoglobulins on performance of early weaned pigs". Journal of Animal Science. 83 (12): 2876–85.
  23. ^ Peace, Ralph Michael (July 2011). "Spray-Dried Porcine Plasma Influences Intestinal Barrier Function, Inflammation, and Diarrhea in Weaned Pigs". Journal of Nutrition. 141 (7).
  24. ^ van Beers-Schreurs, Hetty M.G (June 1998). "Weaning and the Weanling Diet Influence the Villous Height and Crypt Depth in the Small Intestine of Pigs and Alter the Concentrations of Short-Chain Fatty Acids in the Large Intestine and Blood". Journal of Nutrition. 128 (6).
  25. ^ Torralladorna, David (2010). "Spray Dried Animal Plasma as an Alternative to Antibiotics in Weanling Pigs - A Review". Asian-Australasian Journal of Animal Sciences. 23 (1).
  26. ^ Kuchibhatla, R (2015). "Nutritional impact of dietary plasma proteins in animals undergoing experimental challenge and implications for patients with inflammatory bowel disorders. A meta-analysis". Adv Nutr. 6(5): 541–51 – via nih.gov.
  27. ^ Ciampa, BP (2017). "The emerging therapeutic role of medical Foods for gastrointestinal disorders" (PDF). Gastroenterol Hepatol. 13(2): 104–115 – via nih.gov.
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