Bovine colostrum as a biologic in clinicalmedicine: A review – Part II:

Clinical studies

W.G. Struff1 and G. Sprotte2

1Center for Transfusion Medicine Muenster, German Red Cross Blood Transfusion

Service West gGmbH, Muenster, and 2Clinic and Polyclinic for Anesthesiology,

University of Wuerzburg, Pain Clinic for Outpatients, Wuerzburg, Germany

Bo vine colostrum as a bi o logic in clin i cal med i cine: A re view – Part II

Ab stract. The value of bo vine colostrumas a bi o logic in med i cine is doc u mented inclin i cal tri als and sup ported by rel a tivelylarge databases con tain ing case re ports andan ec dotal find ings. The main ac tions in cludean an ti bac te rial ef fect and mod u la tion of theim mune re sponse. The abil ity of bo vine co -los trum con cen trates (BCC are polyvalentbo vine colostrum con cen trates pro ducedfrom the colos trums of sev eral 100 cows) toneu tral ize lipopolysaccharides, i.e. endo tox ins aris ing from Gram-neg a tive bac te rial patho -gens and to in hibit enterogenic endotoxemia in an i mal mod els as shown in the last re view tohave its coun ter part in pa tient ther apy. Clin i -cal tri als with BCC pro vide ev i dence that oralap pli ca tion re duces the in flux of LPS fromthe gut and this ap pears to be a ma jor mech a -nism un der ly ing its ther a peu tic ef fect in pa -tients at risk for Gram-neg a tive sep tic shock;data from two well-con trolled clin i cal stud ieswith a to tal of 100 sur gi cal pa tients haveshown that the in hi bi tion of in tes ti nal LPS ab -sorp tion mea sured af ter the ap pli ca tion ofBCC not only re duced the LPS lev els in thepe riph eral blood but also in flam ma tory pa -ram e ters like IL-6 and CRP were found tobe di min ished. The usual daily dose of thecom mer cially avail able BCC prep a ra tion,Lactobin® (LC1) is 10 – 20 g daily, but higherdoses can be used in the ma jor ity of pa tientsbe cause of the low in ci dence of in tol er anceprob lems. In chronic di ar rhea in volv ing se -vere forms of sec ond ary immunodeficien -cies, pa tients re ceiv ing LC1 were dis -ease-free for about 4 weeks but the re sponsemay be lower in pa tients with AIDS. BCC isef fec tive in in fants with hem or rhagic di ar rhea caused by in fec tions with enterohemorrhagicE. coli and re duces the like li hood of the dis -ease pro gress ing to a hemolytic uremic syn -drome. The safety of newer BCC prod uctsob tained from BSE-free re gions seems nowbe yond con ten tion. In the case of LC1, whichwas used as a com mer cial di etary food stuff inGer many un til 1992 and tested in three Phase1 and 5 clin i cal stud ies (two tri als in pa tients

with sec ond ary immunodeficiencies, one insur gi cal pa tients with gas tro in tes ti nal dis or -ders, one in pa tients un der go ing open heartsur gery and one in pe di at ric pa tients withEHEC in fec tions), there were no cases ofBSE-as so ci ated dis ease such as the new vari -ant of Creutz feldt-Jakob dis ease. Side ef fectsof clin i cal rel e vance are lim ited to pos si blein tol er ance to lac tose and sen si tiv ity to milkpro teins as these are also pres ent in manycom monly used food stuffs. Im por tant syn er -gis tic ac tions with con ven tional drug ther a -pies have been ob served with BCC in clud inga re duc tion in LPS plasma lev els in pa tientswith Gram-neg a tive bac te rial in fec tionstreated with bac te ri cidal an ti bi ot ics. Inhealthy per sons there are only small con cen -tra tions of LPS de tect able in pe riph eral blood(nor mal val ues: 3 – 10 pg/ ml plasma, i.e. ap -prox i mately 0.1 EU/ml). In con trast, el e vatedsys temic lev els with con cen tra tions > 300pg/ml are com mon in pa tients with se vereGram-neg a tive sep sis and sep tic shock.Raised LPS lev els oc cur mainly in pa tientswith Gram-neg a tive bac te rial in fec tions whohave been treated with bacterio cidal an ti bi ot -ics. The LPS-low er ing ef fects of BCC areprob a bly due to the nu mer ous ac tive com po -nents pres ent in BCC which have their or i ginin the in nate humoral and adap tive im munesys tem of their bi o logic source, the cow.

Introduction

Bo vine colostrum has health-giv ing prop -er ties but wide spread use in ther a peu tics inthe past was lim ited be cause of tech ni cal fac -tors af fect ing the man u fac ture such as thesen si tiv ity of the lipid com po nents in rawcolostrum to ox i da tion and the need for cool -ing fa cil i ties during storage.

The stand ardi za tion of the man u fac ture of BCC in clud ing col lec tion pro ce dures, pool -ing meth ods, pro duc tion of ho mog e nous

Key words

ev i dence-based med i -

cine – immunotherapy –

gas tro in tes ti nal in fec tion

– nu tri tional sup ple ment

– chronic id io pathic pain

syn drome – polyvalent

bovine colostrum con -

cen trates (BCC) – clin i -

cal tri als – di ar rhea –

cachexia – in nate im mu -

nity

Re ceived

Sep tem ber 10, 2007;

ac cepted

De cem ber 20, 2007

Cor re spon dence to

Dr. G. Sprotte

Clinic and Poly clinic for

An es the si ol ogy, Uni ver -

sity of Wuerzburg, Pain

Clinic for Out pa tients,

Josef-Schnei der-Straße

6, 97080 Wuerzburg,

Ger many

Sprotte_G@

klinik.uni-wuerzburg.de

In ter na tional Jour nal of Clin i cal Phar ma col ogy and Ther a peu tics, Vol. 46 – No. 5/2008 (211-225)

Re view

©2008 Dustri-Verlag Dr. K. FeistleISSN 0946-1965

batches and an a lyt i cal char ac ter iza tion havebeen de scribed in Part I of this re view [Struffand Sprotte 2007]. Prod uct ho mo ge ne ity inpar tic u lar is a strict pre req ui site for clin i calre search in clud ing the use of BCC as a di etary sup ple ment in the case of some groups of crit -i cally ill pa tients. Re ports on hyperimmune

BCC are not dealt with in de tail here sincethey in volve a dif fer ent type of BCC (uti li za -tion of a lim ited num ber of colostra ob tainedfrom cows vac ci nated with var i ous an ti gens,e.g. Shigella flexneri, E.coli strains, var i ousProtozoa, virus strains: see review by Ward etal. [2005].

Clin i cal re search has in volved both pro -spec tive and con trolled clin i cal tri als andthree re views have been pub lished sum ma riz -ing the most im por tant of the ear lier clin i caltri als with BCC [Davidson 1996, Kelly 2003,Korhonen et al. 1999]. These stud ies in cluded the ther apy of di ar rhea not re spond ing tocom monly used med i ca tion, e.g. in pa tientswith AIDS, those with se vere pri mary andsec ond ary immunodeficiencies and in thetreat ment of rotavirus in fec tions in in fants. Alist of the most im por tant clin i cal stud ies car -ried out us ing hyperimmune prep a ra tions andpolyvalent BCC are shown in Table 1.

Part II of this re view deals mainly withclin i cal stud ies car ried out with polyvalentBCC, the pharmacodynamic po ten tial ofwhich has been tested in an i mal stud ies andap pro pri ate in vi tro ex per i ments for re viewsee [Struff and Sprotte 2007]. A se lec tion ofcon trolled clin i cal tri als with polyvalent BCC are listed be low and their de signs and re sultsdis cussed in the following paragraphs.

Clinical indications for BCC

(current options using

polyvalent preparations and

conforming to evidence-based

medicine standards)

Some of the clin i cal stud ies with the com -mer cially avail able BC-con cen trate, LC1(Lactobin®, Biotest Pharma GmbH, Dreieich, Ger many), have been dou ble-blind and pla -cebo-con trolled and based on com pre hen sivepharmacodynamic in ves ti ga tions. Con sid er -able in for ma tion is avail able on the pro duc -tion and anal y sis of this prod uct and it can bere garded as a pro to type bi o logic for poly -valent BCC [Lissner et al. 1996, Stephan et al. 1990].

LC1 was de vel oped for clin i cal use andwas man u fac tured ac cord ing to the GMP- guidelines and the stud ies have been car riedout ac cord ing to GCP. How ever, as pre cau -

Struff and Sprotte 212

Ab bre vi a tions

AIDS ac quired im munode fi ciency syn drome

AUC area un der curve

BCC bo vine colostrum con cen trate

BSE bo vine spongiform encephalopathy

CD14ac ti va tion marker on monocytes, macrophages, neutrophil and

den dritic cells

CNS cen tral ner vous sys tem

CRP C-re ac tive pro tein

CVID com mon vari able im mu no de fi ciency

E. coli Esch e richia coli

EHEC enterohemorrhagic Esch e richia coli

espP E. coli se creted pro te ase P

ETEC enterotoxigenic Esch e richia coli

ENC endotoxin neu tral iza tion ca pac ity

GCP Good Clin i cal Prac tice

GI gas tro in tes ti nal tract

GvHD graft versus host dis ease

HAART highly ac tive antiretroviral ther apy

HIV hu man im mu no de fi ciency vi rus

HUS hemolytic uremic syn drome

H. pylori Helicobacter pylori

IgG im mu no glob u lin G

IL-4 interleukin-4

IL- 6 interleukin-6

IL-10 interleukin-10

IVIG polyvalent in tra ve nous im mu no glob u lin class G

LC1 Lactobin®

LC2N Lactobin N®

LPS lipopolysaccharide

MALT mu cosa-as so ci ated lym phatic tis sue

MOV multior gan fail ure

NSAID nonsteroidal anti-in flam ma tory drug

PAI patho ge nic ity is land

SCIG sub cu ta ne ously ad min is tered immunoglobulins

SIRS sys temic in flam ma tory re sponse syn drome

stcE se creted pro te ase of C1 esterase in hib i tor from EHEC

STEC Shiga toxin-pro duc ing E. coli

STx Shiga toxin

TGF-b trans form ing growth fac tor b

TLR4 Toll-like re cep tor-4

TNF-a tu mor ne cro sis fac tor a

WR Wal ter Reed classification

tion dur ing the in tro duc tion of BSE safetymea sures, LC1 was re placed by LC2N(Lactobin N®, Dr. Wolz GmbH, Geisenheim,Ger many), a colostrum prep a ra tion fromNew Zea land ob tained from BSE-free cat tle.On the other hand, a fin ger print anal y sis,based on the con tent of anti-LPS specificitiesper mg IgG in di cated that the two prep a ra -tions are equiv a lent [Waaga-Gas ser, un -published observations 2005].

A com mon find ing in Phase II – III clin i -cal stud ies and the Phase I stud ies in healthyvol un teers with LC1 was the ex cel lent tol er -ance and in view of the method of man u fac -ture, this char ac ter is tic can pre sum ably be ex -trap o lated to LC2N with out res er va tion[Struff and Sprotte 2007]. Ad verse re ac tionsare ab sent on re peated ap pli ca tion of highdoses and the only con tra in di ca tions to the

clin i cal ap pli ca tion of BCC known so far arean in tol er ance to lac tose and hy per sen si tiv ityto bo vine milk pro teins which disappear onwithdrawal of BCC-treatment.

Use of BCC to treat chronic

recurrent diarrhea in patients

with AIDS and other forms of

secondary immunodeficiencies

Prior to the in tro duc tion of the poly -pragmatic highly ac tive antiretroviral ther apy (HAART), di ar rhea and weight loss oc curredin more than 50% of pa tients with AIDS. Inmany pa tients, the course of this com pli ca tion was se ri ous and the prog no sis poor. In about30% of pa tients, ev i dence for en teric patho -

Bo vine colostrum as a bi o logic in clin i cal med i cine: A re view – Part II 213

Ta ble 1. Clin i cal stud ies car ried out us ing bo vine colostrum con cen trates (BCC) since 1970 (eth i cal in di ca tions only).

In di ca tions in ves ti gated:Num ber of patients

en rolled In ves ti ga tors

1. Di ar rhea:

1.1. Di ar rhea due to bac te rial patho gens

EHEC in fec tions (in chil dren) 30 [Huppertz et al. 1999]

Helicobacter pylori (infections in in fants) 24 [Casswall et al. 1998]

Shigellosis (in in fants) 70 [Ashraf et al. 2001]

Diarrhea due to in fec tions with enterotoxic E. coli (ETEC) (in chil dren) 60 [Mietens et al. 1979]

1.2. Di ar rhea due to vi ral patho gens

Ther apy of acute rotaviral in fec tions in chil dren 75 [Hilpert et al. 1987]

Pro phy laxis for rotaviral in fec tions in hos pi ta lized chil dren 120 [Davidson et al. 1989]

Ther apy of rotaviral in fec tions in in fants 75 [Mitra et al. 1995]

Ther apy of rotaviral in fec tions in in fants 80 [Sarker et al. 1995]

Ther apy of rotaviral in fec tions in in fants 135 [Ylitalo et al. 1998]

1.3. Di ar rhea due to protozoal patho gens

Chronic cryptosporidiosis in AIDS patients 24 [Greenberg and Cello 1996]

Cryptosporidiosis in HIV-in fected pa tients 37 (Subgroup) [Rump et al. 1992]

Cryptosporidiosis in pa tients with AIDS 21 [Tzipori et al. 1987]

Cryptosporidiosis in HIV-in fected pa tients 5 [Nord et al. 1990]

Cryptosporidiosis in HIV-in fected pa tients 25 [Plettenberg et al. 1993]

2. Neutralization of LPS (enterogenic translocation)

Stud ies in pa tients un der go ing ab dom i nal sur gery 40 [Bölke et al. 2002a]

Stud ies in pa tients un der go ing car diac sur gery 60 [Bölke et al. 2002b]

3. Ther apy of GI-in fec tions with un known patho gens

Dis tal co li tis 14 [Khan et al. 2002]

Sjögren’s syn drome 20 [Pedersen et al. 2002]

Di ar rhea in AIDS pa tients 25 [Plettenberg et al. 1993]

gens was lack ing and only about half of thosewith iden ti fi able etiologic patho gens caus ingdi ar rhea re sponded to an ti bi ot ics. Ther apy ofthis dis ease us ing oral LC1 (10 g/day for 10days) was in ves ti gated in a multicenter pi lotstudy in 37 im mu no de fi ciency pa tients withchronic di ar rhea. Of these pa tients, 29 wereHIV + WR 4-6 (Wal ter Reed classification), 2 had com mon vari able im mu no de fi ciency(CVID), 1 had an im mu no de fi ciency of un -known eti ol ogy and 5 had graft ver sus hostdis ease (GvHD) fol low ing allogeneic bonemar row trans plan ta tion. A good re sponse, insome cases with long-last ing nor mal iza tionof the di ar rhea was ob tained in 22 of the 33treat ment pe ri ods and only 4 pa tients withAIDS were non-re spond ers. The mean dailystool fre quency de creased from 7.4 be foretreat ment with BCC to 2.2 at the end of thetreat ment. A re cur rence of di ar rhea was ob -served in 12 pa tients dur ing the 4-week pe -riod post dose (41%) but 14 pa tients were free of di ar rhea for pe ri ods lon ger than 4 weeks(48%). In tes ti nal cryptosporidiosis dis ap -peared in 4 pa tients. The treat ment was alsosuc cess ful in 4 of the 5 patients with GvHDand no serious side effects were recorded inany of the patients [Rump et al. 1992].

In a sub se quent pla cebo-con trolled PhaseIII clin i cal trial in 63 pa tients with HIV- infection, these find ings could not be con -firmed. The in ves ti ga tors at trib uted this to the in tro duc tion of the HAART ther apy reg i mengiven to the pa tients dur ing the study since itwas ob served that this ther apy caused marked changes in the spec trum of in tes ti nal patho -gens (un pub lished re port, Biotest PharmaGmbH, Dreieich, Germany).

BCC in the treatment of

hemorrhagic diarrhea in infants

In a Phase II pla cebo-con trolled, ran dom -ized clin i cal study, 30 chil dren with acutehem or rhagic di ar rhea due to in fec tion withenterohemorrhagic E. coli (EHEC) weretreated with LC1 [Huppertz et al. 1999]. Dur -ing treat ment the me dian value for stool fre -quency de creased from three to one per day,whereas dur ing treat ment with pla cebo therewas no change (p < 0.05). In the pa tientstreated with BCC, the du ra tion re quired for a

re duc tion in stool fre quency of at least 50%was shorter (p < 0.05).

Treat ment with BCC also in creased theex cre tion of E. coli ex press ing intimin andEHEC-hemolysin al though the dif fer encesdid not reach sta tis ti cal sig nif i cance. The re -sults of this study with colostrum are clin i -cally im por tant since ther apy of EHEC dis -eases with an ti bi ot ics is con tro ver sial and anal ter na tive and safe ther apy other than BCC is not avail able. In deed, a num ber of an ti bi ot icsac tu ally in crease the amount of Shiga toxin invi tro [Kimmit et al. 2000, Kohler et al. 2000,Yoh et al. 1999, Zhang et al. 2000] and Wonget al. [2000] showed in a pro spec tive clin i calstudy that an ti bi otic ther apy in in fants withEHEC in fec tions in creases the risk of de vel -op ing a hemolytic uremic syn drome (HUS).Clin i cal stud ies car ried out later con firmedthat an ti bi otic ther apy of EHEC in fec tions, inpar tic u lar in those pa tients al ready de vel op -ing the syn drome, wors ened the course of dis -ease and the fi nal out come [Bell et al. 1997,Dundas et al. 2001, Tap per et al. 1995]. There sults of the study of Huppertz et al. [1999]are sup ported by the find ings of Lissner et al.[1996, 1998] where the serological anal y sisof LC1 re flect ing a block ade of Shiga toxin(STx) pro duc tion, points to the mode of ac -tion of BCC in the pro phy laxis of HUS.

Se vere di ar rhea and HUS in chil drencaused by EHEC have been re ported fromcoun tries through out the world and EHEC,like serotype O157, non-O157 are known tobe im por tant caus ative agents of these dis -eases. EHEC can per sist in the gut of cat tle,goats, sheep, horses and geese. These do mes -tic an i mals con sti tute there fore di rect or in di -rect in fec tious routes af fect ing man, mainlyin volv ing the in ges tion of con tam i nated foodsuch as raw milk and raw milk prod ucts, un -cooked meat, non-pas teur ized ap ple juice and may on naise. In fants liv ing in ru ral dis trictsare par tic u lar prone to in fec tions from thesesources [Huppertz and Karch 1998].

EHEC are as so ci ated with nu mer ous vir u -lence fac tors, the most im por tant of which arethe Shiga tox ins, the Type III se cre tion sys tem and the re spec tive effector pro teins en codedby the lo cus of enterocyte ef face ment andplasmid-en coded pro teins such as EHEC- hemolysin, EspP and StcE (for re view see[Bielaszewska and Karch 2005, Caprioli et al. 2005, Karch 2001, Nataro et al. 1998,

Struff and Sprotte 214

Orihuela et al. 2005]. In in fants with se verehem or rhagic di ar rhea due EHEC in fec tions,the per cent age who de velop HUS is 5 – 10%of all cases [Huppertz and Karch 1998].

The clin i cal and eco nomic im pact of these in fec tions and the need for hos pi tal ad mis sion to treat de hy dra tion and HUS is a grow ingbur den on the health ser vices [Tarr 1995].

A com mon prob lem in car ry ing out clin i -cal tri als in pa tients with HUS is deal ing withep i de mi o log i cal fac tors and their un pre dict -abil ity and this prob lem arises be cause theres er voir for EHEC-type patho gens is dif fi -cult to iden tify [Huppertz et al. 1999]. The ep -i de mi ol ogy prob lems in Ger many in volv ingin fec tions with Shiga toxin-pro duc ing E. colihas been re viewed by Karch et al. [1997] andin a global context by Noris and Remuzzi[2005].

The strict avoid ance of an ti bi ot ics in thether apy of HUS has been ques tioned re centlybut it is im por tant to note that the ther a peu ticra tio nale for their use in HUS is based on only one meta-anal y sis of clin i cal stud ies, the pro -to cols of which dif fer mark edly in the qual itystan dards ap plied [Phillips et al. 2005]. Onthe other hand, BCC prep a ra tions like LC1and con se quently LC2N are ef fec tive in HUSboth as treat ment and as pro phy lac tic agentses pe cially in children and are well tolerated.

Intra-enteral neutralization of

lipopolysaccharides (endotoxins,

LPS) with BCC in Gram-negative

bacterial infections

The gut as an in ter face with the en vi ron -ment co mes into di rect con tact with bothfood stuffs and in fec tious or gan isms. In quan -ti ta tive terms it is the larg est or gan of the im -mune sys tem. The homeostatic mech a nismsin the gas tro in tes ti nal wall in volv ing per fu -sion with blood, lo cal de fense re ac tions (mu -cosa-as so ci ated lym phatic tis sues, MALT)and thus the in teg rity of the gut wall are es -sen tial for the in take of nu tri ents and pro tec -tion against in vad ing patho gens and their tox -ins. The iso la tion of Gram-neg a tive bac te riafrom the blood of pa tients with a sep sis syn -drome or SIRS (sys temic in flam ma tory re -sponse syn drome) fre quently in di cates asource of in fec tion in the gas tro in tes ti nal or

uri nary tract. Pre ven tion of the in va sion ofpatho gens us ing bac te ri cidal an ti bi ot ics is es -sen tial but can lead to the re lease of endo tox -ins CPS from the de cay ing patho gens fol -lowed by a mas sive sec ond ary re lease ofcytokines such as interleukins and tu mor ne -cro sis fac tor (TNF-a) from mononuclearcells with sub se quent tis sue dam age. It isknown that the re lease of these fac tors in trau -matic con di tions, e.g. fol low ing ma jor sur -gery, can cause mul ti ple or gan fail ure[Livingston and Deitch 1995]. The ex tent ofthe dam age to the GI-tract is de pend ent on the rate at which enterocytes are renewed and this depends critically on the rate of cellproliferation [Rittler et al. 2001].

In ad di tion, any en dur ing def i cit of di etarypro tein sup ply causes a sup pres sion of cell- mediated im mu nity whereas early enteral nu -tri tion of pa tients with intra abdomi nal injuriesre duces the rate of com pli ca tions like sep sisand pneu mo nia [Hasenberg et al. 2007,McClave et al. 1997, Moore et al. 1986].

On the ba sis of the re sults ob tained in pre -clin i cal stud ies, two con trolled clin i cal tri alswere car ried out with LC1 to ex am inewhether the com po nents in the prep a ra tionare able to bind LPS and in hibit invasory pro -cesses in the gas troin tes ti nal tract.

In the study of Bölke et al. [2002a] a to talof 40 pa tients un der go ing sur gery of the gas -tro in tes ti nal tract were ran dom ized to re ceiveei ther LC1 (56 g daily for 3 days pre op er a -tively) or pla cebo and the course of theplasma endotoxin lev els and the endotoxinneu tra li za tion ca pac ity (ENC) were mea -sured daily up to the 10th postop er a tive day.The re sults showed that the LPS-lev els in theLC1-group, ex pressed as AUC, were sig nif i -cantly lower than those in the con trol group(p < 0.05). The dif fer ence be tween the twogroups was ap par ent on the day of the op er a -tion and the day af ter. The fall in endotoxinneu tral izing ca pac ity (ENC) was sig nif i -cantly lower in the pa tients treated with theBCC and the re turn to ini tial val ues was fasterthan in the con trol group (p < 0.006). In thesec ond study car ried out by these au thors, theef fect of post op er a tive treat ment with BCCon in tes ti nal LPS translocation was ex am ined in a randomized, pla cebo-con trolled study in60 pa tients un der go ing open-heart sur gery.The pa tients were treated perioperatively for2 days with ei ther 42 g LC1 or pla cebo. The

Bo vine colostrum as a bi o logic in clin i cal med i cine: A re view – Part II 215

endotoxin con cen tra tion in the LC1-groupwas not sig nif i cantly lower and the dif fer ence in the ENC com pared to the con trol group didnot reach sta tis ti cal sig nif i cance (p = 0.06).The dif fer ence in the con cen tra tion of inter -leukin-6 lev els was also non-sig nif i cant butthe CRP-level was sig nif i cantly lower. Thein ves ti ga tors rec om mend that fur ther stud iesshould be car ried out using a higher pre- operative dose of BCC and should be carriedout in a larger number of patients [Bölke et al.2002b].

These two stud ies, per formed ac cord ingto GCP-guide lines in a to tal of 100 sur gi calpa tients, show that LC1 pro duces a markedand in part sta tis ti cally sig nif i cant de crease,mea sured post op er a tively, in LPS in blood.This is fur ther ev i dence that one of the eventsini ti at ing the sep sis syn drome fol low ing hy -po volemic in sults in trau ma tized hypo tensive pa tients is the en try of bac te ria and lipo poly -saccharides from the gut into the blood stream[Bahrami et al. 1998, Claridge et al. 2000,Pfeiffer et al.1996].

Furthermore, anti-LPS ther apy with mono -clonal antibodies in pa tients with hem or rhageand trauma re duces sep tic com pli ca tions[Demetriades et al. 1999]. It can be con cluded from these find ings, that if the GI-tract is ama jor source of LPS, as the ev i dence sug -gests, then elim i na tion or re duc tion of intra -luminal endotoxin, whilst main tain ing themucosal bar rier func tion in in ten sive care pa -tients, should pre vent or re duce the com pli ca -tions of Gram-neg a tive sep sis and the de vel -op ment of mul ti ple or gan fail ure (MOV)[Fitzal et al. 2001].

Of in ter est in this re gard is a pi lot study ofUlrich et al. [2001] in pa tients suf fer ing fromma jor burns where there is a high risk ofGram-neg a tive sep sis with le thal out come.These in ves ti ga tors de ter mined the LPS levelin plasma be tween the sec ond and third day in such pa tients and ob served a marked in creasein the endotoxin con cen tra tion which reached a max i mum af ter 47 hours. Of the 7 pa tientsex am ined, 2 showed sharp in creases inplasma LPS and these 2 pa tients sub se quently developed sepsis and died.

As in the case of HUS pa tients, a fur therra tio nale for the ap pli ca tion of BCC in trauma pa tients is that the use of bac te ri cidal an ti bi ot -ics can pro voke or re in force endotoxin emia[Holzheimer et al. 1996, Seifert et al. 2002].

LPS in mam mals can be ben e fi cial or det -ri men tal in a con cen tra tion-de pend ent man -ner and these ef fects in volve sen sor mol e -cules such as the Toll-like re cep tors [Beutlerand Rietschel 2003]. The mech a nisms bywhich BCCs neutralize LPS and pre vent theirup take into the sys temic cir cu la tion is notwell un der stood but lactoferrin, prob a bly themost im por tant in hib i tor in BCC of LPS, isable to bind the lipid A part of the LPS-mol e -cule and this ap pears to act syn er gis ti callywith the anti-LPS-spe cific an ti bod ies in BCCin over- coming the ef fects of an in fec tion[Appelmelk et al. 1994, Bellamy et al. 1992,Fomsgaard 1990].

BCC as an adjuvant in the

therapy of patients with

idiopathic pain syndrome

The stud ies car ried out with LC1 in thesepa tients to date have been mainly ex plor atoryand of ten sup ported by un pub lished ob ser va -tions re fer ring back to ear lier ob ser va tionswith pa tients re ceiv ing immunotherapy.Mondorf and Duswald [1979] had treated 54pa tients with her pes zoster and 18 pa tientswith her pes sim plex with in tra ve nous immu -no globulins class G (IVIG). Dur ing the in fu -sion the pa tients ex pe ri enced a re lax ation inskin ar eas with se vere le sions, and re ported acom plete re lief of their con com i tant neu ral -gia. In a fur ther open de sign study car ried outlater, in tra ve nous IgG (IVIG) was given to 6pa tients re ceiv ing cytostatics to treat tu morsand who con com i tantly suf fered from ex -tended her pes sim plex or zoster in fec tionswith se vere at tacks of neu ral gia. All pa tientsre ported im me di ate pain re lief dur ing orshortly after the infusion of IVIG (5 – 10 g ofIgG) [Mondorf et al. 1981].

New in sights into the value of this ap -proach have been ob tained from in ves ti ga -tions at the Uni ver sity Hos pi tal, Wuerzburg,Ger many. The re search groups fo cussed onpa tients with in trac ta ble pain in whom painre lief with es tab lished ther a peu tic reg i menshad failed [Goebel et al. 2002a]. In a pro spec -tive multidose, open-la bel co hort study in 130 con sec u tive pa tients with chronic pain syn -dromes, in clud ing 48 cases with fibromyalgia and a to tal of 12 dif fer ent types of pain syn -

Struff and Sprotte 216

drome, IVIG pro duced ap prox i mately 70%pain re lief in 20% of pa tients and in about half of the pa tients the level of pain re lief wasabove 25%. An in ter est ing find ing was that in pa tients re spond ing to IVIG treat ment, therewas a re turn of al most in ces sant pain in a large pro por tion of those who had had an in fec tion,e.g. com mon cold or in flu enza a short timebe fore or simultaneously. In other pa tientswith chronic pain syn dromes, there were ahigher pro por tion of pa tients with se rum an ti -bod ies against in tes ti nal patho gens whencom pared to healthy con trols [Goebel et al.2005]. These re sults prompted re searchgroups in the Uni ver si ties of Wuerzburg andOx ford to look for suit able di ag nos tic pa ram -e ters in pa tients with de fined pain syndromesprior to their enrollment in further studieswith IVIG [Goebel et al. 2003].

In a clin i cal study in 40 pa tients withwide spread pain, 26 of whom had fibro my -algia, there was a lack of anti-in flam ma toryand an al ge sic Th2 cytokine ac tiv ity whencom pared to age- and sex-matched con trols[Uçeyler et al. 2006]. In con trast to the con trol sub jects, pa tients had a sig nif i cantly lowerrel a tive gene ex pres sion and lower se rumcon cen tra tions of the Th2 cytokines, IL-10and IL-4.

These re sults prompted the in ves ti ga torsto per form an un con trolled field trial at thePain Center, Uni ver sity Hos pi tal, Wuerzburg, Ger many, in which BCC 20 g daily was ad -min is tered to ap prox i mately 1,000 pa tientswith dif fer ent types of id io pathic syndromes.The aim of the in ves ti ga tion was to ex am inethe hy poth e sis that some pa tients had a post- infectious au to im mune dis ease re spon sive totreat ment with BCC. Sig nif i cant pain re liefoc curred in 30 – 40% of pa tients de pend ingon the du ra tion and lo cal iza tion of the dis easeand there was a la tency of 4 – 10 days af ter the treat ment be fore the full ef fect was de tect able[Sprotte, Uni ver sity Hos pi tal, Wuerzburg:un pub lished ob ser va tions]. Pa tients with id -io pathic fa cial pain syn dromes, in clud ingtrigeminus neu ral gia, glossopharyngeal neu -ral gia, myo arthrop athy of the jaw and atyp i cal fa cial pain showed the high est re sponse rateand the short est la tency pe riod. Pa tients withchronic wide spread pain, in clud ing fibro -myalgia with and with out ir ri ta ble bowel syn -drome also showed a marked im prove ment insymp toms. It was con cluded that the pa tients

in both groups had im pair ment in the mucosal bar rier func tion in the gas tro in tes ti nal tractand this find ing was sup ported by mea sure -ments of the re sorp tion rates of var i ous sug ars [Goebel et al. 2002b]. In the case of pa tientswith fibromyalgia, 31 of 40 who were ex am -ined by this method and who had not beentreated with IVIG or BCC pre vi ously re portedan ad verse re ac tion af ter the ap pli ca tion of thetest sug ars. This di ag nos tic tool is there fore not suit able for rou tine clin i cal use.

Ac cord ing to the ex pe ri ence ob tained atthe Wuerzburg Pain Cen ter, pa tients withchronic pain show ing a pos i tive re sponse tothe treat ment with BCC, can also be suc cess -fully treated with IVIG or SCIG and in manycases the re sults of these al ter na tive treat -ments are su pe rior to those us ing BCC. How -ever, BCC has the ad van tage that pa tients re -spond ing can be treated in their homes (i.e. no infusion required).

Pa tients with chronic pain syn dromesgiven BCC, in con trast to those with out suchsymp toms, were of ten found to de velop a pre -vi ously un re cog nized in tol er ance to the milkcon stit u ents in BCC lim it ing their use in these pa tients. Re peated in take of BCC has alsocaused ex ac er ba tion of atopic der ma ti tis withskin le sions. Al though the tol er ance andreponse to BCC is gen er ally ex cel lent, in chil -dren with chronic pain, atopy (al ler gic bron -chial asthma, rhi ni tis and atopic der ma ti tis) isnot an in fre quent oc cur rence dur ing treat -ment with BCC [Sprotte, Uni ver sity Hospital, Wuerzburg: unpublished observations].

Mechanisms of action of BCC

Colostrum, as start ing ma te rial for BCC,in which the cel lu lar com po nents, most of thelipoproteins and some pro teins such aslactalbumin have been re moved, is a highlycom plex mix ture of var i ous effector mol e -cules [Kelly 2003, van Hooijdonk et al.2000]. This ex plains the wide range of phar -macodynamic ef fects de scribed in in vi trosys tems, in an i mals and in clin i cal stud ies.

Synergisms of the colostral effector sys -tems with the in nate defense of a host,especially of pa tients in fected with bac te rialpatho gens, col o niz ing the gas tro in tes ti nalmu cosa ap pear to be suit able. For in stance,the ef fi cacy of antimicrobial pep tides as

Bo vine colostrum as a bi o logic in clin i cal med i cine: A re view – Part II 217

defen sins pro duced per ma nently by the cellsin high con cen tra tions in the small in tes tinewith a broad ac tiv ity range against Gram-neg -a tive and Gram-pos i tive bac te ria might rep re -sent ap pro pri ate can di dates in this re gard[Weh kamp et al. 2007].

Discussion including a

comment on other possible

applications of BCC

One of the pri mary tasks of the im munesys tem in mam mals is the rec og ni tion of an ti -gens and their even tual forced elim i na tion.Bo vine colos trums and BCC made from itcarry out this task and also other im por tanttasks such as the min i miz ing of in flam ma toryevents which fol low ex po sure to an ti gens.The ru mi nant is unique in that there is a se lec -tive pas sage of immunoglobulins class IgGinto the mam mary gland prior to par tu ri tionso that the colos trums con tain large amountsof spe cific an ti bod ies. Gorman and Halliwell[1989] and Kelly [2003], more re cently de -scribed in more quan ti ta tive terms the con stit -u ents of the adap tive and the in nate im munesys tem also pres ent in BCC acting together ina syn er gistic manner.

The ef fi cacy of BCC ther apy ap pears there -fore to stem from those prop er ties of na tivecolostrum which are im por tant for the health ofnewborn mam mals and these in clude the trans -fer in the humoral com po nents as so ci ated within nate and ac quired ma ter nal im mu nity and thecon com i tant pro vi sion of readily avail able nu -tri tional sub stances such as es sen tial amino ac -ids.

The pharmacodynamic ef fects of BCCthus com ple ment or re place those of stan dardther a pies, e.g. with an ti bi ot ics, an al ge sics and anti-in flam ma tory drugs.

One of the sites of ac tion of BCC is themucosal sur face of the gas tro in tes ti nal tractand ac tive com po nents pre sum ably in ter actwith the mu cosa-as so ci ated lym phatic tis sue(MALT). Al though the pro teins in BCC ef -fec tor mol e cules, mainly IgG1, are readilydegradable in the small in tes tine, more than20% of IgG1 reaches the ileocecal valve in anac tive form [Roos et al. 1995]. As shown inTa ble 1, the most clin i cal stud ies with BCC up to now have in volved the pro phy laxis or theearly treat ment of in fec tious dis eases orig i -

nat ing in the GI-tract. In the case of some syn -dromes due to bac te rial in fec tion, adjuvanttreat ment us ing BCC in ad di tion to an an ti bi -otic is usu ally in di cated and suc cess ful.

Un like an ti bi ot ics, de vel op ment of drugre sis tance with BCC is not thought to be aprob lem with BCC and there is no ev i dencethat the con stit u ents in duce en zymes in -volved in the me tab o lism of xenobiotics.

In pa tients with Gram-neg a tive sep sis thegut is usu ally the site for trans fer of LPS vialymphatics into the sys temic cir cu la tion. Themech a nisms in volved have been dis cussed inPart I and ev i dence has been pro vided for theintra-enteral neu tral iza tion of LPS by LC1 inpatients.

The mech a nisms of ac tion of the ac tivecom po nents in BCC is not known in de tailand the ear lier view that the g-glob u lins(mainly IgG1) are the most im por tant ac tiveprin ci ple must be in ter preted only as a work -ing hy poth e sis. More re cent in ves ti ga tions,how ever, such as those of Bölke et al. [2002a],have shown sta tis ti cally sig nif i cant de creasesin LPS plasma lev els in pa tients un der go inggas tro in tes ti nal sur gery af ter treat ment withLC1, and Seifert et al. [2002] us ing a ratmodel of Gram-neg a tive sep tic shock, founda syn ergy be tween anti-LPS specificities(IgG1) and lactoferrin which is also pres ent inBCC and this phe nom e non ap pears to have itsclin i cal coun terpart.

The LPS-re lease phe nom e non, trig geredon the other hand by bac te ri cidal an ti bi ot ics,has been con firmed in clin i cal stud ies by sev -eral groups [Dofferhoff et al. 1991, Prins et al. 1995]. Cer tain types of b-lactam an ti bi ot icsseem to re lease more LPS than oth ers andthis prop erty is strongly cor re lated withpenicillin- binding pro tein-3 [Jack son andKnopp 1992].

These find ings are rel e vant since there ismuch ev i dence to show that the gut is a lo cusminoris resistentiae for in fec tions and a res er -voir for nox ious sub stances like LPS andShiga-like tox ins when the gut wall is dam -aged, e.g. dur ing hypoperfusion states or dur -ing malnutrition.

A re cently pub lished re view, how ever,casts doubt on the role of LPS as a ma jor ini ti -a tor of sep tic pro cesses when the treat ment ofpa tients with anti TNF-a and anti-LPS in ter -ven tions fail [Riedemann et al. 2003]. Theneu tral iza tion in situ of LPS, a ma jor toxin

Struff and Sprotte 218

from Gram-neg a tive bac te ria, by BCC is at -trib ut able to antitoxic effector mol e cules likelactoferrin and spe cific IgG an ti bod ies. Thecom bi na tion of these phar ma co log i cal ef fects ac counts for the ef fi cacy of BCC in the pre -ven tion of Gram-neg a tive sep tic shock in patients. A pro found re view ar ti cle deal ingwith the pathophysiological role of CPS inclin i cal med i cine was pub lished by Al ex an -der and Rietschel [2001].

Com par i son of data on pa tients with sep -sis of non-en teric or i gin with those hav ingenterosepsis may not be very in for ma tivesince the site of in fec tion and stage of the dis -ease have a marked in flu ence on the course ofthe dis ease and the ef fects of ther apy. En tericsep sis com prises about 20% of all cases ofsep sis [Mar tin 1991]. Ev i dence from ex per i -men tal [Fitzal et al. 2001] and clin i cal stud ies[Demetriades et al. 1999] point to the gas tro -in tes ti nal en try of bac te ria and pres ence ofLPS fol low ing trauma and hem or rhage withhypoperfusion of the gut wall as the ini ti at ingevents in sep sis. Break down in the in teg rityof the gut bar rier would ag gra vate or gan in -jury in dis tal re gions of the body be cause ofme di a tors, in par tic u lar those car ried in themesenteric lymph [Magnotti et al. 1998]. Onthe other hand, the sys temic ad min is tra tion ofanti-endotoxin agents neu tral izes the plasmaendotoxin and can pro tect the vi tal or gansagainst the in ju ri ous ef fects of these sub -stances [Bahrami et al. 1997, Bahrami andSchlag 1995, Bauer and Welch 1996,Demetriades et al. 1999, Yao et al. 1995].

Sep sis is one of the most fre quent causesof death af ter a ma jor burn in jury and is usu -ally at trib ut able to an in fec tion in volv ingGram-neg a tive or gan isms and the re lease ofLPS [Ulrich et al. 2001]. When more than40% of to tal body sur face is af fected,endotoxin plasma lev els reach a max i mumbe tween the third and the fourth day [Ulrich et al. 2001, Winchurch et al. 1987, Yao et al.1995]. The au thors de scribe this as a con se -quence of in creased colonization of the gutmu cosa by Gram-neg a tive or gan isms andcon com i tant influx of LPS from burnt tissue.

Nev er the less, LPS mol e cules resorbedcon tin u ally from mucosal sur faces such as the GI-tract with a sur face area of 300 m2 have aphys i o log i cal func tion within a lim ited rangeof con cen tra tions within the mam ma liandefence networks.

Endotoxin is one of the most po tentimmunostimulants, which via the ac ti va tionof Toll-like (TLRs) re cep tors acts as a per ma -nent de fense sys tem against var i ous patho -gens. An in fected host, on the other hand,would over re act in the pres ence of largequan ti ties of LPS, in par tic u lar with a mas sive lib er a tion of TNF-a and other in flam ma torycytokines [Beutler and Rietschel 2003].

Ir re spec tive of the patho log i cal back -ground, it is al ways cor rect in the case of sep sis treat ment, along with fo lic acid ap pli ca tionand an ti bi otic ther apy, to in hibit endo toxinsand the ef fects of these.

In a clin i cal trial in chil dren with se verehem or rhagic di ar rhea due to in fec tion withenterohemorrhagic E. coli (EHEC), LC1 wasable to elim i nate these or gan isms and re ducethe dan ger of de vel op ing a hemolytic uremicsyn drome (HUS), a dis ease which in in fantsis of ten fa tal or can cause se vere damage[Huppertz et al. 1996]. This re sult pro videsev i dence that the an ti body specificities of theg-glob u lins pres ent in BCC are con sis tentwith their abil ity to elim i nate in the hu manGI-tract Esch e richia coli- expressing Shigatox ins 1 and 2, intimin and EHEC-hemolysin[Lissner et al. 1996]. Be cause of the risks ofan ti bi otic treat ment in pe di at ric pa tients andits ineffectivity in pre vent ing HUS, treat mentwith polyvalent BCC is the ap par ent first- choice ther apy in pa tients with EHEC.

Safety aspects regarding the use

of BCC in man

A risk anal y sis of the cases treated long- term with a polyvalent BCC pri mar ily mustin volve the tech ni cal cri te ria of the pro duc -tion pro cess, the re sults of pharmaco dynamicin ves ti ga tions and the clin i cal stud ies andcase re ports, ex am ples of which are de scribed in this review.

i) The raw ma te rial e.g. for LC2N orig i nates from an i mal herds kept un der strict vet er i -nary-con trolled con di tions. It is ob tainedfrom New Zea land colostrum and thusfrom colos trums orig i nat ing from a coun -try cer ti fied as BSE-free.

ii) The pro duc tion of LC1 is car ried out ac -cord ing to GMP. Ho mo ge ne ity of pro duc -tion lots is at tained by us ing a colostrumpool from sev eral hun dred colostrum col -

Bo vine colostrum as a bi o logic in clin i cal med i cine: A re view – Part II 219

lec tions and strict com pli ance with thestan dards of pro duc tion (GMP). SinceLactobin N (LCZN) is a com plex mix tureof pro teins, this mea sure avoids the gen er -a tion of new al ler genic de ter mi nants inthe pro duc tion pro cess. In this re gard,par tic u larly infants are at risk of de vel op -ing cow’s milk al lergy af ter the ces sa tionof breast-feed ing when their in tes ti nal im -mune sys tem be comes ex posed to thesepro teins in other food stuffs [Heyman1999].

iii) There is no ad di tion of for eign ma te ri alsdur ing the pro duc tion pro cess of LC2Nand LC1.

iv) An i mal tests on LC1 have shown no ev i -dence of tox ic ity (fin ger print anal y sis andmi cro bi o log i cal test pro ce dures basedupon the IgG1-con cen tra tion have dem -on strated bioequivalence be tween LC1and LC2N).

v) No ad verse re ac tions were re ported withLC1 in the three Phase 1 clin i cal tri als inhealthy sub jects. In the clin i cal tri als inpa tients, Lactobin pro duced no se vere ad -verse re ac tions with the ex cep tion of pa -tients with a pro longed his tory of chronicpain. Re sorp tion tests with var i ous sug arshave shown that pa tients with chronicpain are able to ab sorb macromoleculesfrom the gut [Goebel et al. 2002b]. Therisk of sen si ti za tion re ac tions againstnon- degraded pro teins means that BCCmight there fore be con tra in di cated in pa -tients with ce liac dis ease and chronic en -ter i tis such as Crohn’s disease.

vi) Lac tose in tol er ance: ab sorp tion of lac tosere quires lactase ac tiv ity in the brush bor -der of the sen si tiz ing small in tes tine. Lac -tose in tol er ance can oc cur in in fants andyoung chil dren with acute diarrheal dis -ease but the clin i cal sig nif i cance of this islim ited ex cept in more se verely af fectedchil dren. Symp toms of lac tose in tol er -ance are rel a tively com mon in older children and ad o les cents but signs of in -tes ti nal in jury re sult ing from it are un -com mon. Lac tose in tol er ance dif fers from milk pro tein sen si tiv ity since a sen si tiv ityto milk pro teins in volves the im mune sys -tem and can cause le sions of the in tes ti nalmu cosa. Dur ing the first 3 months of life,2 – 5% of in fants ex hibit symp toms ofcow’s milk pro tein intol er ance which gen -er ally re solves it self be fore reach ing the

age of 1 year (for re view see Hagemann[1999]).

Sec ond ary lactase de fi ciency can oc curlater in life the eti ol ogy of which most of tenlies in an in fec tion, e.g. due to rota virus.Symp toms can also arise in ce liac dis ease,Crohn’s dis ease and im mune-re lated dis eases[Heyman 2006] or enteropathies as can oc curin pa tients with chronic pain syn dromes. Thepro por tion of pa tients at the Wuerzburg PainCen ter pre sent ing with symp toms of in tol er -ance to in gested lac tose is ap prox i mately10%. The lac tose in BCC, like that in LCprep a ra tions, causes a re in force ment of painsen sa tions in ad di tion to caus ing typ i cal gas -tro in tes ti nal dis or ders [Sprotte, unpub lishedob ser va tions].

Potential clinical indications for

BCC

Some po ten tial in di ca tions for the clin i calap pli ca tion of BCC have been men tionedabove. The mul ti ple effector mech a nismscon tained in BCC can in hibit or de stroy hu -man patho gens and can neu tral ize vir u lencefac tors and lib er ated tox ins. They are also in -volved in antiphlogistic ef fects. The ques tionarises, whether other pa tient pop u la tions inICU such as trans plant re cip i ents might alsoben e fit from sup ple men tary treat ment withBCC. The se lec tive de con tam i na tion of thegut in pa tients af ter mul ti ple trauma, se veresur gi cal stress and in tense immunosup pres -sion ther apy with an ti bi ot ics has been the sub -ject of con tro ver sial dis cus sion since its in tro -duc tion in 1984 [Stoutenbeck et al. 1984]. Inspite of a re duc tion in mor tal ity rates in clin i -cal stud ies in ICU pa tients re ceiv ing com bi -na tions of non-ab sorbed antimicrobial andtop i cal oropharyngeal an ti bi ot ics, con cernex ists re gard ing the de vel op ment of bac te rialre sis tance [de Jonge et. al. 2003, Vin cent2003]. Im ple ment ing the ad di tional treat ment with BCC into the cur rent scheme of se lec tive gut de con tam i na tion could rep re sent an im -prove ment but ev i dence in the form of datafrom ap pro pri ate clin i cal stud ies is needed.The ra tio nale be hind such ther apy in ICU pa -tients could be the erad i ca tion of aerobic,potential ly pathogenic microorganisms fromthe stom ach and gut and the preservation ofuseful indigenous anaerobic flora.

Struff and Sprotte 220

In the same con text Bölke et al. [2002a]for ex am ple, ad vo cate the perioperative treat -ment with BCC as a prom is ing new strat egyfor pa tients un der go ing liver trans plan ta tion,thereby pro tect ing the trans planted or gan forin stance against a mas sive CPS translocationfrom the gut.

The in hi bi tion of enteral LPS-trans fer mightalso be ben e fi cial in pa tients with ma lig nanttu mors since such pa tients may be comeanorexic due to in creased ac tiv i ties of TNF-ain duced by LPS. In creased TNF-a ac tiv i tiesin tu mor pa tients and the ef fects of this mighthave been at trib uted to in duc tion of CD14 onmonocytes in blood and within the tu mor.

It can be spec u lated that re duc tion in thein tes ti nal LPS-in flux would de crease TNF-aac ti va tion and pre vent an orexia in tu mor pa -tients. In sup port of this view is the ob ser va -tion that in pa tients with pan cre atic can cer the ex pres sion of CD14 in both Kupffer cells andblood monocytes is in creased. This changewould ren der them more sen si tive to bac te rial LPS and in crease the like li hood of a pro -inflammatory re sponse with the con se quentdevelopment of cachexia.

Bitzan et al. [1998] ob tained ev i dence that the col o ni za tion of gas tric ep i the lial cells byHelicobacter pylori can be blocked bypolyvalent BCC such as LC1 and that thismight be use ful as an adjuvant in treat inggastroduodenal dis ease in clud ing gas tric ma -lig nan cies when this or gan ism is pres ent. Thecausal re la tion ship be tween the oc cur rence of H. pylori and a va ri ety of gas tric dis eases hasbeen re ported in de tail in a more re cent re -view by Brenner and Rothenbacher [2005].

In a clin i cal study car ried out in 24 in fantswith H. pylori in fec tions, pu ri fied colostrumfrom cows vac ci nated with the or gan ism,how ever, failed to cure the in fants of the dis -ease [Casswall et al. 1998].

A fur ther pos si ble in di ca tion for the use of BCC is the treat ment of in ju ries to the smallin tes tine caused by nonsteroidal anti-in flam -ma tory drugs (NSAID). The ra tio nale forclin i cal in ves ti ga tions on this topic stemsfrom an i mal ex per i ments with BCC in ratswas de scribed in Part I of this review.

In two well-con trolled clin i cal stud ies,Playford et al. [2001] used a non-in va sivemarker to de ter mine the pres ence of gastro -intestinal in jury and in creased gut per -meability and to ex am ine the ef fect of BCC

(Vi a ble Bioproducts, Turku, Fin land) in pa -tients tak ing NSAIDs. In one of these stud ies,a ran dom ized cross over trial in healthy malesub jects, changes in gut per me abil ity, ex -pressed as lactulose/rhamnose re sorp tion ra -tios, were com pared be fore and af ter a 5-daytreat ment with 50 mg indomethacin givenorally 3 times daily whilst ad min is ter ing 125ml colostrum or whey pro teins (con trol) 3times daily. The find ings showed thatindomethacin caused a 3-fold in crease in gutper me abil ity in the con trol arm but no sig nif i -cant in crease dur ing the coadministration ofcolostrum.

In the sec ond study on the ef fect ofcolostral and con trol so lu tions (125 ml, for 7days) on gut per me abil ity in pa tients (n = 15)on long-term NSAID ther apy, the ini tial per -me abil ity ra tios were low and not in flu encedby coad min is tra tion of the test compounds.Fur ther stud ies are there fore needed to con firm that bo vine colostrum prep a ra tions pre ventNSAID- in duced gas tro in tes ti nal dam age.

Cesarone et al. [2007] re ported a clin i calstudy in 144 sub jects with ages in the range of30 – 80 years, com pared the ef fi cacy of oralcolostrum (900 mg/day for 2 months;Concon, Guna, Srl., Milano, It aly) with vac -ci na tion against in flu enza. The study pop u la -tion was di vided into three groups: sub jectsre ceiv ing BCC who had been pre vi ously vac -ci nated against in flu enza vi rus, sub jects with -out pre vi ous vac ci na tion who also re ceivedBCC and Group 3 con tain ing sub jects whore ceived no pro phy lac tic treat ment. Theresults showed that the av er age num ber of flu- episodes in sub jects treated with colostrum wassignificantly lower than in sub jects not re -ceiv ing colostrum. The num ber of days withflu was 3 times higher in the non-colostrum- treated sub jects. The in ci dence of events as -so ci ated with flu was higher in the vac ci natedthan in the colostrum-treated in di vid u als (p <0.05). Pre lim i nary data in healthy vol un teersim mu nized with at ten u ated Sal mo nella typhioral vac cine and who con com i tantly con -sumed liq uid pre packed bo vine colostrumtended to have greater in creases in spe cificIgA (ELISPOT as say and flow cytometry invi tro) in com par i son to vol un teers not treatedwith colostrum [He et al. 2001]. The in creasein spe cific sIgA is re garded by the au thors asthe key mechanismof flu-pre ven tion by BCC.

Bo vine colostrum as a bi o logic in clin i cal med i cine: A re view – Part II 221

Safety and efficacy of BCC

administration to

humans – conclusions

In con clu sion, the re sults of Phase I stud -ies in hu man vol un teers and Phase II/III stud -ies in pa tients have dem on strated that thepharmacodynamic ef fects of BCC ob servedin preclin i cal ex per i ments have their ther a -peu tic coun ter part in a num ber of clin i callyim por tant dis eases al though there is a needfor con fir ma tory in ves ti ga tions in most ar eas. On the other hand, the im pli ca tions of thecon sid er able vol ume of case study data, e.g.those held at the data bank of the Pain Clinicin Wuerzburg, should not be un der es ti mated.The re sults of the stud ies are con sis tent withthe view that BCC ther apy is a “sup port ive”ther apy, i.e. the pharmacodynamic mech a -nisms evolve from the multifold ac tive com -po nents pres ent and that these mod u late thebody defense pro cesses (Fig ure 1 gives anout line of the present medical experience totreat patients with BCC).

The safety of BCC has been well-es tab -lished in the clin i cal stud ies with LC1 and upto now no ma jor or unpredictable risks havebeen re ported. In tol er ance to lac tose, a com -po nent in BCC prep a ra tions, and milk pro -

teins can oc cur but such re ac tions can gen er -ally be an tic i pated from the di etary habits ofthe patient.

Since it is clear that BCC prep a ra tions aresafe and ef fec tive in a broad range of in di ca -tions, this unique form of peroral pas sive im -mu ni za tion de serves attention.

Acknowledgment

The au thors wish to thank Prof. Her bertSchmidt (Uni ver sity of Stuttgart-Hohenheim, Ger many) and Dr. Nils Roos (Bundes for -schungs anstalt für Ernährung und Lebens -mittel, Kiel, Ger many) for their com pe tentad vice.

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