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The scientific information in this journal is educational and is not to be used as a substitute for a doctor's care or for proven therapy. PROVIDING SCIENTIFIC INFORMATION RELATED TO NUTRITIONAL SACCHARIDES AND OTHER DIETARY INGREDIENTS. SEPTEMBER 22, 2000

VOL 1, NO 29 EXTERNAL EDITORIAL BOARD

Tom Gardiner, PhD Global Health Safety Environment and Regulatory Affairs Coordinator Shell Chemical Company (Retired) Houston, Texas

Doris Lefkowitz, PhD Associate Clinical Professor of Microbiology University of South Florida College of Medicine Tampa, Florida

James C. Garriott, PhD, D-ABFT Professor (Clinical Adjunct Faculty) University of Texas Health Science Center Consulting Toxicologist San Antonio, Texas

Stanley S. Lefkowitz, PhD Professor of Microbiology and Immunology Texas Tech School of Medicine Lubbock, Texas

Alice Johnson-Zeiger, PhD Professor of Biochemistry (Retired) University of Texas Health Center Tyler, Texas

MANNATECH INCORPORATED INTERNAL EDITORIAL BOARD Stephen Boyd, PhD, MD Kathryn Dykman, MD John Hall, DDS Bill McAnalley, PhD H. Reginald McDaniel, MD Bob Ward, PED

Robert K. Murray, MD, PhD Professor (Emeritus), Biochemistry University of Toronto Toronto, Ontario, Canada

TECHNICAL STAFF Kia Gary, RN Eric Moore, DChem Jane Ramberg, MS GRAPHIC ARTIST Bruce Peschel EDITOR IN CHIEF Eileen Vennum, RAC

Colostrum Biological Activities: A Review Tom Gardiner, PhD ABSTRACT Colostrum, and, particularly, two of its main components, lactoferrin (Lf) and proline-rich peptide (PRP), act to regulate and balance the immune system. This biological activity is not only important in newborns just beginning to live in a hostile environment, but also in adults with overor under-active immune systems, perhaps resulting from various types of stress. Colostrum and its components also have potent anti-bacterial, anti-viral, and anti-fungal activities to help protect the body from invading pathogens. Colostrum and its growth factors enhance wound healing, cartilage formation, and bone repair, stimulate muscle protein synthesis/inhibit protein breakdown, benefit GI tract structure and function, and act on the immune system to inhibit tissue inflammation and allergic response. The Lf component of colostrum also acts to regulate iron absorption and availability, and has been shown to significantly inhibit tumor development, growth, and metastasis. Colostrum and its components exert their biological activities when given orally, in some cases as a dietary supplement; communication with the immune system via the oral mucosa is believed to be important in initiating many of colostrum’s immunomodulatory activities. Moreover, the composition of bovine (cow) and human colostrum is similar, and colostrum from both sources is biologically active in its own as well as other mammalian species when given orally or injected. INTRODUCTION Colostrum is the first complete food available to newborn

mammals and is even essential for life in some mammalian species.1 It is also the first mammary secretion obtained within the first few hours after birth, and provides many important biological elements and nutrients present in the mother’s blood. This pre-milk substance is nature’s way of providing protection for the newborn against viruses, bacteria, allergens, and toxins. While the health benefits of colostrum consumption for newborns have been intuitively understood by human cultures throughout time, some cultures have also recognized it as an important food for adults. For example, the Amish once prepared a pudding made from the colostrum produced by the mother of a newborn calf. To this day in India, colostrum is consumed by adults.2 Colostrum contains various immune factors, such as lactoferrin (Lf), immunoglobulins (Ig), and proline-rich peptides (PRP), as well as important growth factors for developing healthy muscles and bones.3,4 Colostrum also activates and regulates numerous immune, growth, and repair processes.5,6,7,8,9,10 Additionally, numerous studies cited in this review show that colostrum and its components continue to exert important biological activities when given to adults, so that its beneficial effects extend well beyond the neonatal period of development. Many examples cited in this review also attest to the biological effectiveness of orally administered colostrum and its components. In fact, much of the communication of immunologically active substances with the immune system appears to occur via the membranes that line the oral cavity. Signals in the form of food, germs, and poisonous

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substances are initially recognized in the oral cavity, and messages are distributed by a variety of communication pathways to pertinent parts of the body. There are also protective substances that prevent digestion of the active components of orally administered colostrum before they can exert their biological effect(s).11 The biological activities of colostrum, as well as its major components, have been studied in model animal test sys-

tems both in vitro (cultured cells) and in vivo (live animals) in both newborns and adults. Some controlled clinical studies have also been conducted in humans of various ages. This review will attempt to summarize the most recent scientific literature describing the results of these studies (further summarized in Tables 1 and 2). Earlier reviews of the biological activities of colostrum are also available for those desiring additional information.9,12

Table 1: Activities of whole colostrum and components of colostrum* COMPONENT

SOURCE

ACTIVITY

TYPE OF STUDY

WHOLE COLOSTRUM bovine

improved functioning of GI tract

in vivo, newborn calves

bovine

enhanced efficiency of gamma-globulin absorption

in vivo, newborn calves

bovine

increased levels of serum IGF-1, insulin, glucose, albumin

in vivo, newborn calves

bovine

increased small intestine villus size

in vivo, newborn calves

bovine, human

anti-bacterial

in vivo, against H. pylori

human

stimulated B cell proliferation and antibody secretion

in vivo, mouse

human

inhibited proliferation of activated T cells

in vitro, human

human

inhibited production of IL-2

in vitro, human

human

anti-inflammatory

in vitro, human; in vivo, rats

human

stimulated secretion of IL-1, IL-3, IL-6

in vitro, human

ovine

increased serum IGF levels

in vivo, neonatal pigs

bovine

inhibited muscle protein degradation

in vitro, rat and human cells

human

antioxidant

in vitro, human

human

anti-amoebic

in vitro, human

human

bactericidal and fungicidal

in vitro, against E. coli and C. albicans

bovine

antibacterial

in vitro, against E. coli and Shigella

human

antibacterial

in vitro, against Vibrio cholerae in rats

human

inhibited cytokine release

in vitro, human

human

protected against GI autoantigens

in vitro, human

bovine salivary gland and kidney

accelerated wound healing

in vivo, rats

bovine bone

induced cartilage formation and bone repair

in vitro, rat

bovine

inhibited growth of cancer cells

in vitro, human

bovine

inhibited muscle protein breakdown

in vitro, rat

stimulated protein synthesis

in vitro, and in vivo sheep, rat

protected body protein reserves during dietary nitrogen restriction

in vivo, rats

promoted GI tract cell proliferation

in vivo, newborn pigs

reduced insulin requirements in diabetics

in vivo, human

stimulated would healing

in vivo, rats

stimulated glucose transport in skeletal muscle

in vitro, human

modulated under- or over-active immune system

in vivo, in vitro

CELLULAR FRACTION

IMMUNOGLOBULINS IgA

IgA, IgM GROWTH FACTORS

PROLINE-RICH PEPTIDE (PRP) ovine *The activities of lactoferrin are discussed in a separate review.

Table 2: In vivo, cross-species studies of colostrum COMPONENT SOURCE

MODE OF DELIVERY

SUBJECT

EFFECT

bovine

oral

children with GI tract infection

ameliorated diarrhea

bovine

oral

adults with AIDS with GI tract infection

ameliorated diarrhea

bovine

oral

adult athletes

increased serum IGF levels

sheep (PRP complex)

oral

patients with Alzheimer’s disease

improved dementia symptoms

bovine (Lactoferrin)

oral and injected

rats and mice with tumors

anti-tumor

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BIOLOGICAL ACTIVITY OF WHOLE COLOSTRUM tein breakdown in cultured myoblasts,28 hepatoma cells, and Several studies with fresh, whole colostrum have examfibroblasts.29 Other miscellaneous biological activities of whole human colostrum include an antioxidant property,25 ined its biological activities in newborn animals. Perhaps its apparently due to a component which is similar to ascormost apparent effects are illustrated in calves. For example, bate30 and an anti-amoebic property.31 Bovine colostrum, calves fed colostrum within 1-3 days after birth show given orally as a dietary supplement, enhances resistance to increased energy, improved functioning of the gastrointestiintestinal colonization by C. parvum in mice32 and protects nal (GI) tract, enhanced efficiency of gamma-globulin piglets from the clinical effects of pig rotavirus.33 absorption, and higher serum levels of insulin-like growth factor-1 (IGF-1), insulin, glucose and albumin compared to BIOLOGICAL ACTIVITIES OF COLOSTRUM calves deprived of colostrum.13 Prolonged feeding of colostrum to calves stimulates postnatal development of the IMMUNOGLOBULINS GI tract by enhancing small intestine villus size.10 Beneficial The major components of colostrum are probably responeffects in the GI tract of humans given colostrum have also sible for most of its biological activity. One of the most been observed. For example, both bovine and human important immune components of colostrum, secretory IgA colostrum, given orally, ameliorate diarrhea from GI tract (S-IgA), plays an important role in protecting against infection.3 For example, an immunoglobulin preparation from infections in children.14,15 In a pilot study, bovine colostrum was also effective in treating diarrhea resulting from bovine colostrum that contains IgA reacts against toxins Cryptosporidium parvum infection in adult AIDS patients.16 associated with E. coli and Shigella infections in cell cultures in vitro.34 S-IgA from human colostrum also inhibits adherColostrum has been shown to have significant antibacterial activity in vitro. For example, bovine colostrum is bacence of Vibrio cholera to intestinal tissue in vitro, an activity tericidal to Helicobacter pylori.17 This bacterium is a frequent that is consistent with the ability of IgA to prevent bacterial cause of gastric inflammation in humans.18 Bovine and colonization.35 S-IgA and IgM autoantibodies from human human colostrum also inhibit binding of H. pylori to target colostrum also protect in vitro against GI autoantigens that tissue lipids in vitro.19 In addition, the cellular component of can cause autoimmune disease, and thus act to maintain human colostrum has been shown to phagocytize and kill immune homeostasis.36,37 Results from three separate clinical 20 Escherichia coli and Candida albicans in vitro. Bovine studies also show that oral immunoglobulins from bovine colostrum is also bactericidal to E. coli in vitro.21 Human colostrum are anti-diarrheal in adult AIDS/HIV patients sufcolostrum also stimulates B-cell proliferation and antibody fering from infection by C. parvum,38,39,40 and probably account for this same effect reported for whole colostrum.16 secretion in mouse spleen cells, which is also an anti-infec22 tion activity. In other biological activities, orally administered S-IgAOf course, the most important biological activities of enriched anti-measles bovine colostrum has shown a weak colostrum and its major components are those related to effect in multiple sclerosis patients.41 A follow-up doubleactivation and regulation of the immune system. These blind study, however, found that hyperimmune bovine activities will be discussed for each component, but let us colostrum provided no symptomatic relief to such first consider colostrum itself. For example, in cell culture, patients.42 S-IgA also inhibits cytokine release in vitro, indicating that it may play an anti-inflammatory role in human colostrum has been shown to inhibit the proliferacolostrum.43 Finally, orally administered immunoglobulins tion of immune system T cells that have been previously from bovine colostrum are biologically active in other activated, as well as inhibit production of a key immune sysspecies, such as horses, sheep, deer, and humans.1,44,45,46,47 tem cytokine, interleukin-2 (IL-2).5,23,24 Human colostrum has also shown anti-inflammatory activity (such as inhibition of pro-inflammatory enzymes and antioxidant properBIOLOGICAL ACTIVITIES OF COLOSTRUM GROWTH ties) in neutrophil cell cultures8,25 and in adult rats injected FACTORS with human colostrum.6 These immunosuppressive qualiGrowth factors, also present in colostrum, activate varities can help overcome a hyperactive immune system, ous growth and repair processes in the body that are imporwhich can mediate certain autoimmune disorders. tant for proper development, maintenance and healing of Conversely, human colostrum has been shown to activate GI tract, skeletal muscle and bone structure.48 For example, transforming growth factor TGF-B from bovine salivary the immune system by stimulating secretion of cytokines gland and kidney (which is also present in human (IL-1, IL-3, and IL-6) by peripheral blood mononuclear cells colostrum)49 accelerates wound healing in rats when injectin vitro.26 This activation is important when the immune system is needed, for example, to fight infection or cancer. ed daily into wounds in nanogram amounts.50 TGF-B from Various other biological activities for colostrum have bovine bone, which is identical to cartilage inducing factor, been observed in in vitro and in vivo induces cartilage formation and studies, such as its important role in bone repair in tissue cultures.51 TGFWhile the health benefits of B has also been found to suppress skeletal muscle development. For colostrum consumption for growth of cancer cells (osteogenic example, in colostrum-fed neonatal newborns have been intuitively sarcoma cells) in vitro,52 although the pigs, there is an increase in IGF-1,27 which markedly increases muscle mechanism(s) for this effect is understood by human cultures protein synthesis7 (see also Biological throughout time, some cultures unknown. Epidermal growth factor, Activities of Colostrum Growth also found in colostrum, inhibits have also recognized it as an Factors section). Bovine colostrum muscle protein breakdown in culhas also been shown to inhibit protured myoblasts in vitro.28 important food for adults.

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Another growth factor, insulin-like growth factor (IGF), might contribute to diabetic nephropathy (i.e., kidney dishas been well studied with respect to its biological activiease) by decreasing collagen degradation, as seen in diabetties.53 It is found in abundance in bovine colostrum54 and is ic mesangial cells in vitro.77 However, while this speculation structurally similar to IGF in human colostrum.55,56 It is most based on in vitro data is theoretically possible, there was no abundant immediately after parturition in human and pig evidence for nephropathy in either of the cited studies of diabetics71 or athletes73 in which IGF was either injected or colostrum.57,58 It has cytokine-like activities on lymphoid cells of the immune system, and thus may be a natural comgiven orally. ponent of B and T cell lymphopoiesis.59 It is also worth mentioning that IGF-1 has been suggestThe most important biological activities of IGF are related as a possible indicator (i.e., biomarker) for certain types ed to muscle protein metabolism, repair and glucose utilizaof cancer, since its level sometimes increases when certain tion. For example, IGF stimulates protein synthesis and types of cancer are present.78 However, using elevated serum levels of IGF-1 as a biomarker for cancer has not been estabinhibits muscle protein breakdown in cultured skeletal muslished, since a consistent association with cancer has yet to cle cells (myoblasts)60,61,62 and hepatoma cells,63 and in diabetic rats.64 Injected IGF also appears to partly protect body be discovered.79,80 Since there is no evidence that IGF-1 caus65 protein reserves during nitrogen restriction in rats. Fasting es cancer or adversely alters cellular DNA, it appears that or restriction of dietary protein reduces serum IGF in rats in increased plasma IGF-1 is simply a characteristic of the canvivo.66 Increased body weight has also been seen in aged rats cer process, but is not a cause. This interpretation is consiswhen a serum IGF increase was stimulated by growth hortent with the finding that IGF and IGF receptor binding promone in vivo.67 Oral IGF stimulates cell proliferation in the teins are increased in tumor cells.81,82,83 Moreover, since IGFs GI tract of newborn pigs.68 Injected IGF also stimulates are "growth factors" produced by the liver to provide wound healing in vivo in rats,69 and is increased naturally in endocrine support for cell growth and development, it is the healing wound of mice; its increase is delayed in diabetnot surprising that IGF-1, like many other growth-promotic mice, consistent with the delayed wound healing experiing substances produced by the body, is important for enced by diabetics.70 All of these findings underscore the tumor cell, as well as normal cell, growth in vitro.84,85, 86,87,88 Finally, it should be noted that a scientific review by the U.S. apparent importance of IGF in the healing process. Food and Drug Administration (FDA) does not support a In a randomized, placebo-controlled clinical study of causal relationship between IGF-1 and the appearance of insulin-dependent diabetics, subcutaneously injected IGF tumors.89 reduced both the HbA1c levels (a measure of average blood glucose levels over time) and insulin requirements, apparBIOLOGICAL ACTIVITIES OF OTHER IMMUNOMODUently by suppressing growth hormone activity.71 This activity may be due also to an IGF-induced increase in glucose utiLATORY COMPONENTS OF COLOSTRUM lization, since IGF stimulates glucose transport in human Proline-rich peptide (PRP) is another very important skeletal muscle in vitro.72 immunomodulatory component of colostrum. PRP reguIt is also of significance that serum IGF increases slightly lates the thymus gland, which produces T cells that fight in athletes given oral bovine colostrum supplementation to viruses and antigens, and plays a key role in balancing an their diet during training.73 In this regard, since an adult overactive immune system (such as is found in individuals human produces about 10,000 micrograms (µg)/day of IGFwith autoimmune diseases) or an underactive immune sys1,74 and the range of adult human blood plasma IGF-1 levels tem (seen in immuno-compromised individuals); PRP acts is 42-308 µg/liter (L),75 the low IGF-1 levels present in bovine both in vitro and in vivo, and is not species specific.4,90 PRP colostrum dietary supplements would not be expected to has been tested clinically in the treatment of Alzheimer’s significantly increase the normal background concentradisease (AD). Orally administered PRP complex from sheep tions of IGF-1 in blood plasma. For example, it can be calcolostrum (100 milligrams [mg] every other day) was found culated from the study cited that athletes who consumed to significantly improve Alzheimer’s dementia in a double 125 milliliters (ml)/day of bovine colostrum containing blind, placebo-controlled study. Psychiatrists blinded to the approximately 68 µg/L of IGF-1, received approximately 8.5 treatment assignment assessed outcomes. All 15 AD patients µg/day of IGF-1 (assuming complete absorption from the GI stabilized or improved; none of the 31 selenium-treated or tract). This compares to normal IGF-1 production of 10,000 placebo control patients improved.91 Lactoferrin (Lf) is another key component of colostrum. µg/day. However, since a slight, but statistically significant, It is also secreted in milk, tears, mucus, and saliva, particuincrease in IGF-1 plasma level was noted in the study, the larly in response to a pathogen attack.92,93 Since it is the subincrease may have been due to stimulation of endogenous ject of a separate scientific review by this author and has IGF-1 production by the liver rather than absorption of been reviewed extensively in the published literature,3,94, dietary IGF-1 from the GI tract. 95,96,97 its biological activities will only With regard to any possible be summarized here. Many of the adverse effects of IGF, it has been ...the most important biological biological activities of Lf relate to its observed that levels of renal IGF-1 activities of colostrum and ability to regulate either the immune and IGF binding proteins rise prior system98,99 or the availability of iron.94 to an increase in kidney size in rats |its major components are Based on studies with bovine and with experimentally-induced diathose related to activation human colostrum evaluated in vitro betes; however, the authors did not and regulation of the and/or orally or by injection in test find any resultant kidney damage.76 Another author suggested that IGF animals or humans, its biological immune system.

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activities include anti-inflammatory,95,100 anti-allergenic,101 anti-cancer,102,103,104,105,106,107,108,109,110 anti-bacterial,3,111,112,113,114,115, 116,117 anti-viral,118,119,120,121,122,123,124,125,126,127 and anti-fungal128,129 functions. Its anti-inflammatory activity relates to its ability to inhibit pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a) and IL-6.43,95,99,130,131,132 However, Lf also regulates the immune system by stimulating cytokine release when an activated immune system is needed to, for example, fight infection or cancer.103,133,134,135 Its anti-allergenic activity may relate to its ability to inhibit mast cell tryptase, which is involved in bronchoconstriction and airway hyperreactivity.101 Bovine Lf inhibits the development,102,103,106,107,109,110,117 growth, and metastasis104,108 of tumors in rats and mice when injected or given orally as 0.2% of the diet, perhaps in part by its ability to stimulate natural killer cell release103 and bind to various glycosaminoglycans.135 Its anti-pathogenic activities relate primarily to its ability to bind iron and thus starve pathogens, which require iron as a nutrient.3,112,116 Bovine and human Lf also act to prevent colonization by pathogens in vivo by binding to them and preventing their adhesion to host cells.117,136,137 They are particularly effective against H. pylori,

which is a common cause of gastric inflammation in humans.18 Of additional benefit is the fact that human and bovine Lf have been shown in vitro to actually promote the growth of beneficial bifidobacteria.138 CONCLUSIONS In conclusion, colostrum, and, in particular, two of its components, Lf and PRP, act to regulate and balance the immune system. Studies suggest that this biological activity is important for adults with over- or under-active immune systems as well as for newborns. Colostrum and its components also have potent anti-bacterial, anti-viral, and antifungal activities. Colostrum and its growth factors enhance muscle protein synthesis, wound healing, cartilage formation, and bone repair, benefit GI tract structure and function, and are anti-inflammatory and anti-allergenic. The Lf component of colostrum regulates iron availability and has demonstrated anti-cancer activities. Colostrum and its components exert their biological activities when given orally, in many cases as a dietary supplement. Moreover, bovine and human colostrum are similar enough that they exert similar biological activities in various species.

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REFERENCE LIST (continued) 18. Nakao K, Imoto I, Gabazza EC. Gastric juice levels of lactoferrin and Helicobacter pylori infection. Scand J Gastroenterol. 1997;32(6):530-534. 19. Bitzan MM, Gold BD, Philpott DJ. Inhibition of Helicobacter pylori and Helicobacter mustelae binding to lipid receptors by bovine colostrum. J Infect Diseases. 1998;177(4):955-961. 20. Ho PC, Lawton JW. Human colostral cells: phagocytosis and killing of E. coli and C. albicans. J Pediatr. 1978;93(6):910-915. 21. Reiter B, Brock JH. Inhibition of Escherichia coli by bovine colostrum and post-colostral milk. I. Complementmediated bactericidal activity of antibodies to a serum susceptible strain of E. coli of the serotype O 111. Immunology. 1975;28(1):71-82. 22. Juto P. Human milk stimulates B cell function. Arch Dis Child. 1985;60(7):610-613. 23. Diaz-Jouanen E., Williams RC, Jr.. T and B lymphocytes in human colostrum. Clin Immunol Immunopathol. 1974;3(2):248-255. 24. Mandalapu P, Pabst HF, Paetkau V. A novel immunosuppressive factor in human colostrum. Cell Immunol. 1995;162(2):178-184. 25. Buescher ES, McIlheran SM. Antioxidant properties of human colostrum. Pediatr Res. 1988;24(1):14-19. 26. Bessler H, Straussberg R, Hart J, et al. Human colostrum stimulates cytokine production. Biol Neonate. 1996;69(6):376-382. 27. Wester TJ, Fiorotto ML, Klindt J, Burrin DG. Feeding colostrum increases circulating insulin-like growth factor I in newborn pigs independent of endogenous growth hormone secretion. J Anim Sci. 1998;76(12):3003-3009. 28. Ballard FJ, Francis GL. Effects of anabolic agents on protein breakdown in L6 myoblasts. Biochem J. 1983;210(1):243-249. 29. Ballard FJ, Nield MK, Francis GL, et al. The relationship between the insulin content and inhibitory effects of bovine colostrum on protein breakdown in cultured cells. J Cell Physiol. 1982;110(3):249-254. 30. Buescher ES, McIlheran SM, Frenck RW. Further characterization of human colostral antioxidants: identification of an ascorbate-like element as an antioxidant component and demonstration of antioxidant heterogeneity. Pediatr Res. 1989;25(3):266-270. 31. Acosta AG., Rocha-Ramirez LM, Reyes MR, et al. Antiamoebic properties of human colostrum. Adv Exp Med Biol. 1987;216B1347-1352. 32. Watzl B, Huang DS, Alak J, et al. Enhancement of resistance to Cryptosporidium parvum by pooled bovine colostrum during murine retroviral infection. Am J Trop Med Hyg. 1993;48(4):519-523. 33. Bridger JC, Brown JF. Development of immunity to porcine rotavirus in piglets protected from disease by bovine colostrum. Infect Immun. 1981;31(3):906-910. 34. Lissner R, Schmidit H, Karch H. A standard immunoglobulin preparation produced from bovine colostra shows antibody reactivity and neutralization activity against Shiga-like toxins and EHEC-hemolysin of Escherichia coli O157:H7. Infection. 1996;24(5):378-383. 35. Majumdar AS, Ghose AC. Protective properties of anticholera antibodies in human colostrum. Infect Immun. 1982;36(3):962-965. 36. Vassilev TL, Veleva KV. Natural polyreactive IgA and IgM autoantibodies in human colostrum. Scand J Immunol. 1996;44(5):535-539. 37. Quan CP, Berneman A, Pires R, et al. Natural polyreactive secretory immunoglobulin A autoantibodies as a possible barrier to infection in humans. Infect Immun. 1997;65(10):3997-4004. 38. Rump JA, Arndt R, Arnold A, et al. Treatment of diarrhoea in human immunodeficiency virus- infected patients with immunoglobulins from bovine colostrum. Clin Investig. 1992;70(7):588-594. 39. Plettenberg A, Stoehr A, Stellbrink HJ, et al. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea. Clin Investig. 1993;71(1):42-45. 40. Greenberg PD, Cello JP. Treatment of severe diarrhea caused by Cryptosporidium parvum with oral bovine immunoglobulin concentrate in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;13(4):348-354. 41. Ebina T, Sato A, Umezu K, et al. Treatment of multiple sclerosis with anti-measles cow colostrum. Med Microbiol Immunol (Berl). 1984;173(2):87-93. 42. Bayard BL, James MA. Hyperimmune bovine colostrum inefficacious as multiple sclerosis therapy in double-blind study. J Am Diet Assoc. 1987;87(10):1388-1390. 43. Hanson LA, Mattsby-Baltzer I, Engberg I, et al. Anti-inflammatory capacities of human milk: lactoferrin and secretory IgA inhibit endotoxin-induced cytokine release. Adv Exp Med Biol. 1995;371A669-672. 44. Larson RE, Ward AC, et al. Capability of lambs to absorb immunoproteins from freeze- dried bovine colostrum. Am J Vet Res. 1974;35(8):1061-1063. 45. LeBlanc MM. Is bovine colostrum a suitable alternative source of immunoglobulins for newborn foals? [editorial; comment]. Equine Vet J. 1991;23(2):78-80. REFERENCE LIST (continued next page)

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