The Clinical Use of Bovine Colostrum

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The Clinical Use of Bovine Colostrum

Alejandro Nitsch, M.D.; Fabiola P. Nitsch, M.D.

_http://www.orthomed.org/resources/papers/nitch.htm_

(http://www.orthomed.org/resources/papers/nitch.htm)

 

Abstract

 

The nutritional value of milk is largely undisputed. Colostrum, the first

milk produced by mammals after parturition, has been thoroughly studied on

recent years, after confirming its superior nutritional and protective value

when

compared to milk. Initially, colostrum was used clinically as a vehicle for

passive immunity transfer. It is now known colostrum contains cytokines and

other protein compounds of very low molecular weight that can act as

Biological Response Modifiers (BMRs), which intervene locally in most

biological

processes.This article reviews the composition and current clinical use of

colostrum, and describes the use of a colostral derivative in the treatment of

rheumatoid arthritis and osteoarthritis.

 

Part I: Review and Proposal

 

Milk has always been considered a very important food and food source

worldwide, as it supplies important nutrients in addition to carbohydrates,

proteins and fat, which together contribute to the optimal functioning of the

body.

Maternal milk, in comparison to formula milk, has a far superior nutritional

value. Colostrum has a well acknowledged crucial value for the survival of

the animal species that cannot receive immunoglobulins through the placenta.1

In recent years, due to the favorable effects of colostrum ingestion in

newborn infants and animals, there has been a growing interest in determining

the

composition of this naturally occurring substance and determining its clinical

use, in animals and humans as well. Much has also been investigated about

the composition of human colostrum, and it is interesting to note the

similarity in elements and functions with those of bovine colostrum. This

review will

specifically address data on the contents of human and bovine colostrum that

constitute the basis for their immunomodulatory capacity, the current use of

colostrum, and will describe a new derivative of colostrum and its clinical

use.

 

Human Colostrum is known to be highly immunoreactive, both in the humoral

and cellular systems. In 1993, Grosvenor et al. stated " many hormones, growth

factors and bioactive substances present in the maternal organism are present

in colostrum and milk, often exceeding concentrations that occur in maternal

plasma. " 2 The presence of immunoglobulin containing neutrophils and

macrophages (especially IgA, and lesser amounts of IgM and IgG), and peroxidase

activity identical to serum myeloperoxidase was documented recently in human

colostrum.3,4 It is known that secretory IgA (sIgA) purified from human

colostrum

causes in vitro inhibition of local adherence of enteropathogenic E. coli

(EPEC) to Hep-2 cells because sIgA responds to a plasmid-encoded outer membrane

protein implicated as the EPEC adherence factor acting as a receptor

analogue.5 Thus, colostrum provides passive immunity for the newborn.

 

Until recently the presence of cytokines in colostrum was unsuspected but it

has been now clarified that normally there are at least four cytokines in

colostrum: initially IL-1 followed by IL-2, were determined as being part of the

colostral factors that stimulate resistance to infections. IL-6, tissue

necrosis factor (TNF) and biologically active gamma interferon are thought to

immunostimulate the oropharyngeal and intestinal lymphoid tissues in the newb

orn, and contribute to the development and maturation of the immune

system.1,6,7,8,10 Other factors, like Transforming Growth Factor Beta (TGF§)

are present

in colostrum and milk.9

Colostrum of mothers of

pre-term babies was found to have a higher concentration of IgA, lysozyme and

lactoferrin, and higher macrophage counts when compared to that of mothers of

term

babies. Other substances found to have a significantly greater activity in

pre-term colostrum is a phagocytosis-promoting factor, which not only

increases the number of phagocytic cells, but also stimulates the phagocytic

activity

of the individual cell.11 The fact that colostrum of mothers of pre-term

babies shows a higher nutritional and immunological value is not surprising if

we consider the greater need for protection of pre-term babies. The protective

effect of breast-feeding against diarrhea has been extensively studied. It

is well known that the incidence of diarrhea in third world countries is

inversely related to the prevalence of breast-feeding in the community.12,13

 

Colostrum from Animals

 

Bovine colostrum contains a glucose tolerance-promoting factor, which

consists of a chromium-based complex, with a molecular weight around 1500. This

complex was shown to participate in glucose metabolism closely related to

insulin. The authors of this study hypothesize this complex could be useful to

enhance glucose metabolism in adult diabetic patients.14 The presence of a

Gonadotrophin Releasing Hormone (GRH)-related peptide, presumably synthesized in

the mammary gland has also been demonstrated.15 There is evidence of IgE

transference by colostrum to calves during the first 12 weeks of life, and this

is

assumed to generate protection against intestinal parasites. IgG, IgA, and

IgM are also present in bovine colostrum showing the capacity of neutralizing

human, simian and bovine rotavirus.16 The polymorphonuclear granulocytes (PMNs)

found in colostrum show a greater phagocytic activity against at least two

breeds of S. Aureus than the PMNs from peripheral blood. This was demonstrated

using both the rosette and phagocytosis tests.17 Ovine and porcine colostrum

enhances intestinal protein synthesis to a greater level than the synthesis

induced by milk or lactose in their respective newborns. These findings

support the idea that colostrum is an important factor for tissue maturation in

newborns.18-20 Proline-Rich-Polypeptide (PRP), a polypeptide with a clear

immuno-modulating activity is present in ovine colostrum. PRP acts both in vivo

and in vitro, and is not species specific. PRP increases skin permeability and

causes differentiation of murine thymocytes into functionally active T-cells.

The effects of PRP resemble the effects of thymic hormones on autoimmunity

and T-cell maturation. PRP has a molecular weight of approximately 6000. It is

interesting to note that fractions with a molecular weight of approximately

1000 show the same spectrum of activity of the original molecule, apparently

indicating that a three amino acid sequence is responsible for the

immunological effect of the peptide.21-23

 

Use of Bovine Colostrum in Animals

 

Basically, two presentations of colostrum have been evaluated for their use

in animals: normal and hyperimmune colostrum. Robinson et al. in 1993

demonstrated the protective effect of normal colostrum against specific

diseases: 14

foals were divided in two groups. In the first group, six foals were fed

normal colostrum. In the second group, eight animals were fed whole milk. All

animals were exposed to infection. Seven of the eight animals fed with milk

developed signs of sepsis, and four of them died. In the colostrum-fed group,

one developed diarrhea, but none developed sepsis and none died.24 Colostrum

has been specifically hyperimmunized against bovine rotavirus, and more

frequently against bovine herpes type I virus and Crypto-sporidium parvum. The

goal

of these studies has been to demonstrate the efficacy of colostrum as a

vehicle for passive immunity. In a study, the authors fed bovine colostrum with

neutralizing antibodies against herpes virus type I to calves prior to causing

infection with the same virus. The most severe affection shown by these

animals consisted of small areas of subacute fibrinopurulent rhinitis, but none

of

the animals died. The control group was fed normal colostrum, and all the

calves developed fatal multisystemic infection and died.25 The protective

effect

of hyperim-mune colostrum against Crypto-sporidium parvum was shown in

calves that had a shortened period of diarrhea26 and a similar response was

seen

in mice.27,28 Another study used IgG in powdered hyperimmune colostrum against

serotype 3 rotavirus to prevent diarrhea in foals.29

 

Use of Colostrum to Treat Diarrhea in Humans

 

Many studies have focused in this area, specifically about the advantages of

bovine colostrum as an efficient vehicle in the process of passive immunity

in immunocompetent or immunocompromised humans. In children with diarrhea

caused by rotavirus, the use of bovine colostrum has been tried since the mid

1980s. An important study, reported in 1989, fed 55 children with bovine

colostrum with antibodies against the four serotypes of rotavirus. The control

groups, 65 children, were fed artificial formula. None from the trial group and

nine from the control group developed diarrhea (p<0.001). Parents of children

from the control group sought medical attention seven times more than those in

the trial group. In 1995, children treated with hyperimmune bovine colostrum

were not only protected from diarrhea, but those who were affected showed a

shortened course of disease. Nevertheless, results from many studies are

diverse, and in some cases there seems to be no significant response.30-32

The studies done in immunocompetent and immunocompromised patients with

diarrhea unresponsive to conventional therapies have emphasized the effect on

Cryptosporidium. In 1990 the use of hyperimmune bovine colostrum against

Cryptosporidium was reported to stop a three-month diarrhea in an HIV positive

patient after only 48 hours of direct duodenal infusion. A similar study

reported

five patients with an acceptable response, still not being a success in all

patients. Plettenberg et al. reported 25 HIV patients with chronic diarrhea (7

with Crypto-sporidium and 18 with no identifiable agent). They demonstrated

a favorable effect in 64%, complete remission in 40% and partial remission in

24% of patients, and considered this to be an excellent response, due to

their previous therapeutic failures.33-35

 

Other Alternatives: The " New " Colostrum Derivatives

 

There is at least one other alternative use for new colostrum derivatives

which have been separated by laboratory techniques until a concentrate of basic

particles is left. These particles, although not specific, have a vital and

necessary role in the immuno-modulation processes of the organism. They

include interferon, TNFs and cytokines 1,2 and 6. Other cytokines of recent

description (cytokines 10,12,13,15,16) are presumably found in the resulting

fractions, and it is possible to find other unsuspected elements of equal or

lower

molecular weight, with immuno-modulatory activity of the anti-inflammatory

cytokine-type as well (4,10,13,15,16). The presence of immunomodulators is very

important, because their activity is evident in femtomolar

concentrations.2-7 The reasoning and questions of Professor V. Bocci, from

Italy, are very

valid: " Why are cytokines present in colostrum -is it because they have a role

in the immunological development of the newborn? Could we use this natural

therapeutic strategy in adults? " 1,36

Following this line of thought and encouraged by the result observed in

animals, in 1991 a product derived from bovine colostrum was developed through

a

pro-prietory method. Other protein separation processes were then used in

1995 to isolate and purify the protein component of bovine colostrum

responsible

for the inhibition of S-fimbria-mediated adhesion of Escherichia coli.36

Since the product has no demonstrable biological activity (as of 1993), our

proposed mechanism of action is the induction of cytokine synthesis by the host

(i.e., a true immunomodulator), allowing the organism to recuperate or

reorient its " immunologic memory " thus resulting in adequate response to

autoimmune

conditions. These protein particles, named " Infopeptides " by their

discoverer, have been extensively used in animals, and are now being used in

humans

under the name of Cytologâ„¢ (which was provided by Cellogic Corporation

through

its distributor Allergy Research Group.ª

The initial reports in small groups of patients suggested Infopeptides are

efficacious in diseases such as rheumatoid arthritis, systemic lupus

erythematosus, and AIDS-related intractable diarrhea, among others.37 The next

part of

this article describes a clinical trial using Infopeptides as an adjuvant

for the treatment of rheumatoid arthritis, in patients who did not respond to

adequately established conventional therapies.

 

Part II: Use of Infopeptides as an Adjuvant Therapy for Rheumatoid

Arthritis: A Clinical Trial

 

Rheumatoid arthritis (RA) is a disease in which autoimmunity and the

cytokine network are clearly involved, and despite being the most extensively

studied form of arthritis, all conventional therapeutic regimes are far from

satisfactory in terms of clinical response. In 1996, Feldmann et al. (from the

Mathilda and Terence Kennedy Institute of Rheumatology, London, UK), reported an

open-label trial done in 1992-1993, where they attempted a new treatment for

RA using a chimeric (mouse x human) monoclonal anti-TNF (antibody cA2). The

treatment led to rapid improvement in every patient in all parameters of

disease activity used.38 The proposed mechanism of action of Infopeptides, the

specific protein derivatives obtained from bovine colostrum, is induction of

anti-inflammatory cytokine-type activity by the organism, allowing the immune

system to reorient or correct its response mechanism against autoimmune disease

processes. Thus, this product is expected to work as a true immunomodulator.

The initial clinical observations of the effects of Infopeptides in humans

demonstrated marked reductions of inflammation, edema, pain and fever,

apparently regardless of cause. Severe and active RA, unresponsive to

conventional

therapies, was chosen as a model disease to be managed with immunomodulators.

Starting in March 1996, we initiated a small clinical trial with Infopeptides

(Cytologª on 12 patients with RA, who despite adequate conventional therapy

had clinical signs of active disease. At the same time we followed up 10

patients with Osteoarthrits (OA) who had no relief on conventional therapy.

Because RA and OA have different ethiologic mechanisms, we must make it clear

that

the inclusion of OA patients in this study was incidental.

 

Method

 

Patients included in this trial had an established diagnosis of RA or OA,

with clinical and laboratory evidence of active disease, despite adequate

established conventional therapy (non-steroidal anti-inflammatory drugs

(NSAIDs),

chloroquine, steroids, methotrexate, azathioprine, gold salts). Patients were

encouraged to comply with their conventional established treatment, and were

started on Infopeptides as an adjuvant supplement. Treatment was not to be

considered a failure before a three-month period. The administered dose was 5

mL orally per day, and patients were instructed to keep the product in

contact with the oral mucosa for 2-3 minutes, and then swallow it. If no

clinical

response was observed after four weeks, the dose would then be doubled to 5 mL

two times a day. All patients were evaluated clinically when they entered

the trial and had a follow-up visit every four weeks. Records of clinical

changes, as well as initial X-rays, laboratory exams and photographs were

taken.

Patients were also encouraged to report changes, or feel confident to call in

case of need. RA patients were classified according to clinical severity of

the disease, using the functional capacity classification: Class I: complete

remission, or full capacity to develop Daily Life Activities (DLAs); Class II:

moderate restriction, but still capable of handling DLAs; Class III: marked

restriction, disabled to work, needs help for self care; Class IV: severe

disability, bed or wheel chair confined.

 

RA Patients

 

Twelve patients (10 F, 2 M), with an average age of 52.5 years entered the

trial. The average time of disease duration was 12.4 years. Patients were

taking between one and five therapeutic drugs per day (average two drugs per

day).

 

Results

 

After a minimum three-month follow-up, the results were outstanding.

Clinical and subjective improvement (i.e., subjective and objective reduction or

disappearance of pain, edema and inflammation, improvement in joint mobility and

better tolerance to physical activity) was documented after two to six weeks

of treatment in 10 out of 12 RA patients. Two patients were lost to

follow-up. An objective reduction of inflammation and local joint edema,

usually

preceding reduction or disappearance of pain was observed between 7 and 35

days.

The average response time was 21.3 days. Patients with longer disease courses

took a longer time to respond. The dose was increased to 5 mL twice a day in

five patients. In spite of being advised not to stop using their established

therapies, patients decided to drop other agents on their own. At the end of

the initial evaluation time, the medicine intake ranged from none to 3 drugs

per day (average 1.5 drugs per patient-day). Six of the nine patients using

NSAIDs at the time were not using them on a regular basis; since pain severity

was markedly reduced, medicine intake was not as necessary as before. The RA

patients with more severe conditions (functional class III-IV) have been

followed for over one year, and have shown a slow but significant improvement in

joint mobility, besides the initial reduction in pain, edema and inflam

mation (Table 2, Figure 1, below). With a prolonged course of treatment, we

have

observed dramatic changes in functional classification. In general, patients

report improved quality of life, a state of well-being, better quality of

sleep, increase in appetite and a noticeable reduction of frequency and

severity

of relapses.

 

OA Patients

 

During the initial phase of the RA trial, several patients with OA asked to

be included, because of the excellent results they saw on their friends or

relatives. Since the Infopeptides had initially shown to be very effective in

pain control regardless of cause, and because of its general safety and

tolerance, we decided to initiate a parallel observation including OA patients.

Ten patients, all female, (average age 58.4 years) agreed to participate in

theclinical trials. Duration of disease ranged from six months to 11 years,

averaging 5.6 years. All patients were on a NSAID, and two had other

medications when they entered the trial. OA patients were evaluated based on a

patient

estimated scale of pain, where 0 would be total absence of pain, and 100 the

worst pain.

Nine out of 10 patients reported a significant reduction of pain, and showed

clinical reduction of inflammation, between 15 and 21 days after starting

the therapy. The average response time was 16 days. After the initial

three-month evaluation period, only five patients were taking NSAIDs, while the

others

were taking the Infopeptides as their only therapy. The only patient who did

not report pain reduction or relief despite showing a clinically significant

reduction of local edema and heat, had severe, deforming knee damage, where

surgery was advised.

 

Comments

 

After the initial trials, we concluded that the colostrum derived product

contains one or more immunomodulating agents that promote anti-inflammatory

cytokine-type activity resembling the anti-inflammatory activity of cytokines

4,10,13,15,16. Longer follow-up and laboratory support data will be necessary

to determine whether or not it is possible to stop, or even reverse the

existent articular cartilage damage (this effect was described in vitro using

cytokines 4 and 10 on mononuclear cells of RA patients).39

As expected from a biological response modifier, the effects of the

Infopeptides are relatively non-specific, allowing the organism to recuperate

normal

functioning patterns. This hypothesis is supported by the good responses

observed in both RA and OA. At present time, there are several other autoimmune

processes that are already receiving benefit from this therapeutic

alternative, with promising results.

The results of this initial clinical trial are very significant, not only

because of the high level of clinical response of the whole group of patients,

but also because of the sustained benefit and improvement on prolonged

therapy. Its oral administration, its low cost when compared to other current

experimental biological response modifiers, and the absence of side effects are

remarkable as well. Nevertheless, to us, as clinicians, the most valuable

aspect of this new therapeutic alternative is its profound effect on pain

relief.

 

References