The Clinical Use of Bovine Colostrum Alejandro Nitsch

The Clinical Use of Bovine Colostrum
Alejandro Nitsch, M.D.;1
Fabiola P. Nitsch, M.D.2

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.
111
 

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 newborn, and contribute to the development
and maturation of the immune
system.1,6,7,8,10 Other factors, like Transforming
Growth Factor Beta (TGFß) 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 breastfeeding
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 immunomodulating
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
Cryptosporidium 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 hyperimmune
colostrum against Cryptosporidium
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
112
  
 
 
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 Cryptosporidium
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 immunomodulatory
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 proprietory
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 Cytolog™ (which was
provided by Cellogic Corporation through
its distributor Allergy Research Group.™
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
113
 
open-label trial done in 1992-1993, where they
attempted a new treatment for RA using a
chimeric (mouse x human) monoclonal antiTNF
(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 (Cytolog™ 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. 
 
 
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). (See Table 1, below).
Results
After a minimum three-month followup,
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 inflammation (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. 
 114
 
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 antiinflammatory cytokine-type activity resembling the anti-inflammatory activity of cytokines 4,10,13,15,16. Longer followup 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.
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+380 (63) 646-98-04показать+380 (63) 646-98-04 все+380 (63) 646-98-04 +380 (67) 525-77-41
Адрес:
Украина, Киев, Киев на карте
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