En uno de sus libros titulado “Oxidative Stress in Cancer, Aids and Neurodegenerative Diseases” el Premio Nobel en Medicina Luc Montagnier, dedico el capitulo 42 completo del mismo a Immunocal, este se titula: “Nutriceutical Modulation of Glutathione with a Humanized Native Milk Serum Protein Isolate, Immunocal: Application in Cancer and AIDS” (Modulacion Nutraceutica del Glutation con un Aislado de Proteina de leche, Immunocal y su aplicacion en Cancer y SIDA).
Luc Montagnier (n. 18 de agosto de 1932 en Chabris, Francia) es un virólogo francés. Realizó su doctorado en Medicina en laUniversidad de Poitiers, y en 1967 inició sus investigaciones envirología. En 1972 fue nombrado jefe de la Unidad Oncológica Viral del Instituto Pasteur, y en 1974 fue designado también director delCentro Nacional de Investigaciones Científicas (CNRS, en francés). En 2008 obtuvo el Premio Nobel de Medicina, junto a Françoise Barré-Sinoussi por el descubrimiento del virus de inmunodeficiencia humana (VIH), causante del sida, dicho galardón fue compartido conHarald zur Hausen, quien fue premiado por el descubrimiento de losvirus del papiloma humano que causan cáncer cervical.
Oxidative Stress in Cancer, AIDS,
and Neurodegenerative Diseases
edited by
LUC MONTAGNIER
Centre National de la Recherche
Scientifique Institut Pasteur Paris, France
RENE OLIVIER
Institut Pasteur
Paris, France
CATHERINE PASQUIER
Centre National de la Recherche Scientifique
Faculte Xavier-Bichat
INSERM U294
Paris, France
Capitulo 42: Nutriceutical Modulation of Glutathione with a Humanized
Native Milk Serum Protein Isolate, IMMUNOCAL-TM :
Application in AIDS and Cancer
Sylvain Baruchel and
Ginette Viau
McGill University-Montreal Children's
Hospital Research Institute, Montreal, Quebec,
Canada.
Rene Olivier
Pasteur, Institute Paris, France
Gustavo
Bounous
Montreal General
Hospital, Montreal, Quebec, Canada
Mark A.
Wainberg
Jewish General
Hospital, Lady Davis Institute, Montreal, Quebec, Canada
NUTRITIONAL
IMMUNOMODULATION
AND ITS RELATION TO
GLUTATHIONE SYNTHESIS
Fresh, raw milk includes the group of
proteins that remain soluble in "milk serum." These proteins can be
preserved in their native form if extracted carefully from their natural
source.
In 1981 it was discovered that normal mice
fed a milk serum protein concentrate (specially prepared under mild
nondenaturing conditions) exhibited a marked increase in the humoral immune
response to a T helper cell-dependent antigen (1). In the following years,
numerous experiments confirmed the consistency of this phenomenon (2-10). Over
a period of 12 years and based on these findings a humanized native milk serum
protein isolate (HNMPI) named Immuocal™ was developed (Immunotec Research
Corporation Ltd., Montreal, Quebec, Canada).
This
property was found to be related, at least in part to a greater production of
splenic glutathione (L-.-glutamylcysteinylglycine) (GSH) during the
oxygen-requiring antigen-driven clonal expansion of the lymphocyte pool in
animals fed with this bioactive HNMPI
(9).
Adequate levels of GSH are necessary for lymphocyte proliferation in the
development of the immune response (11,12). Moderate but sustained elevation of
cellular GSH as also found in the liver and the heart of healthy, old mice fed
with this HNMPI for a prolonged period. In addition, HNMPI markedly increased
their life expectancy in comparison to control animals fed nutritionally
equivalent diets (13).
Glutathione
is of major significance in cellular antioxidant activity in what Meister
called the "GSH antioxidant system" because it participates directly
in the destruction of reactive oxygen compounds and also because it maintains
in reduced form ascorbate (vitamin C) and a-tocopherol (vitamin E), which also
exerts a. antioxidant effect (14).
FUNCTION
OF HNMPI AS A CYSTEINE DELIVERY SYSTEM
What
ingredient in IMMUNOCAL™ makes it an effective "cysteine delivery
system" Systemic availability of oral GSH is negligible in man (I 5) and
there is no evidence for transport of GSH into cells (16). Thus, it has to be
synthesized intracellularly. This occurs in two steps: (a) glutamylcysteine
synthesis; (b) glutathione synthesis. Even though the inflow of cysteine,
glutamate, and glycine might prove somewhat limiting under selected
circumstances, numerous observations have shown that it is the transport of
cysteine (or cystine, which usually is promptly reduced to cysteine on cell
entry) which tends to be the ate-limiting event in GSH synthesis. whereas free
cysteine does not represent an ideal delivery system (17) because it is toxic
and is spontaneously oxidized. Cysteine present as the disulfide cystine
released during digestion in the gastrointestinal tract is more stable than
free amino acid. GSH synthesis is submitted to negative feedback inhibition by
the end-product GSH. The disulfide bond is pepsin- and trypsin-resistant, but
may be split by heat and mechanical stress (9). Cystine accounts for about 90%
of the low-molecular -mass cysteine in the blood plasma, while reduced cysteine
is present only at extremely low concentration (18).
In a comparative study, we found that commercial milk serum
concentrates exhibiting far less bioactivity, including less GSH promoting
activity, contain about half the amount of serum albumin (9) and 4 times less
lactoferrin than HNMPI, expressed as percentage of total milk serum protein.
I..UNOCALTM is produced in a proprietary lenient process which results in the
preservation of the most thermolabile proteins in their native conformation.
In the serum albumin, there are 17 cystine residues per 66 kDa
molecule and 6 GluCys dipeptides (19); in lactoferrin there are 17 per 77kDa
molecule and 4 Glu-Cys dipeptides (20); and in the @-lactalbumin there are 4
cystines in a 14,000 kDa molecule
Table
1.
|
||||||
<TD=COLSPAN=
|
||||||
6
|
||||||
Cysteine
|
||||||
Molecular
|
Cysteine
|
Cysteine (Cys)2
|
||||
Residues
|
residues
|
Glu-(Cys)2
|
||||
Mass (kDa)
|
(disulfide)
|
|||||
per molecule
|
||||||
P-Lactoglobuli
|
18,400
|
162
|
5
|
2
|
0
|
|
a-Lactabumin
|
14,200
|
125
|
8
|
4
|
0
|
|
Serum albumin
|
66,000
|
582
|
35
|
17
|
6
|
|
Lactoferrin
|
77,000
|
708
|
40
|
17
|
4
|
|
Source: Refs. 19, 20.
(19). On the other hand, P Lactoglobulin. has
only 2 cystines in a 18,4OOkDa molecule (19), and IGGI, the predominant
immunoglobulin in cow whey, has only 4 disulfide bridges in a 166,OOOkDa
molecule (Table 1). In addition, Meister and colleagues (16) have demonstrated
that the y-glutamylcysteine (Glu-Cys) precursors of GSH can easily enter the
cell and there be synthesized into GSH. It thus become noteworthy that the most
labile milk proteins-, serum albumin and lactoferrin-are those which contain
these putative GSH-promoting peptide components.
Finally,
the bioavailibility of the presumed active component (cystine and Glu-Cys
group) may be influenced by the coexistence of the other proteins throughout
the digestive-absorptive process.
This
newly discovered property of HNMPI was found to be independent of its
nutritional value, as other proteins of similar nutritional efficiency do not
exhibit this unique property (1-10). The concept that a specific biological
activity can exist in addition to and independent of the systemic effect Of
IMMUNOCAL™ as a good protein source is further substantiated by recent in vitro
assays (21).
The dietary provision of cystine is particularly relevant to the
immune system. The coordinated response of macrophages and lymphocytes in the T
cell-mediated immune response is regulated, in part, by macrophage cystine
uptake and subsequent release of reduced cysteine into the local environment
for uptake by lymphocytes. When the antigenpresenting macrophages come into
close contact with antigen-specific T cells, they supply these cells with
additional amounts of cysteine and thereby raise their intracellular GSH level
(18).
The validity of this assumption is confirmed by the demonstration
that the immunoenhancing and GSH-promoting (data not shown) effect of
Immunocal™ is abolished by buthionine suIfoximine, which inhibits
y-glutamylcysteine synthetase, the initial step in GSH synthesis (17).
IN VITRO MODULATION OF
INTRACELLULAR GLUTATHIONE BY IMMUNOCAL
TM
We
demonstrated that normal human lymphocytes cultured for 3 days with HNMPI
100@g/ml show an increase in intracellular GSH content from 4.5 ± 0.4 to 10.5 ±
3.4nmol/10 6 cells, p <0.01 (Figure 1). This increase in GSH correlates with
an increase in cellular proliferation measured by thymidine incorporation (data
not shown). The
Table 2 Presence
of Cytopathic Effects in MT-4 Cells
TCID50/well3
|
||||
IMMUNOCAL™
|
2000
|
200
|
20
|
2
|
(ug/ml)
|
||||
0
|
+++
|
++
|
+
|
-
|
I
|
+++
|
++
|
+
|
-
|
10
|
++
|
+
|
+
|
-
|
100
|
-
|
-
|
-
|
-
|
500
|
-
|
-
|
-
|
-
|
1000
|
-
|
-
|
-
|
-
|
3+ Presence of
cytopathic effects; - absence of cytopathic effects.
|
||||
increase in GSH is
dose -dependent and has not been found for casein or for any commercially
available milk serum protein concentrate (Figure 2).
IN VITRO ANTI-HIV and
ANTIAPOPTOTIC ACTIVITY OF HNMPI
Clinically,
there is direct evidence that HIV infection is associated ,with a GSH
deficiency in the peripheral blood mononuclear cells (PBMC) (18). The depletion
of intracellular GSH suggests an association between oxidative stress and HIV
infection. Oxidative stress may be one of the mechanisms that contribute to
disease progression and the wasting syndrome
through
mediators of inflammation such as TNF-. and IL-6. During this period of
progression, glutathione is consumed owing to an increase in oxidative stress.
GSH depletion, a consequence of chronic oxidative stress, is part
of the spectrum of HIV infection. GSH has, in addition, a crucial role in
lymphocyte function and cell survival. IMMUNOCAL™ functioning as a cysteine
delivery system can enhance GSH synthesis in vitro (Figure 1) and inhibits HIV
replication on a cord mononuclear cell system infected by HTL V-IIIB (Figure
3). IMMUNOCAL™ also inhibits the formation of syncitium between infected and
noninfected cells. The inhibition of syncitium formation occurred at the same
concentration as inhibition of HIV replication(Table 2). This viral inhibition
was not associated with any cytotoxicity. IMMUNOCAL ™, via its GSH-promoting activity,
educes apoptosis in HIV-infected cells. Apoptosis was evaluated by flow
cytometry on PBMC from HIV-infected individuals (Dr. R. Olivier, AIDS and
Retrovirus., Department, Pasteur Institute). HIV -infected PBMC cultured at
concentrations of IMMUNOCAL' of I 00 ug/ml or higher were less prone to die of
apoptosis than untreated cells: 15% ± 2.6% vs. 37% ± 2.4, p<0.001 (Figure
4).
HNMPI SUPPLEMENTATION IN
AIDS AND WASTING SYNDROME
Based
on these preclinical data, we conducted a Canadian clinical trial (Canadian HIV
Trials Network) with IMMUNOCAL™ in children with AIDS and wasting syndrome. The
major objective was to evaluate the effect of oral supplementation with
IMMUNOCAL™ on nutritional parameters and intracellular blood lymphocyte GSH
concentration in children with AIDS and wasting syndrome. This was an open
single-arm pilot study of 6 months duration. Wasting syndrome and severe weight
loss within the 6 months preceding entry into the study was an absolute
criterion for entry.
IMMUNOCAL™
was administered twice a day as a powder diluted in water. In some patients,
IMNUNOCAL™ was administered via nasogastric tube when necessary. The
administered starting dose was based on 20% of the total daily protein
requirement and was increased by 5% each month over 4 months to reach 35% of
the total protein intake at the end of the study. The total duration of the
study was 6 months.
Weight, height, triceps skinfold and mid-arm
muscle circumferences, CD4/CD8 counts, and peripheral lymphocyte GSH
concentrations (measured by spectrophotometric assay) were measured monthly.
Energy intake was assessed by the use of two independent 2-day food records
with , 2-3 week period between the food records. Each food record included a
weekday and a weekend, and the average of these records was calculated to
reflect the daily nutritional intake. Out of 14 patients enrolled, 10 were
evaluable. The ages of the patient were from 8 months to 15 years. The 10
patients studied were enrolled in four different centers across Canada:
Montreal Children's Hospital (Dr. S. Baruchel), The Hospital For Sick Children
Toronto (Dr. S. King), Children's Hospital for Eastern Ontario (Dr. U. Allen),
and Centre Hospitalier Laval Quebec (Dr. F. Boucher). Of the 4 remaining
patients, 2 lacked compliance after 2 months while the other 2 died of AIDS
progressive disease within the first 2 months f entry into the study. None of the
deaths was related to the tested product. >
None of the patients experienced any major toxicity such as
diarrhea or vomiting or manifestation of milk intolerance. One patient had to
Stop IMMUNOCAL™ transiently for minor digestive intolerance such as nausea and
vomiting (, twice/day) at month 3 and was subsequently able to restart the
treatment without any problem.
At the end of the study, all patients experienced a weight gain in
the range of 3.2% to 22% from their starting weight. The mean weight gain for
the group was 8.4% ± 5.7%. On analysis of the mean percentage of requirement
nutrient intake (RNI) per month for all
Table 3 Change from Baseline (expressed as a
Percentage) at Weeks 24 and 36 in Weight, Anthropometric and GSH Patients
Treated with IMMUNOCAL™
----------------------------------------------------------------------
|
|||||||||
Weight
|
Mid-arm Muscle
|
Triceps
|
PBMC GSH
|
||||||
circumference
|
skinfold
|
||||||||
change%
|
change (%)
|
||||||||
change
|
change %
|
||||||||
Patient
|
wk 24
|
wk 32
|
wk 24
|
wk 32
|
wk 24
|
wk 32
|
wk 24
|
wk 32
|
|
1
|
22.1
|
29.8
|
9.5
|
14.3
|
50.0
|
25.0
|
12.2
|
-9.0
|
|
2
|
14.0
|
17.3
|
18.7
|
25.3
|
20.0
|
20.0
|
84.0
|
56.0
|
|
3
|
5.1
|
9.2
|
-3.0
|
-2.0
|
-17.0
|
-3.0
|
37.0
|
55.0
|
|
4
|
3.8
|
3.4
|
4.2
|
NA
|
-42.0
|
NA
|
305.0
|
550.0
|
|
5
|
7.1
|
4.5
|
13.1
|
11.4
|
-24.0
|
-16.0
|
-18.0
|
14.3
|
|
6
|
3.7
|
5.6
|
-2.0
|
-2.0
|
16.0
|
16.0
|
7.1
|
174.0
|
|
7
|
2.5
|
NA
|
5.0
|
NA
|
-13.0
|
NA
|
54.2
|
NA
|
|
8
|
14.2
|
18.2
|
-3.1
|
2.0
|
41.0
|
43.0
|
17.3
|
62.4
|
|
9
|
8.9
|
7.9
|
-4.0
|
-8.0
|
-30.0
|
-39.0
|
-6.6
|
50.9
|
|
10
|
7.0
|
NA
|
1.0
|
NA
|
41.0
|
NA
|
-1.6
|
NA
|
|
NA
the
patients, no correlation was found between the weight gain and any significant
increase in the mean percentage of RNI, suggesting educed catabolism rather
than an anabolic effect of IMMUNOCAL™. Six of ten patients have demonstrated an
improvement in their anthropometric parameters such as triceps skinfold or
mid-arm muscle circumference independently of an increase in energy intake
(Table 3).
Two
groups of patients were identified in terms of GSH modulation: responders and
nonresponders. The responders were those who started the study with a low GSH
level.
The
nonresponders were those who stated with a normal GSH level. A positive
correlation was found between increase in weight and increase in GSH (Figures
5,6,7). No changes were found in terms of blood lymphocyte CD4 cell count, but
2 patients exhibited an
increase
in the percentage of their CD8 cells and 4 patients showed a trend toward an
increase in the number of NK cells.
In conclusion, this pilot study demonstrates that IMMUNOCAL™ is
very well tolerated in children with AIDS and wasting syndrome and is
associated FIGUREF an amelioration of the nutritional status of the patient as
reflected by weight and antrhopometric parameters. Moreover, the GSH-promoting
activity Of I.MUNOCAI™ in vivo seem to be validated in 6 out of 10 patients. An
international multicenter double-blind randomized study is currently under way
in France and Canada in adults patients with AIDS and wasting syndrome.
SELECTIVE GLUTATHIONE
MODULATION OF BREAST CANCER CELLS AND
IMPACT ON CANCER CELL
GROWTH
The specific involvement of GSH in the
carcinogenic process is supported by the major role played by this compound in
the detoxification of carcinogens by conjugation (26). We demonstrated that
feeding GSH-promoting HNMPI to ice chronically treated with dimethylhydrazine
(DMH) significantly reduces the number and size of colon carcinomas induced by
DMH (27,28). These colon tumors appear to be similar to those found in the
human insofar as the type of lesions and the chemotherapeutic response
characteristics are concerned (26). HNMPI feeding appears to exert an
inhibitory effect not only on the initiation (27) of cancer, but also on the
progression of tumors (28).
Recently,
a direct inhibitory effect of HNMPI in human cancer cell replication was
confirmed (21,29,30). In other human cancer cell studies, the inhibitory effect
,as found to be related to the serum albumin component of milk serum (3 1) and
most recently to @-lactalbumin (32). Feeding lactoferrin to mice inhibited the
growth of solid tumors and in addition reduced lung colonization by melanomas
(33). Unlike other proteins, serum albumin ,as found to exhibit a strong
antimutagenic effect in an in vitro assay using hamster cells (34). It is
therefore noteworthy that in this HNMPI we have succeeded in concentrating
serum albumin, @-lactalbumin, and lactoferrin, all containing a significant
number of GSH precursors. A possible explanation for these newly discovered
properties of dietary milk serum protein may be found in recent findings on the
role of GSH in tumor biology (35).
The
search for ways to inhibit cancer cells without injuring normal cells has been
based over the years on a vain effort to identify the metabolic parameters in
which cancer cells are at variance with normal cells. One such function could
well be the all-important synthesis of cellular GSH.
Recent
experimental evidence has revealed an intriguing response of tumor versus
normal cells to GSH synthesis-promoting compounds. Cellular GSH levels have
been found to be several times higher in human cancer cells than in adjacent
normal cells (35). This finding is presumably related to their proliferative
activity. In fact, cancer is the only condition in which elevation of such a
tightly regulated system as GSH has been reported. However, when a cysteine-
and GSH-promoting compound such as 2-l-oxothiazolidine-4-carboxylate (OTZ) as
added to cultured human lung cancer cells exhibiting very high levels of GSH at
the outset, no intracellular increase was noted, whereas GSH
increased substantially in normal cells (35). This differential response is
even more pronounced in vivo. We demonstrated that in tumor-bearing rats, OTZ
treatment was actually found to deplete GSH in the tumors (36).
More specifically, an in vitro
assay showed that, at concentrations that induce GSH synthesis and
proliferation in normal human cells (Figure 1), IMMUNOCAL™ caused GSH depletion
and inhibition of proliferation of cells in a rat mammary carcinoma (Figure 8)
and Jurkat T cells (Figure 9) (21).
The selectivity demonstrated in these experiments may be explained
by the fact that GSH synthesis is negatively inhibited by its own synthesis and
since, as mentioned, baseline intracellular GSH in tumor cells is much higher
than in normal cells, 'It is easier to reach the level at which negative
feedback inhibition occurs in this cellular system than in a nontumor cellular
system.
HNMPI IN CANCER CLINICAL
TRIALS
On
the basis of these experiments, 5 patients ,with metastatic carcinoma of the
breast, I of the pancreas, and I of the liver, were fed 30 g of IMMUNOCAL™
daily for 6 months. In 6 patients, the blood lymphocyte GSH levels were
substantially above normal at the outset, probably reflecting high tumor GSH
levels. At completion of the 6 months of daily supplementation, 2 patients
exhibited signs of tumor regression, normalization of hemoglobin and peripheral
lymphocytes counts, and a sustained drop of lymphocyte GSH levels toward
normal. Two patients showed stabilization of the tumor and increases in
hemoglobin levels. In 3 patients, the disease progressed with a trend toward
higher lymphocytes GSH levels (37).
A
major problem in the use of chemotherapeutic agents in cancer therapy is the
protection offered by the defense mechanisms of cancer cells. An important
element of protection is represented by GSH, which is an effective
detoxification agent that is relatively abundant in tumor cells. Indeed, when
GSH synthesis is inhibited by buthionine sulfoximine (BSO), the activity of
several chemotherapeutic agents such as alkylating agents is increased and drug
resistance can be reversed (36-38). However, the concomitant depletion of GSH
in normal cells greatly limits the practical usefulness of this modality of
treatment.
We
recently demonstrated that a selective GSH prodrug such as OTZ protects some
normal tissue (36) but also potentiates the activity of some alkylating agents
(38). The apparently selective depletion of tumor GSH levels by provision of a
natural precursor of GSH as contained in IMUNNOCAL™ seems to be associated with
inhibition of proliferation of cancer cells in vitro. This natural precursor of
GSH favorably influences the GSH synthesis in normal cells. These in vitro and
preliminary clinical results indicate that this newly discovered property of
HNMPI may be a promising adjunct to the nutritional management of cancer
patients undergoing chemotherapy. We are currently developing a phase 11 study
in breast carcinoma, attempting to confirm that this selective depletion of GSH
may, in fact, render tumor cells more vulnerable to chemotherapy and eventually
protect normal tissue against the deleterious effect of chemotherapy.
ANALOGY BETWEEN HNMPI
IMMUNOCAL TM AND HUMAN MILK
Human
milk contain about 80% of whey protein and 20% of casein. The opposite is true
for cow milk. An analysis of the mass ratio of casein to whey protein in milk
from various mammals clearly indicates that human milk has the lowest ratio in
any mammalian species (39). On the basis of our laboratory studies showing the
immunoprotective and anticancer effects of cow whey protein concentrate, it is
tempting to speculate that this predominance of whey proteins in human milk is
advantageous and thus represent an evolutionary adaptation.
Scientific
data based on the similarity between the bioactive components of this native
milk protein isolate (HNMPI) of cow milk, IMMUNOCAL™, and human whey protein
appear to substantiate this theory, as will now be discussed in more detail.
It is well known that breast feeding is
superior to the use of cow milk-based formulas of similar nutritional
efficiency for the health of human babies. Breast feeding protect against
otitis media, and pneumonia (40,41). Mothers milk also has a protective effect
on the incidence of several types of childhood cancer including leukemia,
lymphomas, bone tumors, and brain tumors (42). Children who are artificially
fed or are breast fed for only a shot period of time are more at risk for
developing several types of cancer before the age of 15 years as compared to
long-term breast feeders (43). Thus, the concept of a biological activity in
addition to but independent of the nutritional efficiency, formulated to
describe the immunoenhancing and GSH-promoting activity of the HNMPI
IMMUNOCAL™, may indeed apply to the breast feeding of neonates and infants.
Glutathione synthesis appears to be the crucial factor in the health benefit of
HNMPI.
It
may then be appropriate to 'Identify the features common to HNMPI and human
whey proteins that are capable of influencing GSH synthesis in the host.
Cysteine, a crucial limiting factor in the synthesis of GSH, is about as
abundant in cow's whey protein as it is in whole human milk proteins and
several times more abundant than in cow's whole milk (39), since most caseins
contain either no cysteine or one or two cysteine residues(19). As mentioned
earlier, our studies showed that the most thermolabile milk proteins, namely,
serum albumin, a-lactalbumin, and lactoferrin, are crucial to expression of the
bioactivity of HNMPI. As shown in Table 1, these proteins are rich in cystine
and glutamylcystine residues, natural precursors of GSH. The presence of these dipeptides
in the product IMMUNOCAL™ is a characteristic shared with human milk (Table 4).
Traditionally, it has been advocated that
"humanized" cow milk should contain more a-lactalbumin because this
protein is twice as abundant in human milk. On the basis of our experimental
findings, we propose instead that the principal health factor in human milk,
Table 4. Protein
Composition of Cow and Human Milk Composition (g/liter)
Componet
|
Cow milk
|
Human milk
|
|
(0 or 2
|
|||
cysteine/molecule
|
|||
no disulfide
bond)
|
|||
Casein (g/l)
|
26
|
3.2
|
|
B-Lactoglobulin(g/l)
|
3.2
|
Neglible
|
|
a-Lactabumin (g/l)
|
1.2
|
2.8
|
|
Serum albumin (g/l)
|
0.4
|
0.6
|
|
Lactoferrin (g/l)
|
0.14
|
2.0
|
|
Total cystine
(mol/L)
|
8.19 x 10 -4
|
13.87 x 10 -4
|
|
Total Cystine (mg/g
|
6.4
|
38.7
|
|
protein)
|
|||
Source:
Ref.19;
Jennes R. Inter-species comaparison of milk proteins. In fox, ed. Developments
in dairy chemistry-1. New York: ASP;1982:8
not denaturated by heat pasteurization, is
due to the predominance of the thermolabile proteins rich in cystine and
containing the Glu-Cys dipeptide which are characteristic of the bioactive
HNMPI, namely, serum albumin, a-lactalbumin, and lactoferrin. This HNMPI
differs from other commercially available milk serum protein concentrates in
having a relatively high content of serum albumin (about I 0%), lactoferrin
(about 0.65 %),
CONCLUSION
This article has addressed the central role
of GSH in providing protection against endogenous oxiradicals and foreign
pollutants. As an antioxidant, GSH is essential for allowing the lymphocyte to
express its full potential, without being hampered by oxiradical accumulation
during the oxygen-requiring development of the immune response. In a similar
fashion, GSH delays the muscular fatigue induced by oxiradicals during the
aerobic phase of strenuous muscular contraction.
It
is, however, the second function of GSH -that of detoxification of chemical
pollutants, carcinogens and ultraviolet radiation-that may well be of greater
concern to medical science today, because of the ever-increasing demand on GSH
as the major detoxifying agent. Under normal circumstances, a nutritionally
balanced diet should provide sufficient precursors of GSH to allow for
intracellular synthesis of adequate amounts of GSH. But in our current polluted
environment, trace amounts of precursors found in an otherwise adequate diet
may not be sufficient to allow for full GSH replenishment. This results in
highly undesirable competition for GSH precursors developing amongst different
systems. Cysteine prodrugs have helped clarify the essential role of GSH in
athletic performance, immune function, AIDS, etc., but their effect is
short-lived and their long-term use is not without adverse effects.
Using modern technology, it has
been possible to obtain and consistently preserve, in their native form, the
specific cow's milk proteins which share with predominant human milk proteins
the same extremely rare GSH-promoting components. This product-the patented
WPC-differs from most commercial WPCs in that it contains the active
ingredients-notably cystine and glutamylcystine-in undenatured form and an
amount sufficient to exhibit its potency when given as a dietary supplement,
without overloading the system with excessive nitrogen intake.
It is therefore possible to
obtain, with the patented milk serum protein concentrate, long-term moderate
but sustained intracellular elevation of GSH and GSH precursors so that, when
the challenge occurs, an efficient cellular response can be achieved.
REFERENCES
1.
Meister
A. The antioxidant effects of glutathione and ascorbic acid. In: Oxidative
Stress, Cell Activation and Viral Infection. C. Pasquier et al (Eds.).
Birkauser Verlag, Basel, Switzerland, 101-11, 1994.
2. Meister A, Anderson
ME. Glutathione. Ann Rev Biochem 52: 711-60, 1983.
3.
Kaplowitz
N, Aw TY, Ookhtens M. The regulation of hepatic glutathione. Ann Rev Pharmacol
Toxicol 25: 715-44, 1985. 4. Witschi A, Reddy S, Stofer B, Lauterburg BH. The
systemic availability of oral glutathione. Eur J Clin Pharmacol 43: 667-9,
1992.
5.
Meister
A. New aspects of glutathione biochemistry and transport selective alteration
of glutathione metabolism. Nutr Rev 42: 397-410, 1984.
6. Bounous G, Gold P.
The biological activity of undenatured dietary whey proteins: role of
glutathione. Clin Invest Med 14: 296-309, 1991.
7. Droege
W, Eck HP, Mihm S, Galter D. Abnormal redox regulation in HIV infection and
other immunodeficiency diseases. In: Oxidative Stress, Cell Activation and
Viral Infection. C. Pasquier et al (Eds). Birkauser Verlag, Basel, Switzerland,
285-99, 1994.
8.
Noelle
RJ, Lawrence DA. Determination of glutathione in lymphocytes and possible
association of redox state and proliferative capacity of lymphocytes. Biochem J
198: 571-9, 1981.
9.
Fidelus
RK, Tsan MF. Glutathione and lymphocyte activation: A function of aging and
auto-immune disease. Immunology 61: 503-8, 1987.
10.
Staal
FJT, Roederer M, Israelski DM, Bubp J et al. Intracellular glutathione levels
in T cell subsets decreases in HIV-infected individuals. AIDS Res and Hum
Retro- viruses 8: 305-11, 1992.
11.
Herzenberg
L, De Rosa S, Dubs G, Roederer M et al. Glutathione deficiency is associated
with impaired survival in HIV disease. Proc Natl Acad Sci USA 94: 1967-72,
1997.
12.
Bounous
G, Stevenson MM, Kongshavn PAL. Influence of dietary lactalbumin hydrolysate on
the immune system of mice and resistance to Salmonellosis. J Infect Dis 144:
281, 1981.
13.
Bounous
G, Kongshavn PAL. Influence of dietary proteins on the immune system of mice. J
Nutr 112: 1747-55, 1982.
14. Bounous
G, Letourneau L, Kongshavn PAL. Influence of dietary protein type on the immune
system of mice. J Nutr 113: 1415-21, 1983.
15. Bounous G, Kongshavn PAL. Influence of protein type in
nutritionally adequate diets on the development of immunity. In: Absorption and
Utilization of Amino Acids. M. Friedman (Ed.). Boca Raton, Florida: CRC Press,
vol. 2, 219-32, 1989.
16.
Bounous G, Batist G, Gold P.
Immunoenhancing property of dietary whey protein in mice: role of glutathione.
Clin Invest Med 12: 154-61,1989.
17. Bounous
G, Shenouda N, Kongshavn PAL, Osmond DG. Mechanism of altered B-cell response
induced by changes in dietary protein type in mice. J Nutr 115: 1409-17, 1985.
18.
Hirai R, Nakai S, Kikuishi H,
Kawai K. Evaluation of the Immunological Enhancement Activities of Immunocal.
Otsuka Pharmaceutical Co. Cellular Technology Institute, Dec. 13, 1990.
19.
Eigel WN, Butler JE, Ernstrom CA,
Farrell HM et al. Nomenclature of proteins of cow's milk. Fifth revision. J
Dairy Sci 67: 1599-631, 1984.
20.
Goodman RE, Schanbacher FL.
Bovine lactoferrin in RNA: Sequence, analysis, and expression in the mammary
gland. Biochem Biophys Res Commun 180: 75-84, 1991.
21. Duncan B,
Ey J, Holberg CJ, Wright AL et al. Exclusive breast-feeding for at least 4
months protects against otitis media. Paediatrics 91: 867-72, 1993.
22.
Frank AL,
Taber LN, Glezen WP, Kasel GL et al. Breast-feeding and respiratory
virus infection. Paediatrics 70: 239-45, 1982. 23. Mather G, Gupta N, Mathur S,
Gupta U. et al. Breast- feeding and childhood cancer. Indian Paediatrics 30:
652-7, 1993.
24.
Davis MK, Savitz DA, Graubard BI.
Infant feeding and childhood cancer. Lancet 1: 365-8, 1988.
25. Richie
JP. The role of glutathione in aging and cancer. Exp Gerontol 27: 615-26, 1992.
26.
Newberne PM, Butler WH. Acute and
chronic effects of aflatoxins B1 on the liver of domestic and laboratory
animals: A review. Cancer Res 29: 236-50, 1969.
27. Meerman
JHN, Beland FA, Ketterer B, Srai SKF et al. Identification of glutathione
conjugates formed from N-hydroxy-2-acetylaminofluorene in the rat. Chem Biol
Interact 39: 149-68, 1982.
28.
Boyland E, Sims P. The metabolism
of benz(a)anthracene and dibenz(a,h)anthracene and their 5,6-dihydro
derivatives by rat liver homogenates. Biochem J 97: 7-16, 1965.
29.
Waterfall JF, Sims P. Epoxy
derivatives of aromatic polycyclic hydrocarbons. The properties and metabolism
of epoxides related to benzo(a)pyrene and to 7-8 and 9-dihydrobenzo(a)pyrene.
Biochem J 128: 265-77, 1972.
30. Yamazoe
Y, Roth RW, Kadlubar FF. Reactivity of benzidine diimine with DNA to form
N-(deoxyguanosin-9-yl)-benzidine. Carcinogenesis 7: 179-82, 1986.
31.
Bounous G, Papenburg R, Kongshavn
PAL, Gold P et al. Dietary whey protein inhibits the development of
dimethylhydrazine-induced malignancy. Clin Invest Med 11: 213-7, 1988.
32.
McIntosh GH, Regester GQ, Le Leu
RK, Royle PJ. Dairy proteins protect against dimethylhydrazine-induced
intestinal cancers in rats. J Nutr 125: 809-16, 1995.
33.
Frei E, Bertram B, Wiessler M.
Reduced glutathione inhibits the alkylation by N-nitrosodimethylamine of liver
DNA in vivo and microsomal fraction in vitro. Chem Biol Interact 55: 123-37,
1985.
34. Roberts
JJ, Warwick GP. Mode of action of alkylating agents in formation of S-ethyl
cysteine from ethyl methanesulphonate. Nature 179: 1181, 1958.
35.
Coles B, Srai SKS, Waynforth B,
Ketterer B. The major role of glutathione in the excretion of N,
N-dimethyl-4-aminoazobenzene in the rat. Chem Biol Interact 47: 307-23, 1983.
36.
Sims P. The metabolism of
3-methylcholanthrene and some related compounds by rat liver homogenates.
Biochem J 98: 215-28, 1966.
37. Sims P.
The metabolism of 7- and 12-methylbenz(a)anthra-cenes and their derivatives.
Biochem J 105: 591-8, 1967.
38.
Djuric Z, Coles B, Fifer EK,
Ketterer B et al. In vivo and in vitro formation of glutathione conjugates from
the K-region epoxides of 1-nitropyrene. Carcinogenesis 8: 1781-6, 1987.
39.
Ripple MO, Henry W, Rago R,
Wilding G. Prooxidant-antioxidant shift induced by androgen treatment of human
prostate carcinoma cells. J Nat Cancer Inst 89: 40-8, 1997.
40. Hazelton
GA, Lang CA. Glutathione contents of tissues in the aging mouse. Biochem J 188:
25-30, 1980.
41.
Lang CA, Richie JP, Chen TS.
Differential glutathione and cysteine levels in the brain of the aging mouse.
Fed Am Soc Exp Biol, 1988. [Abstract 8327]
42.
Lang CA, Naryshkin S, Schneider
DL, Mills BJ et al. Low blood glutathione levels in healthy aging adults. J Lab
Clin Med 120: 720-5, 1992.
43. Jeandel C, Nicolas MB, Dubois F, Nabey-Belleville F et
al. Lipid peroxidation and free radical scavengers in Alzheimer's
disease. Gerontology 35: 275-82, 1989.
44. Calvin
HI, Medvedovsky C, Worgul BV. Near-total glutathione depletion and age-specific
cataracts induced by
buthionine
sulfoximine in mice. Science 28: 553-5, 1986.
45.
Riederer P, Sofic E, Rausch WD,
Schmidt B. Transition metals, ferritin, glutathione and ascorbic acid in
Parkinsonian brains. J Neurochem 52: 515- 20, 1989.
46.
Ebadi M, Srinivasan SK, Baxi MD.
Oxidative stress and antioxidant therapy in Parkinson's disease. Prog Neurobiol
48: 1-19, 1996.
47. Kuzuya M, Naito M, Funaki C, Hayahi T et al. Protective
role of intracellular glutathione against oxidized low density lipoprotein in
cultured endothelial cells. Biochem Biophys Res Commun 163: 1466-72, 1989.
48.
Bounous G, Gervais F, Amer V,
Batist G et al. The influence of dietary whey protein on tissue glutathione and
the diseases of aging. Clin Invest Med 12: 343-9, 1989.
49.
Blumberg JB, Meydani SN. Role of
dietary antioxidants in aging. In: Nutrition and Aging. Hutchinson MG, Munro HN
(Eds.). New York: Academic Press, 85-97, 1986.
50.
Birt DF, Baker PY, Hruza DS.
Nutritional evaluations of three dietary levels of lactalbumin throughout the
lifespan of two generations of Syrian hamsters. J Nutr 112: 2151-60, 1982.
51. Birt DF,
Schuldt GH, Salmasi S. Survival of hamsters fed graded levels of two protein
sources. Lab Anim Sci 32: 363-6, 1982.
52.
Bray TM, Taylor CO. Enhancement
of tissue glutathione for antioxidant and immune functions in malnutrition.
Biochem Pharmacol 2113-23, 1994.
53.
Puri RN, Meister A. Transport of
glutathione, as g-glutamylcylsteinylglycyl ester, into liver and kidney. Proc
Natl Acad Sci USA 80: 5258-60, 1983.
54. Anderson
ME, Powric F, Puri RN, Meister A. Glutathione monoethyl ester: Preparation,
uptake by tissues, and conversion to glutathione. Arch Biochem Biophys 239:
538-48, 1985.
55.
Birnbaum SM, Winitz M, Greenstein
JP. Quantitative nutritional studies with water-soluble, chemically defined
diets. III. Individual amino acids as sources of "non-essential"
nitrogen. Arch Biochem Biophys 72: 428-36, 1957.
56.
Bridgeman MME, Marsden M, MacNee
W, Flenley DC et al. Cysteine and glutathione concentrations in plasma and
bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax 46:
39-42, 1991.
57. Williamson
JM, Boettcher B, Meister A. Intracellular cysteine delivery system that
protects against toxicity by promoting glutathione synthesis. Proc Natl Acad
Sci USA 79: 6246-9, 1982.
58.
Mant TGK, Tempowski JH, Volans
GN, Talbot JCC. Adverse reactions to acetylcysteine and effects of overdose. Br
Med J 289: 217-19, 1984.
59.
Koch SM, Leis AA, Stokic DS,
Khawli FA et al. Side effects of intravenous N-acetylcysteine. Am J Respir Crit
Care Med 149: A321, 1994.
60. Williamson JM, Meister A. Stimulation of hepatic glutathione
formation by administration of L-2-oxothiazolidine-4-carboxylate, a 5-oxo-L,
prolinase substrate. Proc Natl Acad Sci USA 78: 936-9, 1981.
61. Baruchel S, Viau G, Olivier R, Bounous G. Nutriceutical modulation
of glutathione with a humanized native milk serum protein isolate: Immunocal
applications in AIDS and cancer. In: Oxidative Stress and Redox Regulation:
Cellular Signaling, AIDS, Cancer and Other Diseases. Symposium May 21- 24,
1996, Institut Pasteur. [In press]
62.
Watanabe A, Higuchi K, Yasumura S, Shimizu Y et al. Nutritional modulation of glutathione level and cellular immunity
in chronic hepatitis B and C. Hepatology 24: 1883, 1996.
HERMOSILLO SONORA MEXICO TELEFONO 6622 82 13 61
Immunocal recomendado por organización canadiense en VIH / SIDA:
http://www.mx.immunotec.com/IRL/sp/MX/Research_Article_23.pdf
SIDA
Escrito por la Dra. Patricia A.L. Kongshavn. Universidad de McGill, Montreal, Canada.
La enfermedad del VIH ahora es considerada como un problema muy serio en la actualidad, especialmente en paises en desarrollo. Es particularmente destrutiva de los linfocitos T, especialmente las celulas T CD4+, y un estado de profunda inmunodeficiencia es observada en los individuos afectados. Esto lleva a una serie de complicaciones que resultan en el Sindrome de Inmunodeficiencia Adquirida (SIDA). Tipicamente, el paciente se vuelve suceptible a ciertos tipos de neumonia, diarrea, candida y algunos tipos de cancer. Finalmente hay una mala nutricion, perdida de peso y la muerte. Todo esto puede llevar años en desarrollarse, especialmente con las terapias antiretrovirales ahora disponibles en el mundo.
Ha sido bien establecido que las reservas de glutation son inusualmente bajas en individuos con VIH / SIDA (1,2). Esto puede ser atribuido en parte al estres oxidativo (3). Una deficiencia en cisteina provee otra explicacion a la deficiencia observada debido a que este aminoacido es el precursor limitante en la sintesis de glutation en las celulas. Asi, se ha estimado que los pacientes con VIH experimentan una perdida masiva de sulfuro equivalente a 10 g de cisteina/dia aun cuando esten asintomaticos (4).
La deficiencia de glutation en VIH / SIDA es un asunto muy importante, ya que esto contribuye a muchas de las complicaciones de esta enfermedad, particularmente la inmunodeficiencia. Asi muchas funciones de los linfocitos se ven comprometidas por niveles bajos de glutation como el procesamiento de antigenos, expansion clonal durante la proliferacion, destruccion de celulas infectadas por virus o celulas cancerigenas por las celulas citotoxicas T o las celulas NK (3,5). Aun mas, con niveles bajos de glutation, hay una tendencia a tener una respuesta humoral (anticuerpo) a predominar mientras la respuesta mediada por celulas es reciprocamente inhibida (5). La inmunidad mediada por celulas provee un mecanismo efectivo de defensa en muchos tipos de infecciones y en cancer, y esto es real en VIH / SIDA. Una correlacion ha sido observada en individuos seropositivos entre la progresion de a enfermedad y el cambio de mediada por celulas a una respuesta humoral (medida por una produccion de citoquina en las celulas T helper) (6).
Mas aun, el estatus oxidacion/antioxidacion (Redox) en la celula es controlada por el glutation. Un desbalance en el estado redox resulta indirectamente en una elevacion de citoquinas inflamatorias como la TNF alpha, que promueve el desgaste y la perdida de peso, incrementando la replicacion viral e incrementando la apoptosis, incrementando al muerte de celulas T CD4+ T (3,6).
Una deficiencia en el glutation ademas tiene un efeto mayor en otros sistemas y organos en el cuerpo. Los pulmones, por ejemplo, utilizan y consumen glutaion para contrarestar el estres oxidativo asociado a la oxigenacion de tejidos y en la funcion fagocito antimicrobial, asi como en la desintoxicacion de toxinas. Asi, la enfermedad pulmonar frecuentemente se asocia al SIDA. Argumentos similares pueden aplicarse a los desordenes intestinales y neurologicos observados en pacientes con SIDA.
En 1997, Herzenberg mostro que existe una correlacion directa entre valores bajos de glutation en linfocitos T y el nivel de supervivencia de un individuo (1). Obviamente es muy importante reestablecer los niveles de glutation en individuos seropositivos proveyendole del aminoacido precursor cisteina. La N-acetylcisteina puede ser efectiva en incrementar la posibillidad de supervivencia (1,7,8). Sin embargo, los efectos secundarios de este medicamento son considerables especialmente en pacientes con SIDA debilitados (9). Immunocal, por otro lado, esta comprobado que eleva los niveles de glutation intracelular (9), entregando cisteina de una forma biodisponible a las celulas para la produccion de glutation. No tiene ninguna toxicidad conocida, no interfiere con el regimen de medicamentos y ha sido utilizado con exito en pacientes con VIH / SIDA (10,11).
Referencias
1. Herzenberg LA et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci 94:1967 – 72,1997.
2. Droge W and Holm E. Role of cysteine and glutathione in H infection and other diseases associated with muscle wasting and HIV immunological dysfunction. FASEB J 11:1077-89,1997.
3. Pace GW and Leaf CD, The role of oxidative stress in HIV disease. Free Radic Biol Med 19:523-8,1995.
4. Breitkreutz R et al. Massive loss of sulfur in HIV infection AIDS Res Hum Retroviruses.16: 203-9,2000.
5. Peterson JD et al. Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci 95:3071-6,1998.
6. Clerici M et al. Type 1 and type 2 cytokines in HIV infection — a possible role in apoptosis and disease progression. Ann Med 29:185-8,1997.
7. De Rosa SC et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 30:915-29,2000.
8. Droge W and Breitkreutz R. Glutathione and immune function. Proc Nutr Soc 59:595-600,2000.
9. Lands LC et al. Effect of supplementation with a cysteine donor on muscular performance. J. Appl Physiol 87:1381-1385,1999.
10. Baruchel S et al. Nutraceutical modulation of glutathione with a humanized native milk serum protein isolate Immunocal: Application in AIDS and cancer. In: Oxidative stress in Cancer AIDS and Neurodegenerative Diseases. Ed.; Montagnier L, Olivier R, Pasquier C. Pub.; Marcel Dekker Inc. New York, 1996.
11. Bounous G. Immuno-Enhancing Properties Of Undenatured Milk Serum Protein Isolate In HIV Patients. Int. Dairy Fed. Whey: 293-305,1998.
2. Droge W and Holm E. Role of cysteine and glutathione in H infection and other diseases associated with muscle wasting and HIV immunological dysfunction. FASEB J 11:1077-89,1997.
3. Pace GW and Leaf CD, The role of oxidative stress in HIV disease. Free Radic Biol Med 19:523-8,1995.
4. Breitkreutz R et al. Massive loss of sulfur in HIV infection AIDS Res Hum Retroviruses.16: 203-9,2000.
5. Peterson JD et al. Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci 95:3071-6,1998.
6. Clerici M et al. Type 1 and type 2 cytokines in HIV infection — a possible role in apoptosis and disease progression. Ann Med 29:185-8,1997.
7. De Rosa SC et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 30:915-29,2000.
8. Droge W and Breitkreutz R. Glutathione and immune function. Proc Nutr Soc 59:595-600,2000.
9. Lands LC et al. Effect of supplementation with a cysteine donor on muscular performance. J. Appl Physiol 87:1381-1385,1999.
10. Baruchel S et al. Nutraceutical modulation of glutathione with a humanized native milk serum protein isolate Immunocal: Application in AIDS and cancer. In: Oxidative stress in Cancer AIDS and Neurodegenerative Diseases. Ed.; Montagnier L, Olivier R, Pasquier C. Pub.; Marcel Dekker Inc. New York, 1996.
11. Bounous G. Immuno-Enhancing Properties Of Undenatured Milk Serum Protein Isolate In HIV Patients. Int. Dairy Fed. Whey: 293-305,1998.
TEMAS RELACIONADOS:
IMMUNOCAL DE IMMUNOTEC EN HERMOSILLO SONORA MEXICO
TELEFONO 6622821361 ORLANDO CARDENAS IMMUNOCAL DE IMMUNOTEC
LA CURA NATURAL DE LAS ENFERMEDADES UTILIZANDO NUTRACEUTICOS PARA FORTALECER EL SISTEMA INMUNOLOGICO SIN NINGUN EFECTO SECUNDARIO NEGATIVO IMMUNOCAL DE IMMUNOTEC
LA MEDICINA NATURAL AL ALCANCE DE TODOS IMMUNOCAL DE IMMUNOTEC
MEDICINA ALTERNATIVA IMMUNOCAL DE IMMUNOTEC
MEDICINA NATURAL IMMUNOCAL DE IMMUNOTEC
MEDICINA NUTRACEUTICA IMMUNOCAL DE IMMUNOTEC
MEDICINA ENERGETICA IMMUNOCAL DE IMMUNOTEC
MEDICINA HERBOLARIA IMMUNOCAL DE IMMUNOTEC
BLENDED MEDICINE IMMUNOCAL DE IMMUNOTEC
DOCTOR MD PHD MEDICO IMMUNOCAL DE IMMUNOTEC
REMEDIOS CON IMMUNOCAL DE IMMUNOTEC
EMPRESA CANADIENSE GUSTAVO BOUNOUS CANADA FDA PDR CPS MEDICARE
CARDIOLOGO IMMUNOCAL DE IMMUNOTEC
ONCOLOGO IMMUNOCAL DE IMMUNOTEC
NUTRIOLOGO IMMUNOCAL DE IMMUNOTEC
PEDIATRA IMMUNOCAL DE IMMUNOTEC
Especialidades:
Alergia e inmunología clínica
Alergia e inmunología clínica pediátrica
Anatomía patológica
Anestesiología
Anestesiología pediátrica
Angiología y cirugía vascular
Audiología
otoneurología y foniatría
Biología de la reproducción humana
Cardiología
Cardiología pediátrica
Cirugía cardiotorácica
Cirugía cardiotorácica pediátrica
Cirugía general
Cirugía oncológica
Cirugía pediátrica
Cirugía plástica y reconstructiva
Coloproctología
Dermatología
Dermatología pediátrica
Dermatopatología
Endocrinología
Endocrinología pediátrica
Epidemiología
Gastroenterología
Gastroenterología y nutrición pediátrica
Genética médica
Geriatría
Ginecología oncológica
Ginecología y obstetricia
Hematología
Hematología pediátrica
Imagenología diagnóstica y terapéutica
Infectología
Medicina de la actividad física y deportiva
Medicina de rehabilitación
Medicina de urgencias
Medicina del enfermo en estado crítico
Medicina del enfermo pediátrico en estado crítico
Medicina del trabajo y ambiental
Medicina familiar
Medicina interna
Medicina legal
Medicina maternofetal
Medicina nuclear
Nefrología
Nefrología pediátrica
Neonatología
Neumología
Neumología pediátrica
Neuroanestesiología
Neurocirugía
Neurocirugía pediátrica
Neurofisiología clínica
Neurología
Neurología pediátrica
Neurootología
Neuropatología
Neurorradiología
Nutriología clínica
Oftalmología
Oftalmología neurológica
Oncología médica
Oncología pediátrica
Ortopedia
Otorrinolaringología pediátrica
Otorrinolaringología y cirugía de cabeza y cuello
Patología clínica
Patología pediátrica
Pediatría
Psiquiatría
Psiquiatría infantil y de la adolescencia
Radiooncología
Reumatología
Reumatología pediátrica
Terapia endovascular neurológica
Urgencias pediátricas
Urología
Urología ginecológica.
grupos de edad (pediatría, geriatría)
aparatos o sistemas del cuerpo humano (neumología, cirugía vascular)
órganos (oftalmología, otorrinolaringología)
técnicas diagnósticas (radiología, microbiología)
técnicas terapéuticas y rehabilitadoras (farmacología, cirugía, ortopedia y traumatología, rehabilitación, hidrología)
enfermedades concretas (infectología, alergología, psiquiatría)
actividades humanas (medicina del trabajo, medicina del deporte, medicina legal, medicina preventiva)
La especialidad que abarca todos los anteriores apartados desde un visión integral del paciente es la medicina familiar y comunitaria.
[editar]Según su agrupación tradicional
Tradicionalmente se dividen en clínicas, quirúrgicas, y de laboratorio. Aunque con los continuos avances de la medicina, esos límites no son muy precisos.
[editar]Especialidades clínicas
Las especialidades médicas se corresponden con la figura tradicional de "médico": asisten personalmente al paciente con actividades preventivas, diagnósticas y terápéuticas, generalmente sin utilizar técnicas quirúrgicas.
Alergología
Anestesiología y Reanimación
Aparato Digestivo o Gastroenterología
Cardiología
Endocrinología y Nutrición
Geriatría
Hematología y Hemoterapia
Hidrología Médica
Infectología
Medicina del Deporte
Medicina del Trabajo
Medicina Familiar y Comunitaria
Medicina Intensiva
Medicina Interna
Medicina Legal y Forense
Medicina Preventiva y Salud Pública
Nefrología
Neumología
Neurología
Oncología Médica
Oncología Radioterápica
Pediatría
Psiquiatría
Rehabilitación
Reumatología
[editar]Especialidades quirúrgicas
Las especialidades quirúrgicas se corresponden con la figura de cirujano, y utilizan medios invasivos para tratar, modificar o extirpar físicamente la estructura patológica. Se dividen por sistemas.
Cirugía Cardiovascular
Cirugía General y del Aparato Digestivo
Cirugía Oral y Maxilofacial
Cirugía Ortopédica y Traumatología
Cirugía Pediátrica
Cirugía Plástica, Estética y Reparadora
Cirugía Torácica
Neurocirugía
[editar]Especialidades médico-quirúrgicas
Son las que habitualmente usan tanto técnicas invasivas (quirúrgicas) como no invasivas (farmacológicas, etc).
Angiología y Cirugía Vascular
Dermatología Médico-Quirúrgica y Venereología
Estomatología
Ginecología y Obstetricia o Tocología
Oftalmología
Otorrinolaringología
Urología
[editar]Especialidades de laboratorio
De apoyo a los demás médicos, realizan diagnósticos y sugieren tratamientos a los clínicos, por lo que en ellas la relación con el paciente es reducida.
Análisis Clínicos
Anatomía Patológica
Bioquímica Clínica
Farmacología Clínica
Inmunología
Medicina Nuclear
Microbiología y Parasitología
Neurofisiología Clínica
Radiodiagnóstico o Radiología
Alergologo
inmunologo
alergologo
patologo
anestesiologo
pediatra
angiologo
audiologo
otoneurologo
foniatrologo
biologo
quimico
Cardiologo
cirujano
oncologo
cirujano plastico
Coloproctologo
Dermatologo
Dermatopatologo
Endocrinologo
Epidemiologo
Gastroenterologo
nutriologo
Gastroenterologo
Ginecologo
Ginecologo
obstetra
gineco obstetra
ginecobstetra
Hematologo
Imagenologo
diagnóstico
terapéuta
Infectologo
Nefrologo
Neonatologo
Neumologo
Neuroanestesiologo
Neurofisiologo
Neurologo
Neurootologo
Neuropatologo
Neurorradiologo
Nutriologo clinico
Oftalmologo
Oftalmologo neurológo
osteopata
Otorrinolaringologo
Patologo
Psiquiatra
Radiooncologo
Reumatologo
Urologo
