|
THYMUS
EXTRACTS:
An International Literature Review of
Clinical Studies*
Continued...
Surgery
Colorectal surgery
Four hundred and
twenty-five patients received
thymostimulin for 7 days beginning 48
hours before surgery plus cefotetan, an
antibiotic, administered at the time of
anesthesia. The results showed a lower
incidence of post surgical infections
and abscesses compared to those who
received only the antibiotic, even in
patients with compromised immune
responses. Respiratory tract infections
were one-half as frequent compared to
those who received only the antibiotic (Periti
93).
Suppurative surgical
infection (SSI)
Forty-seven infants
with sepsis and 34 with localized
infection were given t-activin thymus
extract as part of the post surgical
treatment complex while 75 other infants
were treated with conventional methods.
Results showed that the clinical course
of SSI was less severe, with more
pronounced positive changes in symptoms,
shortened hospital stay and decreased
mortality in the treated infants. The
authors confirmed that the
post-operative use of thymus extracts in
infants leads to an increase in the
number and functional capacity of
peripheral T-lymphocytes with improved
bactericidal activity of circulating
phagocytes in postoperative newborns
with SSI (Samsygin 89).
Post-operative Sepsis
The thymus extracts
thymalin and t-activin were used in a
study involving post-operative sepsis.
The authors reported after 14 days of
treatment that thymalin stimulated T
cells while acting with immunoglobulins.
T-activin increased the numbers of T
cells and B cells. Clinical improvement
was best when the thymus extracts were
used in combination with other
medication (Bulava 96). After citing
immunologic and clinical studies
demonstrating the immunodeficiency
states are the most probable causes of
post-operative complications following
reparative surgery of the facial bones,
results were presented for 10 cases of
facial surgery for congenital land
acquired deformation using t-activin
conjointly with surgery. This protocol
normalized immune parameters and
prevented development of post-operative
complications (Volozhin 96).
Orthopedic implants
Teicoplanin, a thymus
extract, was shown to be a useful
prophylactic against infection resulting
from orthopedic implant surgery. Deep
prosthetic infections are very difficult
to cure without removing the infected
device; the outcome can be devastating,
such as: total loss of joint function,
amputation, and occasionally, death.
Preliminary results show that
teicoplanin has a role to play both in
treatment of infection and as
prophylaxis against hospital-acquired
infection (Periti 92).
Abdominal surgery
Sixty-one patients
who had been previously classified as
anergic underwent elective abdominal
surgery in conjunction with
simultaneously receiving thymostimulin
thymus extract. The authors found a
notable reduction of postoperative
infection in the treated group when
compared with 62 controls who were
anergic and underwent surgery but
received no therapy (Perotti 47).
Surgery with the
immunocompromised
Two hundred and
twelve surgical patients at risk because
they were immuno-compromised were
divided into 2 homogeneous groups: the
treatment group which received
thymostimulin thymus extract during and
after surgery, and the control group
which received conventional surgical
treatment. All patients were affected by
severe pathologies. Positive results
were obtained in the thymostimulin
treated group in terms of reduced
morbidity, postoperative hospitalization
and mortality as compared to controls.
The author’s conclusion was that
treatment with thymostimulin in immuno-compromised
patients is an important factor in
avoiding or reducing postoperative
infection rates (Lai 92).
Immunosenescence
(Immune Effects of Aging)
A strong and vigorous
immune system is especially important in
the health of the elderly. The
lifestyles of most older persons in our
society compromise immunity in many
ways. Several of the common causes of
compromised immunity listed earlier in
this paper are especially relevant to
aging persons. As a group, older people
tend to exercise less, consume more
prescription and nonprescription drugs,
and are exposed to more medical
procedures. Suboptimal nutritional
intake is also a common problem
associated with aging. These stressors
occur at a time of life in which
inadequate digestion and elimination
combined with decreased liver function
compound their detrimental effects on
immune function. Because these
conditions are additive and cumulative,
it is difficult to determine exactly how
much of the aging in humans is due to
the natural physical process and how
much is incurred by lifestyle components
that lead to compromised immunity. Even
though the exact proportion may be
difficult to assess, it is no
coincidence that many of the causes of
compromised immunity are also involved
in aging. "The programmed decline
in physiologic competence, which we know
as aging, is in fact a series of
concomitant changes primarily manifested
in the immune system" (Weksler 81).
One of the most
consistent findings associated with
immunosenescence in humans and animals
is a decline in T cell numbers, function
and proliferation as aging increases.
This has been attributed to the
involution of the thymus gland (Kouttab
89) and the subsequent decreased
production of the thymic hormones that
control T lymphocyte numbers and
function (Ghanta 90). These decrease
with age and are associated with a
"thymic menopause" and
cellular immune senescence contributing
to the development of diseases in the
aged (Hadden 92). The consequence of
this process is an increased
susceptibility to infections, auto
immune diseases and cancer (Weksler 81).
Liquid thymus extracts have been used to
help restore cellular immunity,
including the number and function of
T-lymphocytes (Skotnicki 89, Kouttab 89,
Hadden 89, Dabrowski 80, Segatta 86,
Park 84, Poli 86, Periti 93, Harrower
32, Weksler 81). The question is whether
liquid thymus extracts can do the same
in the elderly person.
There is scant
literature on the clinical and direct
immunological effects of liquid thymus
extracts in the aged. In one of the few
studies, Pandolfi et al. administered
thymostimulin (TP-1) to 14 randomly
selected persons averaging 80 years of
age who were free of neoplastic,
autoimmune or infections diseases at the
time of selection and had a normal
lymphocyte count (Pandolfi 83). Dosage
was 1 mg/kg per wk for 1 month followed
by 1 mg/kg per 2 weeks for 2 months. The
total treatment time was 90 days. The
results were compared to a control group
of 12 subjects receiving no therapy.
Routine blood, urine and clinical data
were evaluated before therapy, at 90
days and at 180 days. The study found no
change in the absolute lymphocyte count.
There was an increase in T lymphocyte
resetting but it was not statistically
significant due to the small N size. The
only statistically significant
difference in laboratory measurement
between the two groups was a decrease in
the sedimentation rate from a slightly
elevated value of 22 before therapy
began to 12 at 180 days for the
treatment group, a decrease of about
50%. The clinical results of the study,
however, were much more striking.
Significantly fewer patients in the
treated group had infections than
controls (21% vs. 67%). In addition,
there was only 1 episode of urinary
tract infection in the treated group
compared to 6 in the controls and only 2
episodes of respiratory infection in the
treated group compared to 11 in the
control group. No other infections in
the treated group occurred, but there
were 4 in the controls. No side effects
or toxicities were reported.
Because no true T
lymphocyte function tests were
completed, we can only surmise that the
cause of this improved resistance to
infection may have been due to increased
T cell function, as has been shown by
previous studies in humans and animals (Kouttab
89, Stankiewiez 86, Dabrowski 80,
Segatto 86, Park 84, Poli 86). The
results of this study provide a very
interesting indication that thymus
extracts may not significantly increase
lymphocyte numbers in relatively normal,
healthy, elderly persons, but may
significantly alter their clinical
course, even when their lymphocyte count
is normal.
Studies presented
earlier in this paper demonstrated the
beneficial effects of thymus extracts in
treating the most common diseases
associated with aging: infections,
auto-immune diseases and cancer. The
study presented above, however,
demonstrates the possibility of benefits
of liquid thymus extracts given to
elderly subjects on a prophylactic
basis.
Although the
increased clinical response was probably
due, at least in part, to the increased
functional capabilities of T
lymphocytes, there may also have been
other factors involved. The thymus
appears to be involved in decreasing
some of the normal processes of aging in
association with other organs and
systems. In other words, they may have
extra-immunological functions as well (Fabris
90, Czaplicki 89).
For example, studies
have shown the beneficial effects of
liquid thymus extracts on the structure
and function of livers in aging animals.
Typically, the hepatocyte nuclei of
livers in aging animals increase in
size. Mitochondria are also swollen and
have deficient membrane composition with
dark and electron dense internal
structures. The rough endoplasmic
reticulum (RER) and smooth endoplasmic
reticulum (SER) also show characteristic
patterns of degeneration. These
characteristic changes should be taken
as a criterion of aging and diminished
biological activity (Weindruch 80).
Fetal thymic calf extracts have been
shown to induce a significant decrease
in the size of hepatocyte nuclei in
aging (450 day old) mice (Czapliki 90).
Microscopic examination of hepatocyte
mitochondria from treated mice showed
the histological picture of healthy
young mice. In contrast, histology of
hepatocytes from the control group
showed the typical patterns of
degeneration associated with aging. In
another study, thymus peptides (thymic
factor D) extracted from swine and
injected into 24-month-old rats
(senescent rats) in a dosage of 2 mg/kg
every other day for 3 months resulted in
decreased liver content of
malondialdehyde & lipofusion
accompanied by increased liver
glutathione peroxidase (GSH) levels.
Microscopic examination revealed that
hepatic mitochondrial and microsomal
membranes of these aged rates had
recovered to be like those of young
adult rats (Chung-Kuo 93). Another
finding from this study was that liver
and spleen function did not deteriorate
with age in the treated animals.
Other studies have
shown decreased levels of unsaturated
fatty acid peroxides in cerebral and
splenic tissue of adult rodents (Czaplicki
89). Histologies of these animals
revealed the preservative and antiaging
effects of embryonic and early fetal
calf thymus extracts. The authors’
conclusion was that the active
substances produced by embryonal thymus
and early fetal thymus not only affect
the immunological system, but also
interfere with the process of organ
aging. Investigators have reported that
the administration of liquid thymus
extracts has been associated with the
disappearance of presbyopia and
climacteric changes in elderly persons (Kaliuzhnaia
89). Other investigators demonstrated
that thymus extracts significantly
increased the longevity of treated mice
(Hadden 89, Kaliuzhnaia 89).
Taken as a group,
these studies indicate that liquid
thymus extracts may be useful in
preserving antioxidant activity, may
decrease the typical response to aging
in the liver and possibly other organs,
and may influence longevity in some
animals.
The thymus is also
fundamental to the integration and
proper interaction between the immune,
endocrine and central nervous systems
(CNS). There is recent evidence that
indicates the thymus plays an indirect
but considerable role within the
neuroendocrine network. A number of
homeostatic processes governed by the
hypothalamopituitary axis are involved,
including regulation of tissue
metabolism (Fabris 90, Dabraowski 90).
In summary, decreased
cellular immunity is directly associated
with increased aging. Liquid thymus
extracts have been shown to be
beneficial in some clinical conditions
affecting the elderly. They have been
shown to have extra-immunological
benefits on other organs and systems.
The use of thymus extracts may be an
important, but overlooked, option in
treating the possibly preventing many
clinical conditions of the aging person.
Miscellaneous
Burns
Opportunistic
micro-organisms causing infections in
burn patients are often acquired in
hospitals. These infections commonly
involve Gram-positive organisms which
may be resistant to several antibiotics.
Teicoplanin, alone and in combination
with additional antibacterial drugs,
proved effective in the treatment of
Gram-positive infections of various
types in hospitalized burn patients (Periti
92).
In another study the
thymus extract t-activin was used in
combination with sodium nucleinate plus
lidocaine to restore phagocytic function
of peripheral blood lymphocytes and
increase humoral immunity in severely
burned animals. Treatment decreased
colonization of pseudomonas aeruginosa
and candida pathogens and decreased the
death rate (Shatalova 97).
Preeclampsia and
eclampsia
Progressive immune
depression accompanied by a parallel
drop in parathyroid hormone level to
critical values has been demonstrated in
patients with eclampsia. Patients with
preeclampsia delivering by cesarean
section were treated postoperatively
with the thymus extract, t-activin.
Cellular immunity was compared with
patients receiving no t-activin. A
marked immunostimulatory effect of the
thymus extract on T-lymphocytes and
especiallky on theophylline-resistant
T-lymphocyte subpopulations was
observed. The effect of t-activin was
most marked on the 3rd to 5th
day of the postoperative period (Ianiushina
92).
Male Infertility
In an unusual 2 part
study, the effect of complete thymic
extract on the motility and progression
of sperm from men with previously
confirmed asthenozoospermia was
investigated. In the first part, the
thymic extract was incubated in vitro
with sperm obtained from men with
asthenozoospermia and compared to
untreated in vitro sperm from the same
men. In the second part of the study, 10
men with asthenozoospermia were given
injections of the thymic extract
(150mg/day IM) for y days and sperm
samples were compared before and after
therapy. In both parts of this study
results showed a significant increase in
sperm motility and progression with the
introduction of complete thymic extract
(Arsenijevic 96).
Cardiac Function
In a 4 year study
comparing treatments for men with biopsy
proven myocarditis or dilated
cardiomyopathy, 13 men were treated with
thymomodulin plus conventional
treatment, 13 with interferon-alpha plus
conventional treatment, and 12 with
conventional treatment alone for a
period of 2 years. Results at the 2 year
follow-up showed significant improvement
in left ventricular ejection fraction
(81% vs 66%), and maximum exercise time
(5 vs 3 minutes) during exercise. At the
2 year follow-up, 88% of the men in the
2 treatment groups had normal
electrocardiograms compared with 22% of
the controls, and 73% had improved their
functional class compared to 25% of the
men in the control group (Muric 96).
Side Effects
Over 200 articles
were reviewed in the preparation of this
paper. One of the most striking
consistencies throughout the many
articles was the absence of harmful side
effects produced by thymus extracts.
Except for two incidents of toxicity
(see "Toxicities" section), no
hazardous side effects were listed, even
in the studies involving injections. A
few authors noted the lack of harmful
side effects. This is unusual in medical
literature, especially in new or
experimental therapies. One review
article found "a complete lack of
detrimental side effects" in over
50 studies it reviewed (Kouttab 89).
Beneficial side effects are not usually
measured or reported in clinical
experiments, however, one study reported
a decreased sensitivity to viral and
bacterial infections and an improvement
in the general clinical state and
overall well-being of subjects taking a
thymus extract (Skotnicki 89).
Some studies used
thymus extracts to decrease the
iatrogenic side effects and toxicity of
radiotherapy, chemotherapy and surgery (Vuckovic
92, Alba 91, Negri 92).
Toxicities
Only 2 toxicities
were reported in all of the papers
referenced here or in any of the other
papers reviewed. This is an important
finding, particularly when compared to
the side effects and toxicities of some
of the drugs used to treat the same
conditions that thymus extracts have
successfully treated, especially in the
frail or chronically ill patient.
One study, however,
showed a severe anaphylactic reaction to
thymostimulin. This was a report of a
single 36-year-old male receiving
thymostimulin as part of the treatment
for a neck tumor. In this unusual case,
the man showed an anaphylactic response
on the first injection. Subsequent tests
showed no skin response to bovine
material but a response specific to the
thymostimulin (Marcos 91). In light of
this we would suggest routine skin tests
before injection of any thymus extracts
as a precautionary measure.
Contraindications
Although none have
been reported, all patients with an
organ transplant or other forms of
allografts (same species, different
genetic strain) or xenografts (different
species) must be cautious of any agent
capable of stimulating a cellular immune
response as there is the potential risk
of increasing the graft-versus-host
response rejection rate of implants.
Orthopedic implants, however, may be an
exception as the study noted above
successfully used a thymus extract to
prevent complications of orthopedic
implant surgery and reported no increase
of implant rejection (Periti 92).
Summary
Thymus extracts have
been shown to be of significant
therapeutic value using both clinical
and laboratory indices. It is important
to note that the improvements taking
place in several of these experiments
were not just palliative improvements.
In some studies there were indications
of an actual reconstitution of the
cellular immune system as indicated by
the increase in the numbers of T
lymphocytes (Skotnicki 89, Kouttab 89,
Hadden 89, Stankiewiez 86), macrophages
(Andolina 87) and suppressor cells (Kouttab
89) and a restoration of function of
these and other cells as shown by:
increased conversion of immature
thymocytes to non-dedicated T cells in
human bone marrow (Kouttab 89); enhanced
proliferation response to concanavalin A
(Con A) (Dabrowski 80) and
phytohemagglutinin (PHA) (Segatto 86,
Poli 86, Vuckovic 92, Marjanska 75);
increased E-rosette formation (Macchiarini
89); increased phagocytosis and
bactericidal activity of circulating
phagocytes (Kartasheva 91, Samsygin 89,
Alba 91), increased numbers of
macrophages and monocytes (Kouttab 89,
Tas 90); decreased carcino-embryonic
antigen (CEA) levels in cancer patients
(Reinke 85); and a restoration of skin
test responsiveness (DTH response) in
previously unresponsive patients (Kouttab
89, Lasisz 90, Periti 93, Marjanska 75).
Laboratory tests have also confirmed the
favorable effects of thymus extracts on
humoral immunity as shown by: an
increase in the B lymphocytes (Twomey
82) and serum immunoglobulins to normal
(Kouttab 89); an increase in depressed
salivary IgA levels (Fiocchi 86); and a
down regulation of elevated IgE (Kouttab
89, Fiocchi 87, Bagnato 89, Cavagni 89)
and eosinophil counts (Kouttab 89,
Fiocchi 87).
The positive effects
of thymus extracts have even been
demonstrated in laboratory tests for
autoimmune reactions by reducing
rheumatoid factor alpha 2 and serum G
globulin levels (Skotnicki 89, Skotnick
86, Lasisz 90) with an accompanying rise
in the depressed hemoglobin and serum
iron levels as the autoimmune factors
decreased (Skotnicki 86). The ability to
affect these multifactor autoimmune
reactions provides further indications
that the regulatory mechanisms modified
by thymic extracts are systemic. Their
effects do not come from just focal
inhibition or stimulation of a single
mechanism.
This broad range of
laboratory indices taken as a whole
indicates that thymus extracts are
capable of affecting the immune response
at a fundamental level.
One of the most
striking features of therapy using
thymus extracts is the wide variety of
conditions in which these extracts have
been successfully employed. They have
been used orally and as injectables; by
themselves and in combination with other
therapeutics. In some instances, they
have been the only effective treatment.
These extracts have been successfully
used clinically to prevent and treat
primary and secondary infections (Kartasheva
91, Periti 92), prevent relapses (Kouttab
89) and secondary complications of
infections (Kartasheva 91), and to
reduce postoperative infection rates(Lai
92). They have also been used to:
modulate the deleterious effects of
radiotherapy, chemotherapy and surgery (Vuckovic
92, Alba 91, Negri 92); accelerate the
rate of wound healing (Skotnicki 89);
decrease some of the effects of aging (Czapliki
90, Chung-Kuo 93); improve the efficacy
of other treatments (Grigor’ev 89);
and as an adjuvant in surgery (Periti
93, Samsygin 89, Periti 92, Lai 92) and
treatments using antifungal, antibiotic
and antiviral agents (Skotnicki 89,
Radomska 87, Czaplicki 89, Ianiushina
92, Gilman 87, Drews 84).
Few medicines can
boast effectiveness in treating
conditions so diverse as: infections
[deep disseminated (Dworniak 91), or
focalized (Grismondi 91) of bacterial (Guliamov
91) and viral (Kicka 86, Dworniak 91,
Zeman 91, Skotnicki 84) origins];
respiratory diseases [infections (Kouttab
89, Fiocchi 86), non-infections (Stankiewiez
86, Matusiewicz 87, Gieldanowski 81,
Smogorzewska 84), acute (Stankiewiez 86)
and chronic (Gieldanowski 81,
Smogorzewska 84, Frolov 92, Tortorella
92)]; diseases of immunodeficiency
(Davies 82, Valesini 87); autoimmunity (Skotnicki
84, Kartasheva 91, Suchkova 90);
allergies (Chachoua 89); degenerative
skin diseases (Skotnicki 89, Kouttab 89,
Pecora 91, Cavagni 89, Kaliuzhnaia 89);
as well as neoplasias of the lung (Capelli
92), larynx (Mantovani 92), leukocytes (Skotnicki
89, Martelli 82, Makhonova 91, Drozdova
90, Marjanska 75), breast (Alba 91,
Negri 92, Reinke 85, Griffith 88) and of
colorectal and gastric origin (Ciconi
92, Urban 77, Cybulski 87). They have
also been shown to be of benefit in
increasing the survival time of patients
with severe or terminal illnesses (Kartasheva
91, Cybulski 87, Samsygin 89, Periti
92).
In some cases these
results persisted long after the
treatment was discontinued. This
indicates that it was effective in
changing the natural course of the
disease by working at the causative
level, i.e. the faulty immune process
rather than at the combative
(antibiotics) or symptomatic (bronchodilators,
etc.) levels. In other cases, the change
was seen only while the extracts were
being administered, indicating that even
though these extracts were not effective
at the causal level, they were still
able to play a significant role in the
therapeutic regimen and, at the least,
provide an improvement in the clinical
state land general well-being of the
patient (Skotnicki 89). The combined
results of the many studies on the
various thymus extracts, taken as a
group, is very encouraging and appears
to offer a possible new alternative
and/or adjunct to present therapies.
Individually, many of
the studies showed design weaknesses.
Small N-size plagued most of these
studies with as few as 4 subjects in
some. In several studies there was no
randomization of groups and in a few, no
control groups. Only a few of the
studies used double-blind trials.
Although there is a need for better
designed studies, the combined results
and the variety of health conditions
reported to respond to the thymus
extracts tested provide enough material
to consider thymus extracts as a
potentially promising and useful new
area of treatment and research.
In summary, thymus
extracts have been shown to be extremely
versatile in treating a wide variety of
illnesses and clinical conditions
ranging from mild to life threatening.
They appear to primarily affect the
cellular branch of immunity but other
areas of influence are probable. Some of
the most severe clinical conditions
showed the most profound recovery.
Thymus extracts were
beneficial in nearly all studies with a
degree of efficiency varying from
symptomatic relief to curative. The
overall clinical impact was extremely
positive with no reports of undesirable
side effects and only 2 toxicities. The
favorable clinical response combined
with the lack of side effects or
toxicity makes the use of thymus
extracts a potential treatment and
research option that has yet to be
recognized on this continent.
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Due
to the recent problem with the madcow disease,
the FDA has inspected and cleared our Natcell products
for sale.
FDA Clearance No. 110-3122937-2
NO
MADCOW HERE! |
 |
|
