Techrpt2 New

LifeChoice FACTOR-R Immunostimulant
TECHNICAL REPORT
PREFACE
I deliberated for some time as to whether or not to address myself in the first person to you in
the introduction of a "Technical Report". My first thoughts were against it. I believed that it
would be unprofessional and seem too familiar. But after careful consideration and recalling
the reason for the existence of LifeChoice I determined that not only was it appropriate but
mandatory.
Each time I read the medical data I am amazed by the scientific and personal significance of
the information. I have forwarded this information about Factor-R to close associates and
critical third parties. The response to Factor-R and its approach has been varied to say the
least, from praise of its simple logic to ridicule of its mode of operation.
To me the ultimate goal of medicine is to improve the quality and duration of life. And the
technology responsible should never be presented as anything more than what it is, a way to
achieve that goal. Factor - R is just one more way to realize it, nothing more, especially for
those of us who are not suffering from any disease. But Factor-R holds the promise of a
healthier and less diseased future. For those of you suffering from acquired immune deficiency
syndrome (AIDS) and secondary immune deficiency (SID) it holds the choice of a better life
or life itself.
While medical science has made near miraculous progress over the last 100 years it still does
not understand all of the complex links and enigmatic relationships which exist within our
bodies. Evidence and common sense would suggest that the treatment of disease could be
significantly improved if it was somehow possible to harness the more complex and capable
resources of the human immune system.
Factor-R does exactly that. It motivates your body into producing natural substitutes to the
synthetics your Doctor may prescribe. By stimulating your natural defenses against disease
Factor-R provides an important link in your treatment that drugs are incapable of reproducing.
In my discussions with a number of doctors one of the major points of resistance to the use of
Factor-R in the treatment of secondary infections is that certain effects can be simulated more
rapidly through the introduction of various drugs. But these drugs can only duplicate specific
parts of that effect. In order to get the broad effect of Factor-R you would need to be
provided with several different drugs, none of which strengthen your immune system. As well
long term treatment with these substances will result in some morbid side effects. Factor-R has
no known side effects.
Because of the side effects of chemical treatments they are generally provided only after an
infection has taken hold and you become detectably ill. If you're HIV positive or an AIDS
sufferer that will be to late.
LifeChoice does not claim, nor will it claim, that Factor-R holds all the answers. It is,
however, an important element. An element which has been ignored primarily because it
affects the immunoresponse of the body rather than the affecting the infection itself.
In many respects to date the battle against HIV and AIDS can be compared to the United
Nations recent undertaking in Somalia. "Rapid Deployment Forces" and "Rambo" solutions
are fine when they work quickly and take immediate control of a situation. But in the long
term, if no political solution is found, you end up with another Vietnam. Treatment with
chemicals is a "Rapid Deployment" solution which, in the case of HIV/AIDS, results
ultimately in a "biological Vietnam". Neither AZT nor any other chemotherapeutic agent has
yet managed to overwhelm HIV's "guerrilla" tactics. Factor-R proposes a "political" solution
by strengthening your immune system against the effects of the virus and allowing "mutual
coexistence" rather than mutual "self-destruction".
The effect of Factor - R in the treatment of HIV and AIDS will become clear only after time
and use. I ask is that you attempt to understand and embrace, rather than resist, the concept
which Factor - R represents, that healing and good health can be accomplished in a more
uncanny and indirect way by stimulation of the body's immunocompetent components rather
than only through varied chemical assaults on the infection or offensive tissues. Even if the
latter may prove the only life saving alternative, recent laboratory evidence indicates that the
therapeutic introduction of Factor-R may offset the damaging effect of chemotherapeutic
treatment sufficiently so as to permit remission and recovery.
Factor - R has is relatively inexpensive and it provides one more alternative in a life versus
death struggle. Whether or not you approve of our technology or approach you should at least
consider it as an option, a life could depend on it maybe yours.
Introduction
In my opinion much of our healthcare has become dehumanized, whether or not you share this
opinion it will be a consequence of your own personal experience. I suppose it is inevitable for
many of our health professionals to lose their sense of benevolence when they are constantly
exposed to suffering. Add to that the economic realities of quality healthcare and the picture
becomes somewhat dismal. Often it seems that medical breakthroughs only become available
to us when the profits are significant enough to the multinational pharmaceutical giants to
justify the investment. These corporations think more in terms of dollars made than in lives
saved. Much of this conclusion comes from my own personal experience.
But what really amazes me is how corporate and governmental bureaucracy has made the
physicians and researchers employed by these corporations and agencies disinterested and in
many instances downright callous. Part of the blame rests with government and the
ecopolitical realities of each country's healthcare system. Institutions like the Food and Drug
Administration (FDA) and Canada Health & Welfare Protection Branch (CHPB) require so
many controls and tests that the cost of introducing a new drug becomes prohibitive except for
only the largest of companies. Furthermore, their approval guidelines have forced researchers
and companies to seek out only that technology which will be endorsed or funded by these
agencies under their established guidelines. Are these regulations a political tactic to maintain
control over a multi-billion-dollar-a-year industry?
While much of this caution is justified, the FDA and CHPB have progressed over the years to
the point of deciding what's good for us. As a result this and the financial and political realities
have restricted the introduction of many new and viable treatment options. I personally view
this as a violation of your and my right to make an informed choice.
And I feel strongly about having the right to that choice. Because it is a choice that will affect
my life and the lives of those I love. The fact that each day as you and I grow older, we
become, as the blush of youth passes, more aware of our mortality. I don't know about you
but it causes me to consider these choices carefully. But maybe not so surprisingly I, like many
of you, have noticed lately that I sometimes have very little real choice, particularly when it
comes to healthcare. Like death and taxes there have been few alternatives except to acquiesce
to the system.
It appears that our ability to make a choice, or the lack of it, is directly affected by our
financial, intellectual and social limitations. Much of the point of life is to overcome certain of
those limitations and increase our choices. Another limitation of choice is "morality". This is
often the most complex and difficult choice. It is based on issues of personal conviction,
experience, legislative restrictions, conscience and need.
The issue you and I must be concerned with is the morality of permitting access to a treatment
which shows significant benefit in laboratory and clinical use, but has not yet been blessed by
local regulatory authorities. The prevalent professional and legislative opinion is not to permit
such access, regardless of the consequences.
I find this interesting. Currently there is a rather sizable lobby lead by physicians and politicians
to permit euthanasia in several states. Yet many of the same individuals and groups when
questioned about permitting us the right to have a choice, a life versus death choice, are
against it. They view making an unapproved treatment available as immoral. But according to
them its "O.K." and justifiable for a physician to administer a poison to end life, but not a drug
or compound that might prolong it or even end the suffering? Of course you could wait until
its approved, 5 to 7 years later, if you have the time. Or you could use their alternative and end
your suffering, even though there might be another choice.
\In fact a LifeChoice you could identify if someone, anyone, had taken the time to provide the
information so you could make an informed decision.
All of the facts surrounding healthcare: its costs, its administration, the distribution of
information and funds, regulations, attitudes, and the importance of choices brought about the
formation of LifeChoice International. But sadly it took HIV and AIDS sufferers around the
world to make many of us aware of the current situation.
I am personally grateful for all of the political activists who have raised the issues, asked the
questions and demanded the right of choice. The many brave and committed acts of so few
may in the end be responsible for changes that will benefit the many. But I am disquieted by
the lives which had to be lost in order to bring these issues out. Not only the lives of AIDS
victims, but the thousands of mothers, fathers, brothers, sisters, wives, husbands, daughters
and sons that have perished to rare disorders for which no one was interested in producing a
treatment even though within the reach of technology. Add to that the millions that died
waiting for a new cancer medication to be approved and you will understand the scope of this
tragedy and my indignation with the healthcare industry's current state.
But even with all this suffering and loss of life what in fact is being done? Admittedly there is a
lot of public relations and political talk. But are the current approaches both medically and
politically appropriate? In the case of HIV and AIDS this is not an inconsequential question.
There are over 40 million lives at risk before the end of this decade. It is predicted that more
than 4 million women will die as a result of HIV by the end of this decade. Will the cure show
up only when enough people are infected and dying to make it cost effective? Are there other
alternatives? Are we being given the right choices? Or even the right to choose?
We often forget how fragile and precious Life is. Our preoccupation and rush through its
everyday burdens and momentary pleasures often leaves barren our conscious appreciation of
it. Each of us has a perception of our own existence and how we relate to the world and those
around us. Yet we often lose this awareness in the chaos.
As cognizant beings we sometimes only appreciate something when we are about to relinquish
it. Whether it's love, youth, money, health, or Life, even our own. Frequently it is then and
only then, that we are mobilized into acknowledging the need of attempting to understand
some of the complexity of our own existence. The suffering caused by the ravages of disease is
one such instance and the very nature of HIV and AIDS has forced us to attempt to become
more aware, better informed and more active.
To some degree we are overwhelmed by the complexity of the mechanism of our own bodies
and minds. It truly seems incomprehensible that so many of us understand so little about what
constitutes our very being. Rather than attempting comprehension we deferred judgment to
the professionals and blindly accepted the administration of their counsel. For some reason
doctors, like accountants, lawyers, and the government are not to be questioned. Our
willingness to accept, without scrutiny, decisions that affect our heath, possibly our very
existence, should not be viewed as a unique trait.
Most of us just accepted the pill. Whatever it might be without asking why. We were lulled
into complacency with a gentle pat on the back and an understanding nod from an
overeducated, uninformed, arrogant glorified mechanic. It was assumed that we were either
too stupid or uneducated to understand our own physiology. To some degree this opinion was
true. Despite the fact the we had to suffer through the experience, pay the penalty or shoulder
the consequences along with the bill. Few of us, if any, exhibited much interest in informing
ourselves.
Historically, as a society we have sought instant gratification from everything, including our
medicines. We permitted the idea of symptomatic relief and "silver bullets" to take hold. As a
result the medical community in the industrialized world became preoccupied with relieving
symptoms or finding seemingly impossible cures. Admittedly they have been successful at
both. But industry developed products that acted upon the disease or its symptoms rather than
our body and its intrinsic ability to fight disease.
Some of you may argue that these products assist the immunocompetent system by bringing
the infection to a controllable state. It is true that in many respects these drugs are near
miraculous in their effect. They subdue an infection quickly, and allow our immune systems to
finish the job. While their effect is usually immediate and the mode of action understandable
they do nothing whatsoever to directly strengthen or prepare the immunocompetent system
against infection. In fact they can make that system lazier than before their introduction.
The alternative, and in my mind preferred, method against disease is to create immunity. This
has been old news for sometime. The idea is to introduce a small amount of inactive bacteria
or virus and stimulate your immune system. Simple. You didn't need a cure because you didn't
get sick. Smallpox, polio and tuberculosis are all examples. Vaccines and immunostimulants
have been developed in order to deal with some of humanities biggest menaces.
Vaccines are immunostimulators and biological, not chemical, in nature, they influence versus
simulate the body's immunocompetent action Factor-R is a vaccine. As a result your body is
better prepared to resist future infection through the production of natural antibodies and who
knows what else before rather than after you need it. These are not cures, they are better. Nice
idea but what happened?
Too expensive to make, difficult to patent and worked to well. Not much money if you can't
control ownership of your product and if people don't get sick. This may sound insensitive but
it's difficult to build a medical industry around people that don't need what you've got to sell.
So if it is an epidemic and people are dying then we develop vaccines and the government will
usually pay for it. But if the disease can be controlled, say by condoms and the numbers are
acceptable, only a few thousand deaths a year, then a cure is proposed rather than a vaccine.
People will and usually do pay a lot to be cured. Death and suffering is a great motivator. But
somehow all of us forgot about the old proverb "an ounce of prevention is worth a pound of
cure". The cases of HIV and AIDS are no different.
AIDS is claimed to be the result of the active virus. The treatment strategy currently employed
is to kill the virus through the use of anti-viral agents like AZT. Frankly, I am not convinced
which is worse, the "cure" or the disease. AZT does not help the HIV infected; to the contrary
- it may cause the immunocompetent system to weaken enough to actually force the onset of
AIDS. Those who are only HIV positive and have no AIDS symptoms could possibly be
helped by a stimulation of their immune system. A vaccination in effect. Only recently has
information surfaced to support this theory. On September 7th, 1993 the Los Angeles Times -
Washington Post News Service reported that scientists believed that "...it seems logical that a
severe jolt to the immune system might set the system back on proper course before the first
opportunistic infections occur...".
Finally, maybe researchers and physicians are waking up and smelling the coffee. Or, as one
scientist so accurately put it, " It's like St. Paul seeing the Light on the road to Damascus..".
LifeChoice came to this conclusion two years ago but nobody listened and we didn't have the
financing to carry the message. Researchers in Bulgaria where developing the required
strategy over 7 years ago but not for HIV and AIDS. Now you know, but what will you do,
for yourself or for others?
The reason so much worthwhile research of the type now required in order to deal with HIV
and AIDS is dismissed is because industry has forced us to accept the maxim "an ounce of
cure is worth a pound of prevention". And it would seem worth a lot more judging by the cost
of AZT and other similar drugs. Our whole pharmaceutical industry is built around this notion.
The regulatory authorities structured laws to administer it. The result: a chemical society.
Antibiotics, chemotherapy, cold medicines, antihistamines and a wealth of other products.

Rather than industry and government concerning itself with preventing the onset of disease we
became concerned with finding cures. A noble and profitable goal. So the majority of us got
hooked on instant gratification rather than long term benefit. But this approach built stronger
bacteria, viruses and chemicals instead of building stronger bodies and immune systems.
Thanks to this scheme there are now more virulent strains materializing.
What folly to think we can overcome rather than understand nature. There is not a day that
goes by without some article appearing in the international press about the reappearance of
some of medicine's old adversaries. And HIV has provided us a shrewd new nemesis and a
rude awaking.
It seems that medical researchers failed to take into consideration the almost miraculous
resilience, diversity and complexity of life on this planet and the human body itself. The ability
to adapt and overcome obstacles is a trait not only exhibited by the human mind but by the
human body. As much as bacteria and viruses can increase their resilience to drugs, the body
can adapt its defense and offence.
This battle of wits between disease and our immune system begins from the day we are
conceived when our bodies start to learn and adapt. At first simple infections, then more
complex and sophisticated ones. No laboratory or pharmaceutical factory in the world has the
diversity and capacity to produce such complex and varied biological and organic substances.
Whenever this capacity has been harnessed, as with vaccines, and enormous amounts of
human suffering has been ended.
But industry and government are still determined as ever to struggle for the "silver bullet".
The laws which were enacted over the years support only those substances which are 90% or
more pure. Anything that could not be seen to directly affect an illness, even though there
might be an improvement of the condition, is carefully scrutinized and usually not approved
for distribution as a medicine.
To date I am not aware of one immunostimulant that has been approved for the United States
or Canada. They exist elsewhere and have proven through years of clinical use their efficacy,
yet because of the broad nature of their effect the FDA, CHBP and the mainstream medical
community have shown little to no interest. Until now.
Vitamins, like immunostimulants, were similarly censured for their medical value. Now it is
admitted that significant long term medical benefits may be derived, no one knows why exactly
why, but the results speak for themselves. The same is true for certain herbal medications and
folk medicine. In fact there is a whole body of science where the results are sometimes
significant, but the "how" unclear. Typically when something cannot be explained it must be
flawed; few of these medicines find their way into therapy.
This created an unregulated subculture of vitamin gurus and natural/holistic medicine

advocates. And opportunists. As always, good science got mixed up with new age theology
and business. While much of what these groups have to say has a foundation in truth, the
problem is that like all things where there's a profit there are profiteers. The result is that it
becomes difficult sometimes to segregate science from science fiction, or just plain fiction. So
where do we draw the line?
The FDA and CHPB are now attempting to do so. While historically these organizations have
been adamant against anything except what it considered pure science, there is presently an
undercurrent of political will to begin investigating substances offered in non-regulated
products which purport medical claims.
It may soon come to pass that many of these complex substances will require extensive clinical
testing. While I believe that many of the FDA and CHPB requirement are overkill, I consider
this move positive for several reasons. For me it’s primarily because now the scientific and
regulatory community is acknowledging the efficacy of previously ridiculed substances. These
studies will put to rest the years of misinformation from both proponents and detractors.
This is an encouraging result. The mysteries of our bodies are being unlocked and unveiled to
us in such a way that we can at least have a better understanding of how disease and treatment
will affect us, immediately and in the long term. Better communication and concerned
professions are finally giving each of us the opportunity to access more information so we can
make better life choices.
But as more of the miraculous nature of our body begins to unfold before each of us we will
gain a deeper understanding and appreciation of its/our own potential. This comprehension
will help us reach conclusions and possibly seek out preferred options. Better understanding
will inevitably help us better appreciate the advice of competent concerned physicians.
It pleases me to say that this may be heralding a new era for medical care. That fact that I can
speak to you now represents a major breakthrough. Never before have each of us been able to
influence so much the selection and course of the treatment we will receive. We can now ask
more questions and make better informed choices. In fact medical professionals are now
encouraging such curiosity.
I encourage you to be informed. It might seem like a bit of a struggle at first but life is in itself
a struggle. But most importantly Life is durable and not easily given up. In order to
understand how best to be helped you must make some effort at helping yourself. Taking the
time to read this report and many others like it is an important step.
Prior to your commencing the assessment of the medical information on the following pages
there are a number of things which are important for you to note. While we have presented
this report in its original text, some proprietary material has been excluded. Visual aids and
foot notes have been added in order to make those parts of the report relating to Factor - R's
potential benefit in treating HIV or AIDS clearer.
The introduction I have provided contains information about the Company and its activities.
This is important in order that you can understand how we located the technology which
originated Factor - R and how it's benefit as an HIV and AIDS treatment was determined. The
introduction is written primarily for readers with little to no medical knowledge but who are
interested in understanding the principle behind Factor - R and how it relates to HIV and
AIDS.
A glossary is provided to assist your understanding of the terms utilized in the technical report.
In order to further substantiate the credibility of the information rendered here I have included
brief biographies of the principal developers of Factor - R.
Being non-medically trained, I have attempted to write the following in an understandable

form. For those of you who are medical professionals please forgive the simplicity of my
explanation.
LifeChoice is keenly aware that there are many as yet unanswered questions concerning the
whole issue of not only how to treat HIV and AIDS but what in fact causes AIDS itself. Some
of these issues are controversial at best. The Company has taken no opinion in what may be
right or wrong, scientifically or morally, the inescapable truth is that people are suffering and
dying, and Factor - R is the least toxic and possibly the best first step in the prophylactic
treatment of HIV, AIDS and SID.
The Company
Over the last few years LifeChoice, the "Company", has been primarily involved in examining
new processes and drugs which might prove effective in the treatment of a variety of cancers.
The LifeChoice approach has been to seek complex compounds which produce a biological
reaction either through the production of metabolites or through the stimulation of the
immunocompetent system.
The great expense associated with the identifying of such compounds and the required testing
should never be underestimated. As a small research company LifeChoice has struggled to
maintain its financial and philosophical independence, a difficult thing to do in the
pharmaceutical industry and the current economic climate. In an effort to obtain the highest
yield for each investment dollar LifeChoice in 1991 began a limited research and development
program with several institutes located in Sofia, Bulgaria.
The Company was pleasantly surprised to find that the skills of researchers were well
developed and more innovative than expected. While the pharmaceutical manufacturing
capacity within the region is sizable it has historically focused its attention towards mass
production of generic products. These state owned enterprises have shown little innovation or
interest in new technology. But the various academic organizations, which are in many
instances pioneering new methods, had also developed limited production capacity in order to
introduce their innovations. It is this production capacity that is currently responsible for
producing Factor - R in association with LifeChoice.
The Company was impressed with the researchers, their originality, willingness and
competence. Even though the facilities of these various institutes are in many ways limited
technologically, the accomplishments have proven to be of a superior nature. As a result much
of the efforts of LifeChoice turned to evaluating technology already in use. As part of this
evaluation the work of Prof. Petrunov, MD, DSc, Prof. Nenkov, MD, DSc, Prof. Shekerdjiski,
PhD., and Prof. Todorov, MD. DSc, on immunomodulation through immunostimulation was
observed.
At first the benefits of their research seemed primarily an alternative to antibiotics in the
treatment of chronic respiratory infections. Closer examination of the action of the substance,
later to become known as Factor - R, demonstrated significant stimulation of the
immunocompetent system of the patient. The action while being non-specific in nature
provided a demonstratable improvement in overall immunoresponse to infection.
This immunostimulating effect led LifeChoice to the conclusion, based on recent studies of
HIV, AIDS and SID patients, that the stimulating effect of Factor - R would be of significant
benefit, both in the treatment and prophylaxis of the disease or condition. After you complete
your examination of this report I am hopeful that you will understand the significance of this
new development and arrive at the same conclusions as I did.
Immunomodulation
Currently all treatments being offered to those of you who are HIV positive or in the
alternative are already suffering from AIDS can be categorized as having an
immunomodulating effect. Most of these substances affect in someway your immune system.
However, the impact of some of these compounds can be quite morbid or self-defeating. In the
long term they can often prove more destructive to your immune system than the disease itself.
This is the very reason why physicians will, after a period, discontinue their use.
Immunostimulation vs Immunosuppression
Immunosuppression - Chemotherapy
The most devastating impact on the immune system is that of chemotherapy. Different
substances will typically affect different tissue. But regardless of the tissue to be effected the
objective is still the same - to kill the offensive cells.
Chemotherapy typically is not very discerning and as a consequence healthy tissue is often
lost. The objective of the treatment is to kill the cancerous tissue before the chemotherapy kills
you. If successful you should recover. AZT, ddI and ddC are all chemotherapeutic agents with
high toxicity and historically low therapeutic indices. Yet they continue to be administered to
HIV\AIDS patients in order to kill the virus by killing the infected T-cells. To date no
HIV/AIDS sufferer has recovered after this treatment.
The worst side effect of such treatment is immunosuppression. Your immunocompetent system
becomes so battered by the chemotherapeutic treatment that it is in many cases incapable of
mounting a significant offense against the simplest of afflictions. If you are subjected to such
treatment you will not only have to contend with the original affliction but also potential
secondary infections. This is true even if your immune system is functioning properly, never
mind that it may have already been significantly damaged.
It is most likely that you will inevitably require, as a result of the immunosuppressive nature of
chemotherapy, antibiotic treatment. Cancer patients will recover their immunocompetence
with the cessation of the chemotherapy. The foregoing recovery is premised on the assumption
that your immune system has not been so severely damaged as to reduce your body's ability to
produce the necessary cells. If the damage is severe enough from certain forms of
chemotherapy then often it means that a bone marrow transplant may be required.
Yet your bone marrow is only partially responsible for the production of immunocompetent
cells. It can be replaced at great cost, pain and risk to both the donor and recipient.
AIDS sufferers are currently being subjected to severely toxic agents for prolonged periods of
time for the singular purpose of attacking the HIV virus by interference with its reproductive
cycle. This treatment modality carries along with it the added consequence of the disruption of
your immunocompetent capacity. The underlying concept being that the damage to the
immune system resulting from the chemotherapy will be less than the resultant damage if the
virus is allowed to reproduce uncontrolled. There is a significant school of thought that is
tending to disagree with this hypothesis.
The problem with the foregoing obsession with chemotherapy is that it not only disrupts the
reproductive cycle of the virus but also that of the cells responsible for maintaining your
immune system. This represents three active events: the virus killing the cells; the
chemotherapy killing the cells and the virus; and the chemotherapy killing the cells responsible
for the production of new cells, these cells are evidently not affected by the virus.
In order to compensate for this immunosuppressive downward spiral you are then subjected to
ever more powerful antibiotics or immunoglobulins. Eventually the treatment, because of its
side effects, must be discontinued and you are then overwhelmed by ever more difficult
infections which are progressively more resistant to various antibiotics. The conclusion is self-
evident.
The foregoing scenario seems reminiscent of something you may experience as an HIV/AIDS
sufferer. The principal similarity is that medications designed for cancer are being used against
the virus. But HIV is not cancer. Certain researchers even claim that this type of treatment
may in fact be compounding the immunological problems of an AIDS sufferer.
While chemotherapy and antibiotic treatment will continue to have their place in dealing with
both minor and serious afflictions, their side effects are undesirable and damaging. Neither
provide any direct benefit to your long term immunocompetence, they do not make you more
resistant to infection, in fact the contrary is true, they will make you more susceptible.
Admittedly these compounds are a preferred alternative in most instances to no treatment at

all, but only as a last resort. I remember as a child my grandfather, who was a physician,
avoided any kind of antibiotic treatment if at all possible. His theory was that my body would
become too lazy in fighting even the simplest of infections. He may have been more right than
even he realized. Is it possible that several decades of uninhibited chemical use could have
weakened a whole generation?
Immunostimulation - Factor - R
LifeChoice has for sometime been involved in attempting to identify compounds that would
work with, rather than assault, your immunocompetent system. The Company's original
interest was in developing products that would stimulate the body's production of complex
elements that had the ability to assist the immune system's natural reaction to these destructive
cells. It has been know for sometime that lymphocytes are in fact capable of identifying and
discerning cancerous tissue from healthy tissue. However, the accelerated rate of reproduction
of cancer cells, often six times the rate of normal cells, typically overwhelms the natural
immune response.
If a method could be identified that rapidly stimulated these "killer" cells then it would be
theoretically feasible to stimulate the body into reacting to the cancer. This would be a
preferred, more selective, natural alternative to chemotherapy. It had also been hypothesized
that early stimulation of these "killer" cells could lead to immunity that could potentially
control the early appearance of cancerous tissue.
Based on the facts and results it should therefore be possible to achieve two significant
objectives with Factor - R. If you are HIV positive early treatment with Factor - R will
provide a major boost to your immunocompetence, this will improve your chances of resisting
both the virus, its effect (AIDS) and any opportunistic secondary infections (SID).
If you are already suffering from AIDS and undergoing treatment with AZT or other
chemotherapeutic drugs Factor - R can offset the negative side effects. Significant evidence
exists that Factor - R can increase the production of important healthy cells during these
morbid treatments. This could prolong the treatment period and promote recovery.
Factor-R's effect can provide relief from AIDS-related disorders of the immune system, the
basic one being secondary immune deficiency (SID). SID is a result of infectious diseases
caused by bacteria and respiratory viruses. SID is a temporary suppression of the cellular
immunity to bacterial antigens. This temporary immune suppression (3-4 weeks) increases the
susceptibility to infections and developing bronchial complications. SID can also damage
selectively T and B lymphocytes which will weaken the body's immune response to a wide
variety of antigens, microorganisms or tumours of different origin. SID is manifested in
chronic contagious diseases and continuous infections of the immune system's cells.
1. Introduction
1.1. Setting up of the problem
The first infection one contracts after birth very often affects the respiratory tract, and it is not
unusual for this disorder to also become one's last ailment before death. Between these two
extremes, the airway infections, whether they are angina, otitis, bronchitis or a simple cold,
constitute a frequent nuisance in one's lifetime.
In the United States, it is estimated that every adult suffers from two to four respiratory
infections a year. A critical statistics for HIV and AIDS sufferers.
The treatments of those infections necessitate the administration of antimicrobial drugs

amounting to nearly half their prescription in ambulatory care and to one-third in hospital care.
These statistics are even more elevated in the cases of AIDS patients.
Respiratory infections are one of the ten leading causes of death in the United States and rank
first among the infections leading to the death of the HIV and AIDS sufferers.
The respiratory and ear, nose and throat ailments are often aggravated, if not triggered, by the
deterioration of ambient air quality: acid vapours, sulphur compounds and hydrocarbons in the
urban area and the confined and smoky atmosphere of many workplaces and homes.
Among the adult population, the environmental deterioration has caused not only a spectacular
increase in febrile episodes but also the appearance of chronic diseases leading to a gradual
reduction in the vital capacities. Under these conditions, could HIV and AIDS be a "disease of
civilization"?
Recently researchers have expended a great deal of effort to create preparations influencing
the functions of the immunocompetent system. These efforts established the following
directions in medicine connected with the stimulation of the body's defensive mechanisms:
Passive immunotherapy
Passive immunotherapy aims at replacing the functions of the body's own immune system with
ready immune products (specific antiserums, gammaglobulins and immunocompetent cells).
Immunoprophylaxis
Immunoprophylaxis refers to effective control and removal of epidemic processes through

stimulation of the immunocompetent system with proper antigens creating effective immunity.
Immunomodulation
Immunomodulation can be either the restoration or the suppression of the functions of the
immunocompetent system. The preparation of synthetic vaccines capable of intervention in the
genetic regulation of the power of the immune response is also regarded as part of the
immunomodulation.
Immune target
It is important to be noted that a new direction in immunotherapy, the so-called "immune
target" has been established. This implies the use of preparations which will attack and destroy
the cancer or mutated cells in different tissues and organs.
The cells of the immunocompetent system have receptors for medications and hormones
which participate in the biotransformation of medicines. Many of the preparations may display
properties of allergens and others can suppress or stimulate the immune response. These
immunopharmacological preparations can change the immune mechanisms in cases of diseases
due to immune deficiency, acute and chronic infections or neoplasms.
Long-term experience in the application of classic bacterial and viral vaccines has undoubtedly
led to the limitation of some infectious diseases. However, for other contagious diseases
effective and harmless vaccines have not been found yet. That is the reason why new methods
in the creation of efficient immunopreparations should be looked for.
Antibiotic Treatment
Since their advent, prior to World War II with the industrial development of penicillin,
antibiotics have long been considered ideal therapeutic drugs for the eradication of the
pathogenic bacterial strains. But this was to grossly misjudge the numerous means which those
germs have at their disposal to circumvent the action of antibiotics. Through genetic
mutations, some of those bacterial strains have become insensitive to antibiotics by
developing, for instance, the ability to secrete an enzyme such as penicillinase that inactivates
the penicillin supposed to destroy them.
The current level of bacterial resistance is extremely worrisome in view of the growing number
of strains resistant to several, if not all, antibiotics, as is the case of bacteroides that causes
certain forms of septicemia. This evolution is all the more alarming because resistance to one
or several antibiotics is transmissible from resistant bacteria to sensitive bacteria within the
same species as well as among different species. Antibiotics are also hardly effective against
fungal and viral infections.
It has been proved that if antibiotics are applied excessively their activity on various strains of
bacteria causing infections is weakened. For this reason specialists do not recommend the
administration of antibiotics if the disease is not serious enough, e.g. cold, influenza, etc. In
such cases a timely and proper prophylaxis with the right immunostimulant will lead to
successful treatment.
Vaccination - an Absolute Weapon
In the 11th century B.C., Chinese physicians had already noticed that inhaling small-pox crusts
prevented the later development of this disease. It was only in the late 18th century, however
that modern vaccinotherapy was introduced by Edward Jenner who noticed that inoculating
man with a virus related to the cowpox virus, or vaccinia, provided him with effective
protection against small-pox.
Following the first inoculation of an immunogen foreign to the body, it is first detected in the
lymphoid organs (spleen, bone marrow or lymph nodes) rich in macrophages and other
phagocytes.
Thus, after capturing and processing the antigen, the macrophages present it to the
lymphocytes which undergo differentiation into T-lymphocytes (T-helpers and T-suppressors)
and B-lymphocytes (plasmocytes and memory B cells) and proliferate, which leads to the
biosynthesis by the B-lymphocytes of specific antibodies or immunoglobulins - key elements of
humoral immunity. If it is the vaccinee's first exposure to the antigen, the response is called
primary, and few or no antibodies at all are detected in the serum immediately after the
introduction of the antigen. It is in this induction phase that the antigen is recognized as a
foreign by the T-lymphocytes and that this information is transmitted to the B-lymphocytes so
that these can synthesize specific antibodies.
The first specific antibodies synthesized by the body are IgM, followed by IgG and IgA.
When the host is exposed for the second time to the same antigen, be it after a few weeks or a
few years, a secondary response occurs very rapidly without going through any induction or
latency phase. This response is characterized by accelerated proliferation of immunocompetent
cells (B- and T- lymphocytes) and increased synthesis of antibodies, mostly IgG, thanks to the
cells with immunological memory that have appeared during the primary response and that are
thus capable of immediately recognizing the antigen. It is on this mode of heightened
secondary response that are based the recall principle of vaccination or booster and the build
up of both specific and lasting protection against the administered antigen.
Original Antigenic Sin
However, specific protection provided by vaccination is only relative, especially in the case of
antiviral vaccines. This ability to recall or memorize appears following stimulation not only by
the same viral antigen but by related antigens as well. Thus, the influenza virus causes
recurrent epidemics - despite large-scale vaccination campaigns as a result of an antigenic
change in certain strains.
In addition to the benefits of vaccination in the fight against infectious diseases, it is necessary
to consider its negative effects associated with the very process of active immunization.
Moreover, inactivated living vaccines may develop a real pathogenic power in the subject
whose immunological reactions are diminished as in the case of AIDS sufferers. Certain
viruses of the vaccinal strain may also mutate and recover their virulence. Current thinking
suggests that HIV mutates regularly. Like many other viruses HIV develops different means to
escape the defense mechanisms of the body. It hides inside healthy cells and is able to destroy
T-lymphocytes thus eliminating the possible defenses of the body. This potential pathogenic
power precludes the development of any vaccine based on the AIDS virus either now or in the
near future.
An Arsenal for Defence
Current hypothesis connects HIV to acquired immune deficiency syndrome. This connection is
based on the reproductive process of the virus. As a result, the viral host becomes susceptible
to new infections that may be bacterial or viral in nature. Thus setting up specific defence
against a single germ strain through vaccination and relying on the bactericidal effects of
antibiotics may be inadequate to bring this type of disease under control. Against infection, the
body, and the respiratory tract in particular, has, in fact, a whole array of natural and
interdependent defences that are localized or generalized as well as specific or non-specific.
Hence the idea of trying to reinforce this protective potential of the body instead of acting
primarily on the symptomatic manifestations of opportunistic infections as in the case of AIDS.
As well we should not confine ourselves to activating specific immunity only, as in the case of
traditional vaccines, but set up a mechanism by which to establish a broad-spectrum non-
specific immunity.
Immunomodulation
These different constituent mechanisms, mostly non-specific, play as important a role as that
of the acquired specific mechanisms, described above in connection with vaccination, in the
process of modulation or regulation, whether they are of a cellular immune nature such as the
T-helper and T-suppressor lymphocytes, or of a humoral nature such as the stimulating and
inhibiting lymphokines, or of a hormonal and neurological nature such a thymosin of the
thymus and norepinephrine. This natural immunomodulation helps not only to determine the
type, intensity and duration of the immune response to the foreign antigen but also to prevent
autoimmune reactions and their serious clinical consequence.
Immunoregulation is not, however, the exclusive attribute of these endogenous parameters of

the body. Exogenous substances may also play an important immunological role. These
substances must not, however, be of high antigenicity so as not to cause immune complex
diseases - characterized by accumulation of antigen-antibody complexes instead of their
elimination - or hypersensitization in case of repeated administration. These
immunomodulating substances include traditional adjuvants such as Freund's adjuvant and
various bacterial extracts or lysates whose effects on humoral and cellular immunity are
increasingly better documented. The latter substances offer the additional advantages of being
orally administrable instead of injected.
The idea of oral immunization or immunomodulation is based on the research work done at
the Pasteur Institute by Alexandre Besredska, a Russian pathologist, and on his theory of local
immune system at the mucosal level which was subsequently demonstrated by John
Bienenstock, Thomas Tomaci and coworkers at McMaster University, Hamilton (Canada) and
Mayo Clinic, Rochester (USA). They identified along the mucosa of the small intestine a large
number of lymphatic follicles and large specialized lymphoid organs - Peyer's patches - forming
the GALT (gut - associated lymphoid tissue).
The hypothesis of a common mucosal defence system set forth in 1971 by Susan Craig and
John Cebra at John Hopkins University, constitutes a major advance in the knowledge of
immunomodulation in relation with mucosal immunity. Other mucosas of the body possess, in
fact, a more or less large network of lymphoid tissues whose morphological structure is very
similar to that of Peyer's patches. Such is especially the case of the BALT (bronchus-
associated lymphoid tissue) where they proliferate and differentiate into IgA-producing cells
with memory and thus capable of synthesizing the antibodies very rapidly in case of need. This
cardinal fact introduces a major new concept into the treatment of bacterial or viral infections.
Thanks to this mucosal solidarity, one can, in fact conceive that any immunogen brought into
contact with a given lymphoid tissue causes the release of IgA antibodies at the very point
where they are needed.
The Future of Immunomodulation
The oral administration of freeze-dried bacterial extract and the whole killed bacterial body
with all its components, derived from selected pathogenic strains, seems therefore to induce,
starting from the lymphoid organs of the intestine wall, a coherent large-scale pharmacological
action on all the mucosal sites of the body, thus ensuring functional modulation of the entire
immune system. By inducing antibodies, especially secretory ones,this product associates
certain properties of vaccines with the properties of adjuvants by modulating cell-mediated
immunity such as is reflected in the activation of macrophages and other killer cells.
Therapeutic application of immunomodulation will lead to the discovery of the involvement of

immune components in an increasing number of diseases including AIDS, herpes, malaria.
1.2. Presentation of Factor-R
The oral immunostimulant Factor-R was created by a team of Bulgarian researchers at the
National Centre of Infectious and Parasitic Diseases and the Faculty of Pharmacy, Department
of Industrial Pharmacy, Sofia, Bulgaria.
Factor-R is a polybacterial immunostimulant intended for oral immunotherapy and

immunoprophylaxis of non-specific bacterial and viral infections. Besides freeze-dried lysate it
contains dead bacterial bodies of microbial species principally causing the occurrence of non-
specific respiratory diseases.
It has a proved stimulating effect on the cells of the immunocompetent system of the
intestines, the mesenteron and to a great extent on the lymphoid formations peribronchially
situated in the lungs. It reinforces the body's own resistance to non-specific infections through
stimulation of humoral and cellular factors of the immunocompetent system.
In the case of Factor-R the whole bacterial cell (lysate and bacterial body) is made use of, thus
a more complex and potent stimulation of the defensive mechanisms of the human body is
achieved: phagocytosis, secretory immunoglobulin (IgA), immunocompetent cells,
complement, properdin, etc.
As well a double standardization is achieved: with respect to the number of bacterial bodies
per dose and to the amount of lyophilisates per tablet.
The body's immune system, stimulated by Factor-R, is able to control the onset of AIDS and
related secondary infections, even those which are resistant to antibiotic treatment. By
modulating the immune system, Factor-R provides what LifeChoice believes to be currently
the best possible defence against "active" AIDS.
HOW FACTOR-R WORKS AS AN ANTI-AIDS TREATMENT
Factor-R enters the body via the digestive tract and simulates an invasion of morbid
microorganisms. This simulation prompts the human immunocompetent system to immediately
respond by producing the corresponding antibodies to fight the intruders.
In this way Factor-R harnesses the human immune system and boosts the body's natural latent
ability to cope with AIDS and the related infections. The boost which Factor-R gives to the
immune system provides a canny mechanism of controlling further, more dangerous infections
and may provide a source to cope with the virus itself.
Currently developed treatments attempting to attack the HIV virus directly on a specific basis
have shown to be limited in their success. Factor-R puts into work the body's own immune
system as a safeguard against the specific mutations that may develop in each individual.
Respiratory infections are the most common secondary infections that HIV bearers suffer.
Factor-R has an established therapeutic effect in patients with recurrent and chronic infections
of the respiratory pathways, nose and throat included. The following is a partial list:
a. acute, chronic and recurrent bronchitis and

tracheobronchitis;
b. acute and chronic tonsillitis, pharyngitis, laryngitis;
c. acute and chronic rhinitis, sinusitis, otitis;
d. recurrent bronchopneumonia;
e. infectious bronchial asthma.
Individuals with chronically suppressed immune systems, such as those with advanced HIV
disease, have historically developed certain cancers more frequently than the general
population. Unlike some current anti-AIDS treatments, Factor-R has shown very optimistic
results with respect to anti-tumour activity. Some of the clinical and experimental evidence
showing that Factor-R may increase non-specific defense mechanisms in the lungs, the most
frequently targeted organ for haematogenous metastases can be found further in this
publication.
Factor-R is offered as stable tablets. It is easily ingested and, if necessary, can be dissolved in
milk, tea or water. It is important to be noted that Factor-R is particularly suitable for patients
with hypersensitivity to antibiotics and in cases of infections caused by antibiotics-resistant
bacteria.
Factor-R acts in synergy
It can be used in combination with any other treatment, including treatment of AIDS and
related secondary infections without any risk of side effects caused by the combination of the
treatments. In fact, Factor-R can neutralize the negative effects of some chemotherapeutic
agents which can be seen from the information provided further in this report. Factor-R also
allows for repeated dose administration without risk of dependence and has demonstrated
excellent tolerability and absolutely no contraindications.
2. Evidence of Bioavailability and Pharmacokinetics
of the Active Component
2.1. Establishing the Immunostimulating Activity of Factor-R
2.1.1. Action on Antibody Formation
The immunostimulating activity of Factor-R was thoroughly studied. The following tables
represent several cases of studied immune response in mice resulting from different schedules
of administration of Factor-R. Some important conclusions about the stimulating and
preventing efficacy of Factor-R are set out based on the described studies.
Table 1 represents the results of the immune response to sheep erythrocytes in mice treated
with Factor-R.
Table 1
Hemoagglutination of antibodies titre against sheep erythrocytes
in mice treated with Factor-R.
______________________________________________________________
Test groups of animals Antibody titre after administration of 8 white mice each
of the antigen (sheep erythrocytes)
treated with: -----------------------------------
Primary antibody Secondary
response antibody
response
-----------------------------------
7th day14th day 7th day
______________________________________________________________Factor-R orally
7 days
before and 7 days after Ag 1:512 1:1024 1:2048
______________________________________________________________Factor-R orally
7 days
after administration of Ag 1:256 1:512 1:2048
______________________________________________________________Factor-R s.c. 7
days
______________________________________________________________
Factor-R s.c. 7 days
______________________________________________________________Control group -
injected
with Ag only 1:32 1:128 1:256
______________________________________________________________
Ag - antigen - each mouse was injected i.v. with 0.2 ml of 50% suspension of sheep
erythrocytes.
On the 28th day after the first administration the antigen was injected again in order to follow
up the secondary antibody response. Factor-R was administered in a daily dose of 2 mg/0.5 ml
saline orally and s.c.
The results of the immune response to human serum albumin in mice are displayed in Table 2.
Table 2
Hemoagglutination of Antibodies Titre Against Human Serum Albumin in mice treated with
Factor-R
-----------------------------------------------------------------Test groups of animals
Antibody titre after administration of 8 white mice each of the antigen
human serum albumin
treated with: -----------------------------------
response antibody
response
-----------------------------------
________________________________________________________________
Factor-R orally 7 days
______________________________________________________________Factor-R orally
7 days
______________________________________________________________Factor-R s.c. 7
days
______________________________________________________________Factor-R s.c.7
days
______________________________________________________________Control group -
injected
with Ag only 1:8 1:16 1:64
______________________________________________________________
Ag - antigen - each mouse was injected i.v. with 0.2 ml human serum albumin. On the 28th
day after the first administration the antigen was injected again in order to follow up the
secondary antibody's response. Factor-R was administered in a daily dose of 2 mg/0.5 ml
saline orally and s.c. The antibody titre was determined by passive hemoagglutination with
sheep erythrocytes treated with tannin.
The above results show that regardless of the schedule of application and the way of
administration - orally or subcutaneously Factor-R evokes statistically significant higher
antibody titre against the antigen used than that of the control group. This indicates that
Factor-R has an obvious adjuvant action and stimulates the immunocompetent cells which
synthesize the antibodies.
2.1.2. Determination of the spleen index in immunized mice
The stimulating activity of Factor-R was also proved by the higher spleen index in mice fed
with the drug orally or injected subcutaneously in the course of 7 days compared with a
control group (see Table 3).
Table 3
......................Spleen index of white mice immunized with human serum albumin
and treated with Factor-R
_____________________________________________________________
Test group of 8 white mice each Spleen Index
treated with:
______________________________________________________________Factor-R orally
7 days before and
7 days after administration of Ag 1.660 mg
-----------------------------------------------------------------Factor-R orally 7 days after
administration of Ag 1.670 mg
______________________________________________________________Factor-R s.c. 7
days before and
7 days after administration of Ag 1.790 mg
______________________________________________________________Factor-R s.c. 7
days after
administration of Ag 1.400 mg
______________________________________________________________Control group
injected with Ag only 1.030 mg
-----------------------------------------------------------------
Ag - antigen - each mouse was injected i.v. with 0.2 ml human serum albumin. The Spleen
Index is the average mass of the spleens of all mice in the group (the total spleen mass of the 8
mice is divided by 8). The Spleen Index was determined 7 days after the second injection of
the Ag.
This shows that the intake of Factor-R leads to the activation and the involvement of the
spleen - the basic organ of the immune system in the immune defense of the organism.
2.1.3. Protective action on infections in white mice
In order to prove the stimulating action of Factor-R on the non-specific mechanisms which
determine the natural resistance of the body to infections a series of experiments were carried
out. Infection of white mice with strain of Staphylococcus aureus Sg 511, coagulase positive,
which is pathogenic for mice, was used as a model . Groups of 10 white mice each were
injected intraperitoneally with Factor-R in a dose of 5 mg/0.5 ml physiological saline solution
2 and 18 hours before being infected intraperitoneally with a 25 million suspension/0.5 ml of
an 18 hour culture of Staphylococcus aureus Sg 511.
Other groups of white mice (also 10 mice in a group) were fed in the course of 10 days with
Factor-R also in a dose of 5 mg/0.5 ml physiological saline solution daily. On the 11th day the
mice were infected in the same way as the first group. All groups of mice were followed up for
12 days after being infected. The dead mice were counted every day. A Salmonella typhi Ty 2
glatt endotoxin solution according to Westphal method (phenol-water) was used as a control.
It was injected to groups of 10 white mice in a dose of 15 microgram/0.5 ml physiological
saline solution 2 and 18 hours respectively before being infected with Staphylococcus
aureus.The results of the experiments are presented in Tables 4 and 5.
Table 4
Results of the protective efficacy of Factor-R administered subcutaneously to white mice
infected with Staphylococcus
______________________________________________________________Test group of
mice treated Number of dead mice on: (day)
with: ----------------------------------------------------------
1 2 3 4 5 6 7 8 9 10 11 12
Factor-R
before
infection:
18 hrs
2 1 1 2 2 1 1 - - - - -
2 hrs
2 2 1 2 3 - - - - - - -
______________________________________________________________Endotoxin
before
infection:
18 hrs
1 1 2 2 - - 1 1 1 1 - -
2 hrs
2 1 2 1 2 1 1 - - - - -
______________________________________________________________Saline
before
infection:
18 hrs
5 3 1 1 - - - - - - - -
2hrs
6 2 1 1 - - - - - - - -
______________________________________________________________
Each test group consisted of 10 white mice weighing between 15 and 18 grams.
Table 5
Results of the Protective Efficacy of Factor-R Administered Orally to White Mice Infected
with Staphylococcus
______________________________________________________________Test group of
mice treated Number of dead mice on: (day)
with: ----------------------------------------------------------
1 2 3 4 5 6 7 8 9 10 11 12
______________________________________________________________Factor-R
10 days
before
infection:
2 2 1 1 2 1 1 - - - - -
______________________________________________________________Saline
10 days
before
infection:
6 3 1 - - - - - - - - -
______________________________________________________________
Each test group consisted of 10 white mice weighing between 15 and 18 grams.
It is evident that when applied orally and subcutaneously

Factor-R has a clearly expressed favourable effect on the non-specific immune mechanisms
which is manifested by the longer survival of the mice treated with Factor-R than that of the
untreated ones. On the 4th day of the experiment when all control mice had already died, 40%
of the mice treated with Factor-R were still alive when the drug was injected 18 hours before
the infection and 30% were alive when the drug was injected 2 hours before the infection. The
oral test showed that all control mice died until the 3rd day while 50% of the mice treated with
Factor-R were still alive. This result is quite logical since Factor-R contains the cellular shells
of the bacteria and thus can exert a stronger endotoxic influence on the organism which is
manifested in this case by the stimulation of the factors of the non-specific resistance to
bacterial infections.
The protective activity of Factor-R administered intragastrically to mice weighing 22-26 grams
against intraperitoneal infection with the K.pneumoniae "B" strain possessing high virulence
was also investigated. The mice were immunized during 9 days - each day with 10 mg Factor-
R and were infected on the 5th day after the last dose. After the infection with 5 live bacterial
cells, 24% of the immunized animals survived the infection.
The K.pneumoniae "B" strain used possesses high virulence and in the first case destroys the
immune defense built as a result of the immunization with Factor-R.
Good results were obtained after a double intragastrical immunization with 50 mg and 20 mg
doses of Factor-R with an interval of 9 days between the injections.
44% of the animals infected with 4 K.pneumoniae "B" cells were still alive during the 7 days
(see Table 6).
Table 6
Protective effect of Factor-R applied intragastrically on intraperitoneal infection with
K.pneumoniae "B"
______________________________________________________________Group
Number Infection dose Dead mice Viability
No. of mice(live bacterial out of the in %
cells) total number
on the 7th
day
______________________________________________________________1.
75614
2. 6 10 5 17
3. 8 5 5 38
4. 7 10 6 14
5. 9 5 8 11
6. 9 5 5 44
______________________________________________________________
No. 1, 2, 5 are control groups of mice not treated with Factor-R.

No. 3, 4 are groups of mice immunized intragastrically with 10 mg of Factor-R.
No. 6 is a group of mice immunized intragastrically with 50 mg and 20 mg of Factor-R with
time interval of 9 days.
2.2. Immunomorphologic studies of organs of mice treated subcutaneously or orally with
Factor-R
Microscope and electron microscope studies were carried out on paraffin and ultrathin
sections of immunilogically competent organs of 4 groups of mice treated subcutaneously and
orally with Factor-R.
In the regional inguinal lymph nodes of mice treated subcutaneously with Factor-R a
manifested hyperplasia and highly dilated marginal and intermediary sinuses filled with cell
elements of the plasmocyte series were found out microscopically (fig. 1).
Fig. 1. Inguinal lymph node of a mouse treated five times subcutaneously with 1/10
human dose (5 mg) of Factor"R"; on the 5th day after the last treatment.
Strong extended intermediary sinus filled with the cells from the plasmatic line.
Staining - H.E.
Magnification - 140 X.
For a control mouse - see fig. 16.
The mesenterial lymph nodes were activated with highly expressed hyperplasia of the lymph
follicles with dilated marginal and intermediary sinuses filled with cells of the plasmocyte series
(fig. 2).
Fig. 2. Mesenterial lymph node of a mouse treated five times subcutaneously with
1/10 human dose (5 mg) of Factor-R; on the 5th day after the last treatment.
Strong extended intermediary sinus filled with the cells from the plasmatic line.
Staining - H.E.
In the spleen a hyperplasia of the white pulp and a considerable number of blast and plasma
cells in the highly dilated marginal sinuses were found (fig. 3).
Fig. 3. Spleen of a mouse treated five times subcutaneously with 1/10 human dose (5
mg) of Factor-R; on the 5th day after the last treatment. Strong extended
marginal sinus filled with blast and plasma cells.
Staining - H.E.
The small intestines were with preserved intestinal villi. Manifested mononuclear
infiltration of the subepithelial tissue and mild edema of lamina propria mucosae with a
considerable number of plasmoblasts - precursors of the cells which synthesize specific
immunoglobulins were found (fig.4).
Fig. 4. Small intestine of a mouse treated five times subcutaneously with 1/10 dose (5
mg) of Factor-R; on the 5th day after the last treatment. The brush border is
well preserved.
Magnification - 30.000 X.
Lymphoid tissue hyperplasia and enlargement of the T-dependent zone were established in the
Peyer's patches. A considerable number of cells of the plasmocyte series were found too
( fig.5).
Fig. 5. Peyer's patch of a mouse treated five times subcutaneously with 1/10 dose (5
mg) of Factor-R;on the 7th day after the last treatment. Numerous plasma cells
in the strong extended sinus.
Staining - H.E.
Thickened alveolar septa and peribronchial mononuclear infiltrates were established in the
lungs (fig.6).
Fig. 6. Lung of a mouse treated five times subcutaneously with 1/10 dose (5 mg) of
Factor-R; on the 7th day after the last treatment. Peribronchial mononuclear
infiltration.
Staining - H.E.
Well-formed lymphoid nodules with blast cells were also found. These findings showed that
the lungs were actively involved in the immunogenesis as a secondary organ (fig.7).
Fig. 7. Lung of a mouse treated five times subcutaneously with 1/10 dose (5 mg) of
Factor-R; on the 7th day after the last treatment. Newly formed lymph nodes in
the parenchyma of the lung.
Staining - H.E.
The electron microscope examinations showed that the plasma cells localized in the dilated
sinuses of the regional lymph nodes had a highly developed endoplasmic reticulum and that
they were in an active functional state (fig.7). The same types of plasma cells were found in
the mesenterial lymph nodes (fig.8) and in the spleen (fig.9).
Fig. 8. Inguinal lymph node of a mouse treated five times subcutaneously with 1/10
dose (5 mg) of Factor-R; on the 7th day after the treatment. Plasma cells with a
very well developed endoplasmic reticulum.
Fig. 9. Mesenterial lymph node of a mouse five times treated subcutaneously with 1/10
dose (5 mg) of Factor-R; on the 7th day after the last treatment. Functionally
active plasma cells with a very well developed endoplasmic reticulum.
Mature plasma cells in an active functional state with highly dilated cisterns filled with
secretory immunoglobulins were also found in the lamina propria mucosae of the small
intestines and in the Peyer's patches (fig. 10).
Fig. 10. Spleen of a mouse five times treated subcutaneously with 1/10 dose (5 mg); on
the 7th day after the last treatment. Plasma cells with a very well developed
endoplasmic reticulum.
In the small intestines the villi were well preserved (fig. 11). The electron microscope
examinations proved that the so- called "brush border" was fully preserved. No shortening of
the villi and no structural changes in the epithelial cells were found. A great number of
subepithelially located lymphocytes were established.
Fig. 11. Peyer's patch of a mouse five times treated subcutaneously with 1/10 dose (5
mg ) of Factor-R; on the 7th day after the last treatment.Plasma cells in a very
good functional state and with a very well developed endoplasmic reticulum.
In the Peyer's patches a hyperplasia, an enlargement of the T- dependent zone and a

considerable number of cells of the plasmocyte series in the dilated sinuses were found (fig.
12).
Fig. 12. Small intestine of a mouse five times treated per os with 1/10 dose (5 mg) of
Factor-R; on the 7th day after the last treatment. Well- preserved brush border.
The mesenterial lymph nodes were also highly activated. The sinuses were dilated and full of
blast and plasma cells(fig. 13).
Fig. 13. Peyer's patch of a mouse five times treated subcutaneously with 1/10 dose (5
mg) of Factor-R; on the 7th day after the last treatment. Plasma cell with a very
well developed endoplasmic reticulum in an active functional state.
In the inguinal lymph nodes a less expressed hyperplasia was found but with dilated sinuses
filled with cell elements of the plasmocyte series(fig. 14).
Fig. 14. Mesenterial lymph node of a mouse treated five times per os with 1/10 dose (5
mg) of Factor-R; on the 7th day after the last treatment. Strong extended
intermediary sinus filled with the cells from the plasmocyte line.
Staining - H.E.
The same picture was seen in the spleen - a hyperplasia of the white pulp, dilated marginal
sinuses filled with lymphocytes, blast cells and plasmocytes.
In the lungs of the 5-times orally treated mice thickened alveolar septa with a considerable
number of lymphoid formations as well as peribronchial mononuclear infiltrations were
established (fig 15).
Fig. 15. Lung of a mouse treated five times per os with 1/10 dose (5 mg) of Factor-R;
on the 7th day after the treatment. Newly formed lymph nodes localized
peribronchially.
Staining - H.E.
The findings were similar to those seen in the mice subcutaneously treated with Factor-R.
In the control mice the inguinal lymph nodes, the mesenterial lymph nodes, the Peyer's
patches and the lungs were calm. In the lymphoid organs single functionally inactive plasma
cells were found (fig. 16).
Fig. 16. Inguinal lymph node of an untreated mouse. Only separate plasmoblasts were
seen. The plasma cells with a very well developed endoplasmic reticulum were
not seen.
No thickened alveolar septa, peribronchial mononuclear infiltrations and lymphoid

nodules were seen in the lungs (fig. 17).
Fig. 17. lung of an untreated mouse. Peribronchial mononuclear infiltrations and newly
formed lymph nodes were not seen.
Staining - H.E.
The results indicate that Factor-R stimulates to a considerable degree the immunologically
engaged organs (lymph nodes, spleen and lungs) on the background of preserved "brush
border" of the small intestines and the lack of pathological changes in the cell elements of the
other organs studied.
2.3. Changes in the Pulmonary Surfactant System in Rats Stimulated with the Polybacterial
Immunostimulant Factor-R
Experiment:
Bronchiole-alveolar inflammatory processes owing to different respiratory infections affect the

pulmonary surfactant system and develop a respiratory distress syndrome.
Factor-R provokes humoral immune response in which the lymphoid tissue of the intestines
and bronchi are involved as well as the lung where lymphoid nodules are formed, functioning
as independent lymph follicles. It is known that the pulmonary surfactant takes part in the
protection of the lung against the influence of different non-bacterial and bacterial factors on
it.
The level of the pulmonary surfactant in rats stimulated with Factor-R on the background of
the immunological changes occurring after the stimulation, as a secretion playing decisive role
in the protection of the lung against different morbid external influences, including bacterial,
has been studied.
Materials and Methods:
The experiments were conducted on 20 male rats, Wistar breed, with body weight of 150-180
grams divided into two groups: a control group of 8 rats and an experimental group of 12
rats.The animals were fed 4 times daily in the course of 5 days with 25 mg Factor-R - 20
stimulations in all. On the 5th day after the last stimulation the animals were tracheotomized
after a preliminary local anaesthesia with 1% solution of procaine. The trachea was cannulated
with plastic cannula for realization of broncho-alveolar lavage by standard method. A part of
the lavage liquid was separated for studying lung macrophages. The lungs were taken out for
the purpose of studying their phospholipid content. At the section material was taken for
histological and electron-microscopical study of the lungs, Peyer's patches, mesenterial lymph
nodes, spleen and bronchial lymph nodes. The materials were processed by the usual
histological and electron-microscopical methods and were observed on an ordinary light
microscope and on an electron microscope JAM 100 C at different magnifications. The
phospholipid extraction was carried out by the method of Folch et al. (1947). The
phospholipid fractions were separated by thin layer chromatography and the inorganic
phosphorus was determined by the method of Kahovkova and Odavic (1969). The protein
was determined by the method of Lowry et al. (1951). The results were processed statistically
using the T-criterion of Student.
Results and Conclusions:
At the oral immunization the immunomorphological changes occurring in the Peyer's patches,
mesenterial lymph nodes, small intestines, bronchial lymph nodes and the lung were studied.
1. Significant immunomorphological changes were observed in the Peyer's patches. The

lymphoid tissue localized in their T- and B- dependent area was strongly hyperplasied. A
significant number of plasmatic cells with strongly developed endoplasmatic reticulum was
detected (Fig.18).
Fig.18. Peyer's patch of a rat treated with Factor-R; on the 5th day after the last dose.
Plasmatic cell with strongly developed endoplasmatic reticulum. (Magnification
- 20,000 X)
This is a morphological evidence that the Peyer's patches are not only a source of cell
predecessors of the plasmatic cells observed in the lamina propria of the small intestines but
that the Peyer's patches with the plasmatic cells occurring in therein directly take part in the
secretion of specific immunoglobulins. The activated lymphoid cells in the Peyer's patches
indicate a functional state conditioning the generalization of the immune response.
2. In the lamina propria mucosa of the small intestines was detected a great number of
plasmatic cells with a strongly developed endoplasmatic reticulum (Fig.19).
Fig.19. Small intestine of a rat treated with Factor-R; on the 5th day after the last dose.
In the lamina propria mucosa plasmatic cells in a very active functional state
with a strongly developed endoplasmatic reticulum were observed.
(Magnification-12,000 X)
3. The mesenterial lymph nodes were also strongly activated and in their enlarged sinuses were
proved plasmatic cells in a very active functional state with a strongly developed
endoplasmatic reticulum (Fig.20).
Fig.20. Mesenterial lymph node of a rat treated with Factor-R; on the 5th day after the
last dose. Strongly activated lymphoid cells with numerous ribosomes in their
cytoplasm and a plasmatic cell with a strongly developed endoplasmatic
reticulum.
(Magnification - 16,000 X)
4. Important immunomorphological changes were established in the lung in the parenchyma of

which were detected formed lymphoid nodules in which were proved plasmatic cells in an
active functional state. This finding was similar in the bronchial lymph nodes where plasmatic
cells with a strongly developed endoplasmatic reticulum were also proved (Fig.21).
Fig.21. Bronchial lymph node of a rat treated with Factor-R on the 5th day after the
last dose. A significant number of plasmatic cells with a strongly developed
endoplasmatic reticulum in an active functional state. (Magnification - 16,000
X)
In the rats treated with Factor-R the total phospholipids as well as the separated phospholipid
fractions were increased significantly. The phosphatidylcholine and phosphatidylglycerol
possessing the most impressed surface active properties were increased with high rate of
authenticity as the latter had increased its level twice. The svingomyelin, phosphatidylserin,
phosphatidylinositol and phosphatidylethanolamin manifested statistically significant increase.
An exception in this respect was the diphosphatidylglycerol (cardiolipin) the increase of which
was not statistically significant. The phospholipid content of the lung presented statistically
significant changes(Table 7).
Table 7
Phospholipid content of alveolar surfactant and lung from rats, treated with Factor-R
*p<0.05; **p<0.01; ***p<0.001
The increase in the phospholipid fractions of the alveolar surfactant could be due to stimulated
synthesis, activated transport of the phospholipids effected by lipid carrying proteins or to
inhibited catabolism of the phospholipid molecules.
The described data speaks convincingly that the oral immunization with Factor-R provokes a
generalized humoral immune response. The hyperplasia of the bronchial lymph nodes, the
observed immunomorphological changes in the lung and the increase of the phospholipid
fractions in the alveolar surfactant system represents a steady evidence of the positive
immunimodulating action of Factor-R in the orally treated animals, proven in numerous
clinical studies.
3. Evidence of Efficacy of Factor-R.
3.1 Introduction
In the following chapter are set out some experiments which will undoubtedly reveal the
efficacy of Factor-R in its multiple applications. There are some important notes that you
should consider before reading the information provided in this chapter.
In the experiments that follow some other products have been used to show, through a
comparative study, the efficacy of Factor-R. One of these products is the synthetic
immunomodulator diethylditiocarbamate. In certain trials treatment with diethylditiocarbamate
is compared to the treatment with Factor-R, while in other a combined treatment is studied
and compared to the above single treatments. Another pharmacological agent that has been
used in the experiments summarized in this chapter was Cyclophosphamide. This drug, being a
typical immunosupressor was utilized to demonstrate the immunosupressive nature of
chemotherapy versus the strong immunostimulative index of Factor-R. Moreover, the study of
the combined treatment with Factor-R and Cyclophosphamide allowed for a very strong
representation of the complete neutralizing effect of Factor-R with respect to the negative
effect of immunosupressors.
In order to achieve more flexibility in the representation of the information, the following
abbreviations are used in the information provided in this chapter:
C - Control group
FR - Factor-R
CY - Cyclophosphamide
DTC - Diethylditiocarbamate
T/C - Treated / Controls
Statistical Processing
The Statistical processing of the information was carried out through the methods of the
variation analysis. The reliability of the data was analyzed according to the t-criterion of
Student.
3.2. Examination of the effect of Factor-R on non-specific respiratory diseases in humans.
3.2.1. Application of Factor-R for prophylaxis of broncho-pulmonary infections in children
A basic problem of the medical practice in cases of

chronic and recurrent broncho-pulmonary infections is prophylaxis. Modern researchers
entirely reject the preventive antibiotic treatment because of possible allergies or secondary
activation of pathogenic flora.
This necessitates the application of antibacterial vaccines which through activation of the
immunocompetent system lead to the creation of short-term or long-term, local or systemic
specific or non-specific immunity. The new Bulgarian preparation Factor-R is intended for
strengthening of the body's defensive mechanisms against acute and chronic pulmonary
diseases in frequently ailing children.
Clinical Experiment:
50 children at the age of 4 to 12 registered as frequently suffering from acute broncho-
pulmonary infections were observed for three months.
The immunostimulant was administered according to the following dosage scheme: 1 tablet of
50 mg daily in the morning before breakfast for 30 days, then followed a 30-day period of rest,
afterwards according to the above dosage scheme the first 10 days in 3 consecutive months.
Side effects of the preparation were not observed.
The children were divided into two groups:
(1) A group of 30 children treated with Factor-R

(2) Placebo group of 20 children
For proper observation of the clinical effect of the application of Factor-R the following
indices were examined:
(1) The rate of secretory IgA in saliva

(2) The bactericidal activity of the serum
Serum and saliva were examined before the course of treatment, on the tenth, thirtieth and
ninetieth day after its beginning.
Results:
The results before the course of treatment and those from the tenth day were compared with a
placebo group of children whose serum and saliva were observed.
The results of the clinical effect of the administration of Factor-R are shown on table 8.
Table 8
Diseases, antibiotic treatment and number of days of stay in hospital of the examined children
for a 3-month period of the previous year and the period of observation.
n-number of observations
It is evident that there is a significant decrease in the number of diseases and a reduction of the
period of antibiotic treatment which is a marker of the seriousness of the diseases.
In support of the results of the clinical effect are the results of the dynamic examination of
several immunologic parameters (see Table 9).
Table 9
Dynamics of the level of IgA in the saliva of the children treated with F-R and those from the
control group.
Before 10th 30th 60th 90th

treatment day day day day
__________________________________________________
Children
treated with 9,64 14,58 15,36 14,12 13,95
F-R n=47 n=42 n=44 n=39 n=41
Control 8,92 10,18

group n=16 n=12
______________________________________________________________
Conclusions:
1.The application of Factor-R for prophylaxis of broncho-pulmonary infections in frequently

ailing children led to a significant decrease in the number of diseases.
2.The administration of the immunostimulant led to a considerable increase of the level of IgA
in the saliva of the children for the whole period of observation.
3. According to modern opinions the body's resistance to antibiotics is due to disorders in the
immunocompetent system. In that sense the application of the medicine will lead to
strengthening of the immune system and to reinforcement of the body's resistance to different
respiratory infectious diseases.
3.2.2. Prophylaxis of broncho-pulmonary infections with Factor-R in adults
IgA has a great importance for the protection against bacterial infections of the respiratory
system. The immunological strength of a given immunostimulant can be estimated by the
increase of the IgG concentration in the serum and bronchial secretion.
In case of oral administration of Factor-R a protection of the respiratory tract is realized as a

result of considerable increase of secretory IgA, e.g. Factor-R induces resistance on patients
suffering from chronic bronchitis.
Clinical Experiment:
34 patients with chronic bronchitis (bronchial form of chronic obstructive pulmonary disease)
at the age of 19 to 65 were treated with Factor-R. Factor-R was administered in a period of
clinical stabilization of the patients.
During the first month the patients were given 1 tablet daily in the morning before breakfast.
Then followed a 30-day period of rest and in the end 1 tablet was administered during the first
10 days of the third, forth, fifth months out of a total treatment period of six months. Every
month the following indices were examined: from the anamnesis - cough, expectoration: from
a physical study of the lung - evidence of bronchial obstruction, functional study of the
breathing - vital capacity, forced expiratory volume per second and Tiffno index; laboratory
studies - quantitative determination of IgA, IgG, IgM in the blood serum, of IgA, IgG, of the
secretory component SC and of albumin in the bronchial secretion using Mancini's method.
The changes in the characteristic of the passing of the chronic bronchitis were determined by
the frequency and duration of the fits as well as by the duration of the temporary incapacity for
work compared with the same period of the previous year. With each observation the
tolerability and the possible side effects of the preparation were taken into consideration.
Results:
After the treatment with Factor-R the clinical picture changed. In the beginning all the patients
had a cough. At the end of the first month it stopped in 20 of the patients (58,8%) and at the
end of the sixth month only 4 of them had a cough (1,1%). Similar changes were observed in
the character of the expectoration. At the beginning of the treatment course all patients had
mucous expectoration (up to 20 cm3 - 22 and above 20 cm3 - 12 patients). At the end of the
first month only 2 patients (0,6%) remained with more abundant expectoration (above 20
cm3). The expectoration was scarce in 20 (58,8%) and completely disappeared in 12 patients
(40,6%).
In the beginning while a physical study of the lungs was carried out 17 patients had symptoms
of bronchial obstruction. At the end of the first month obstruction was established only in 4
patients (23,5%) and at the end of the treatment in none of them.
Important changes in the basic functional indices of breathing were observed. The vital
capacity (VC) was increased from 2500 up to 3500 cm3. Similar were the changes in the
forced expiratory volume (FEV1) and Tiffno index. They were a result of an influence of the
inflammatory component on the bronchial obstruction.
The changes in the serum immunoglobulins could be seen on fig. 22. A certain increase in IgA
and IgM was observed. The stimulating effect was slow and long. The decrease in IgG
probably reflected a tendency toward stabilization of the inflammatory process.
Fig. 22 Levels of the serum immunoglobulins (IgG, IgA and IgM) during the 1st, 2nd,
3rd and 4th months
Fig. 23 Levels of the immunoglobulins (IgA, IgG), of the albumin (Alb) and of the free
secretory component (SC) in the bronchial secretion during the 1st, 2nd and
3rd months.
The changes in the local immunity had a crucial importance for the passing of the chronic
bronchitis. Fig. 23 shows the changes which occurred in some of the basic components of the
bronchial secretion. The quantity of albumin and of IgG decreased. This reflected decrease of
the degree of inflammation of the bronchial mucous membrane. The stimulation of the local
immunity is presented with an increased level of IgA no matter that a certain decrease of the
secretory component could be observed. This is probably a result of the general stabilization of
the local inflammatory changes. A certain stimulation of the cellular immunity could be
observed in the treatment period.
Significant changes were established in the passing of the chronic bronchitis. The number of
fits as compared to the observed for the same period of the previous year decreased from 3,1
to 1,3 and their duration - from 14,6 to 6,8 days. The temporary incapacity for work for the
two compared years decreased from 45,5 to 22,7 days. Side effects as a result of the
administration of the preparation were not observed.
Conclusions:
The clinical treatment that was carried out gave reason for the following conclusions:
1. In the treatment of patients with chronic bronchitis with Factor-R it was established that the
main clinical indices changed for the better. The bronchial obstruction was influenced
significantly which was a result of changes in its inflammatory component.
2. Changes in the levels of the serum immunoglobulins were observed (stimulation of the
humoral immunity). Some components of the bronchial secretion which reflects the condition
of the local immunity changed significantly. Mainly the production of IgA was being
stimulated. A certain stimulation of the cellular immunity could be observed during the
treatment period.
3. As a result of the treatment the number and duration of the bronchial fits decreased. The
temporary incapacity for work dropped with 50%.
4.The preparation has a very good tolerability.
3.3. Examination of the effect of Factor-R on mice
3.3.1. Effect of diethylditiocarbamate (DEC) and Factor-R on the immune response of normal
and immunosuppressed with cyclophosphamide (CY) mice
Fig. 24 shows the results of the effect of Factor-R and DEC on the primary humoral immune
response of normal mice BDF1. It was established that the 10-day oral treatment with Factor-
R caused a significant increase (P<0.01) in the number of antibodyformation cells (AFC) in the
spleen. On the contrary, the injection of DEC brought about a decrease in the number of AFC.
When the two immunomodulators were applied in combination a great increase (P<0.001) in
the number of AFC, even more expressed than the one caused by Factor-R was observed.
Fig.24 Effect of Factor-R (F-R) and DEC on Antibody Formation Cells in the spleen of
normal mice BDF1.
The evidence of the effect of Factor-R and DEC on DHR (delayed hypersensitivity reaction)
of normal mice BDF1 is displayed on fig.25/A/. The peroral treatment with Factor-R led to a
slight (insignificant) growth of the plantar edema. The fourfold administration of DEC,
however, significantly increased DHR. The combined treatment with the two agents caused
even a more expressed (P<0.001) growth of the plantar edema.
A significant increase (P<0.001) of DHR was established in the injected with

cyclophosphamide (CY) (100 mg/kg) animals as compared to the untreated controls
(fig.25/B/). The combination of the cytostatic with Factor-R led to a more expressed growth
of the plantar edema in comparison with the animals treated with CY only. The involvement of
DEC in the therapeutic scheme did not cause a significant change of DHR in the animals
treated with CY or with CY and Factor-R.
Fig.25 Effect of Factor-R (FR) and DEC on DHR of normal (A) or injected with CY
(B) mice BDF1.
Fig.26 shows the effect of Factor-R and DEC on the primary humoral immune response of
immunosuppressed with CY mice BDF1. The injection of CY caused a great reduction of the
number of ABC in the spleen (36.3 +/- 6.2) in comparison with the untreated normal animals
(451.6 +/- 29.8). The combined therapy with CY and Factor-R led to a significant
reinforcement of the humoral response suppressed by the cytostatic. A significant increase in
the number of AFC was also established in the group treated with CY and DEC. The
combined treatment with the three agents caused the most strongly expressed (P<0,001)
restoration of the humoral immune response suppressed by CY. In this case significant increase
in the number of AFC was observed as compared to the administration of CY with DEC
(P<0.01) or with Factor-R only (P<0.05).
Fig.26 Effect of Factor-R (FR) and DEC on ABC in the spleen of immunosuppressed
with cyclophosphamide (CY) mice.
While analysing the effect of DEC on the Natural killer cells' function of hybrid mice BDF1 we
established that the splenocytes of the treated animals manifested an intensified rosette-
forming and cytolytic activity in vitro towards target YAC-1 cells (table 10).
Table 10
Effect of DEC on the spleen Natural killer cells (NK cells) of immunosuppressed with
cyclophosphamide mice.
*p<0.05; **p<0.01; ***p<0.001
The injection of CY (100 mg/kg) caused a slight lowering of the binding ability of the NK cells
and a strong inhibition of their cytotoxicity. While a combined treatment with the two agents
was carried out we observed a significant increase both of the cytotoxicity and the rosette-
formation of the NK cells with target YAC-1 cells.
The spleen NK cells of treated with Factor-R mice manifested a slight intensification of the
rosette-formation with target YAC-1 cells but their cytolytic activity in vitro towards the same
target cells marked with 51Cr was significantly reduced(table 11).
Table 11
Effect of Factor-R on the spleen NK cells of normal mice BDF1.
*p<0.05; **p<0.01; ***p<0.001
Fig.27 shows the results of the test for formation of rosettes of the spleen NK cells with target
YAC-1 cells.
Fig.27 Effect of Factor-R on the NK cells' activity of injected with cyclophosphamide
(CY) mice BDF1.
We observed strongly (P<0.001) reduced rosette-formation with the target cells in the injected
with CY animals. The oral treatment with Factor-R led to a complete normalization of the
suppressed by the cytostatic rosette-formation.
Conclusions:
1. The research on the effect of Factor-R on the spleen NK cells produced the first evidence of
the influence of the preparation on this effector cellular population. The established increase of
the rosette-formation of the NK cells with target YAC-1 cells implies an increased number of
surface receptors whereas the suppressed cytolytic activity most probably marks a
hypoactivity of the NK cells in the spleen.
2. While the effect of Factor-R on the immune response of immunosuppressed with CY mice
was being examined it was established that the preparation increased twice the suppressed
humoral response and stimulated DHR.
3.3.2. Effect of Factor-R and DEC on animals with implanted tumours.
The limited success to date of conventional cancer therapy in the treatment of disseminated
malignancies has prompted many attempts at developing immunotherapeutic regimens which
aim to activate host defense "in situ". As the lung is frequently a site of development of
primary and/or metastatic tumours, many efforts have been made to activate cells found in this
organ which have potent antitumour activity, such as natural killer (NK) cells or macrophages.
The clinical and experimental evidence suggesting that Factor-R may increase non-specific
defense mechanisms in the lung, the most frequently targeted organ for haematogenous
metastases, encouraged us to explore the possibility of the immunostimulant's inhibiting the
formation and the growth of pulmonary metastases. The continuous oral treatment with
Factor-R
can reinforce the immune mechanisms of the lung against circulating tumour cells and may
also prevent the lung parenchyma from localization of metastatic foci. White mice treated with
Factor-R were used to test these hypotheses.
Clinical Experiment
Spontaneous metastasis model: Lewis lung carcinoma was implanted in the hind
footpads of the mice where a local tumour was growing, metastasizing spontaneously in the
lungs. The tumour-bearing legs of the mice were amputated 22 or 25 days after the tumour
implantation, and their lungs were fixed overnight in Bouin's fixative.
Agents: Factor-R; Cyclophosphamide at a single dose of 50, 100 or 150 mg/kg was injected
i.p.
Animals - normal and tumour-bearing mice.
Results:
It was found that oral treatment with Factor-R caused significant reduction of the number of
the lung metastases in mice. The therapeutic efficacy of Factor-R was greater when the
treatment was initiated prior to or immediately after
the implantation of the tumour (fig 28).
Fig.28 Effect of Factor-R on the number of lung metastases of LLC as a result of different
schemes of administration (1st-10th day after tumour implantation; 5th-14th day after
tumour implantation; 10th-19th day after tumour implantation)
Factor-R has an inhibitory effect not only on the number, but also on the volume of
metastases. In this case the early prophylaxis with Factor-R immediately after the implantation
of the primary tumour was more effective than that applied on preexisting pulmonary
metastases. The therapeutic efficacy of Factor-R depended on the degree of dissemination of
LLC- cells.
Oral administration of Factor-R was significantly more effective in case of comparatively
minor secondary tumours.
20-70% of the animals treated with Factor-R were without visible lung metastases on the 22nd
day after the tumour implantation. The greatest reduction of the number and volume of lung
metastases was achieved in the early phases of tumour dissemination. Administration of
Factor-R after surgical resection of the primary tumour also produced a significant therapeutic
effect in animals with spontaneous metastases.
Collectively these results demonstrated that Factor-R was effective against lung metastases
when administered orally and that the maximum therapeutic activity was limited by the
metastatic tumour burden. Therefore, the therapeutic potential of Factor-R was examined in
combination with chemotherapy to determine if there was additive activity for the treatment of
well established metastatic lesions.
3.3.2.1. Combined prophylaxis with cyclophosphamide and Factor-R
The effects of the combined therapy with cyclophosphamide and Factor-R are summarized in
Table 12. The development of pulmonary metastases was inhibited by each of these treatments
alone. Cyclophosphamide exhibited a strong inhibitory effect in a dose-dependent manner
against lung metastases and the dose of 150mg/kg cured 40% of the animals. Oral
immunotherapy with Factor-R had comparatively minor therapeutic activity on the large
tumour burden of preexisting pulmonary metastases. The combination of cyclophosphamide at
each dose tested with Factor-R had additive inhibitory effects on lung metastases. The mice
receiving a single dose of cyclophosphamide at 50 mg/kg in combination with Factor-R
showed a significantly reduced number and volume of lung metastases as compared to animals
injected with cyclophosphamide only. This combined therapy prolonged significantly the
survival of the mice as compared to chemotherapy alone. In contrast, the addition of Factor-R
to the treatment did not prolong the survival of mice injected with 100mg/kg
cyclophosphamide. However, in this case a significant reduction of the number and volume of
lung metastases was also observed. Four out of ten mice receiving a single dose of
cyclophosphamide at 150% mg/kg were freed from lung metastases, while no metastatic
nodules could be seen in six or seven of ten mice treated with cyclophosphamide and Factor-R
respectively. In short, these results demonstrated that the therapeutic effect of
cyclophosphamide on preexisting pulmonary metastases was enhanced by subsequent oral
treatment with Factor-R.
Table 12
Combination therapy of spontaneous lung metastases with cyclophosphamide (CY) and
Factor-R.
Significant difference from the group treated with CY only:

*p<0.05; **p<0.01; ***p<0.001
3.4 Immune mechanisms in the activity of Factor-R
The number of alveolar macrophages (AM) in the tumour-bearing mice was less than the
number of isolated AM in mice treated with Factor-R (both normal and tumour-bering mice).
In mice with i.m. implants of LLC there was a correlation between the increase of AM
tumouricidal activity and the inhibition of metastatic tumour growth.
Another interesting observation was the difference in the number of AM isolated from the
control and the treated with Factor-R animals. In confirmation of this observation two
experiments were carried out - the effect of Factor-R on the number of AM in normal (fig. 29)
and implanted with LLC (fig. 30) mice C57BL/6.
Fig.29 Effect of oral treatment with Factor-R on the number of alveolar macrophages
(AM) in normal C57BL/6 mice. Factor-R was administered orally for 10 days
and the AM were collected on days 1, 2, 5 and 10
Fig.30 Effect of oral treatment with Factor-R on alveolar macrophages (AM) in LLC
bearing C57BL/6 mice. Samples of cells were inoculated i.m. on day 0. Factor-
R was administered for 10 days, beginning on day 11. The AM were collected
on days 11, 12, 15 and 20
Results:
1. In normal mice 24 hours after the first administration of Factor-R (on the 2nd
day) the number of the isolated AM increased significantly. On the fifth and
tenth days this increase became even more pronounced. Ten days after the end
of the treatment there was a great difference between the numbers of AM
harvested from the lungs of the treated and control animals.
2. In tumour-bearing mice oral administration of Factor-R caused an increase in

the number of AM which was insignificant at the beginning of the treatment but
on the 10th day was nearly as great as that in normal animals.
Conclusions:
1. The activation of AM is the basic mechanism through which the peroral

immunostimulant Factor-R inhibits the growth and dissemination of pulmonary
metastases. The accumulation of activated AM in the lungs and respiratory
pathways shows the defensive mechanisms of Factor-R against chronic
respiratory infections (fig.29).
2. The peroral medication has antimetastatic activity in animals with spontaneous

pulmonary metastases. The greatest reduction of the number and volume of
lung metastases was achieved when the treatment began in the early phases of
tumour dissemination or after surgical resection of the primary tumour (fig.30).
3. The combined therapy with Factor-R and cyclophosphamide led to more

effective inhibition of the metastatic growth in comparison with chemotherapy
alone. This combined therapy could avoid the severe side effects associated
with high doses of cyclophosphamide. These results suggested that the
application of Factor-R could be successful in the therapy of secondary
pulmonary micrometastases. The success of immunotherapy of tumour
metastases depends on the capacity of Factor-R to activate immune
mechanisms in the target organ which contains metastatic foci. It is necessary
to examine the activity of AM in order to establish the antimetastatic effect of
Factor-R.
4. The cytolytic activity of AM recovered after an oral therapy with Factor-R for
ten days was higher than that of the control AM.
5. It was proved that there was a correlation between the capacity of Factor-R to
induce the accumulation of tumouricidal AM in the lower respiratory pathways
and the lungs and the vaccine's antimetastatic properties.
In conclusion we can say that the activation of the AM is one of the basic means of inhibition
of the growth of neoplasms.
Clinical Experiment
In another experiment we followed the effect of Factor-R on the induced by CY changes in the
normal composition of the cells isolated by broncho-alveolar lavage (fig. 28).
Fig.28 Effect of Factor-R on the composition of the broncho-alveolar cellular

populations of immunosuppressed with cyclophosphamide (CY) mice
C57BL/6. AM,alveolar macrophages; LY,lymphocytes;
PMN,polymorphonuclears.
In the animals treated with Factor-R we observed a great (760%) increase in the total number
of the lavage isolated cells. The increase was significant (P<0.001) for all cellular populations
(AM, lymphocytes and polymorphonuclears).
The number of AM and polymorphonuclears was particularly increased in comparison with the
normal controls. In the immunosuppressed with CY mice we observed a strongly reduced
number of the AM whereas the number of the lymphocytes was not changed significantly. The
twofold administration of Factor-R to the injected with CY animals led to a restoration of the
inhibited by the cytostatic normal number of alveolar cells.
In a separate experiment we examined the effect of Factor-R on the peritoneal macrophages

(PM) of normal and implanted with LLC mice BDF1 (table 13).
Table 13
Activation of peritoneal macrophages (PM) by Factor-R in normal and implanted with LLC
mice BDF1.
It was established that the oral therapy with Factor-R caused a significant increase of the
cytotoxicity of PM. It was observed that the cytotoxicity of the PM in the tumour-bearing
control animals was decreased in comparison with that of the normal animals. However, the
treatment with Factor-R led to a significant rise in the tumouricidal properties of the
macrophages as compared to both the tumour-bearing and the normal controls.
Evidence of long-term safety
FACTOR-R
TABLETS
Investigation of the preparation's stability
Factor-R's stability is investigated straight after the production of the tablets and after two
years of storage at temperatures from 20oC to 25oC. The tests are carried out with Factor-R
tablets of a series produced from active substance stored for two years at temperatures from
2oC to 8oC.
For the investigation of the stability the following criteria are used:
- tablet's appearance;
- tablet's solubility;
- protein content; high effective liquid chromatography.
The methods here are the same as the ones used for defining the quality of Factor-R tablets.
Table 14 displays the results of the investigation of the appearance, solubility and total protein
content of a Factor-R series straight after production and in two years of storage. No changes
in the indicators tested are viewed after two years of storage at temperature in the range of
20-25oC.
Table 14
Stability data of Factor-R
Indicators Tablets after Tablets after

production 24 months
______________________________________________________________
Appearance Tablets of Tablets of

mosaic structure mosaic structure
Solubility 10 min. 10 min.
Total protein 4,20 mg/50 mg 4.21 mg/50 mg

to Lowry 2,20 mg/25 mg 2.09 mg/25 mg
In charge of the experiment Dr. B. Dragulev. State Institute for Control of Drugs. Time of the
investigation-March 1985 and March 1988 at temperatures ranging from 20 to 25oC.
Figures 33 and 34 reveal the results of high effective liquid chromatography of Factor-
R tablets straight after production and after two years of storage at temperatures of 20-25 oC.
No changes in the retention times, number of components and their concentrations are viewed
which is indicative of the good stability of the preparation tested.
The results obtained show that Factor-R tablets possess a good stability. No changes
related to the storage of the preparation for two years are viewed. Estimation of the specific
biological activity - stimulation of the immunocompetent system using Factor-R tablets stored
for 22 months at room temperature was assessed.
The values of hemoagglutinating antibody against sheep erythrocytes in the mice

treated perorally or subcutaneously with Factor-R tablets stored at room temperature for 22
months are presented in table 15.
As could be seen, no difference was observed between the capability for stimulation of
the immune system with freshly prepared Factor-R tablets and tablets stored for 22 months at
room temperature and relative humidity 90% (table 14).
The preserving of the specific biological activity of Factor-R after storing the tablets
for 22 months at room temperature was determined. During the study of the protective effect
Factor-R was applied orally to white mice with staphylococcus infections.
These results could be seen in Table 16. No difference was found after the application
of freshly prepared or stored at room temperature for 22 months Factor-R tablets (compare
with table 5).
Table 15
Hemoagglutination of antibodies titre against sheep erythrocytes in mice treated with Factor-R
stored for 22 months at room
temperature
______________________________________________________________
Test groups of animals Antibody titre after administration of 10 white mice each
of the antigen sheep erythrocytes
treated with: -----------------------------------
response antibody
response
-----------------------------------
-----------------------------------------------------------------Factor-R orally 7 days
______________________________________________________________
Factor-R orally 7 days
______________________________________________________________Factor-R s.c. 7
days
______________________________________________________________Factor-R s.c.7
days
______________________________________________________________Control group -
injected
with Ag only 1:8 1:16 1:64
______________________________________________________________
Ag - antigen - each mouse was injected i.v. with 0.2 ml of 50% suspension of sheep
erythrocytes. On the 28th day after the first administration the antigen was injected again in
order to follow up the secondary antibody response. Factor-R was administered in a daily dose
of 2 mg/0.5 ml physiological solution orally or s.c.
Table 16
Results of the protective efficacy of Factor-R, stored for 22 months at room temperature,
administered orally to white mice infected with Staphylococcus.
_____________________________________________________________
Test groups of mice* Number of dead mice on:
treated with __________________________________________ 1
2 3 4 5 6 7 8 9 10 11 12 day
_____________________________________________________________
FACTOR-R orally 10 days before infection 2 2 2 2 1 - 1 - -
- - -
______________________________________________________________
Physiological sol.
orally 10 days
before infection 8 1 1 - - - - - - - - -
______________________________________________________________
* Each test group is of 10 white mice with body mass between 15 and 18 gr.
CURRICULUM VITAE
Prof. BOGDAN NIKOLOV PETRUNOV, MD, DSc.

Director of the National Centre of Infectious and Parasitic Diseases, Sofia; Head of
Department of Allergy and Immunology
1954 Completed a high-school training course in Sofia.
1960 Graduated with honours from the High Medical Institute, Sofia.
1960-63 Worked as an intern at the Department of Internal Diseases at the regional

hospital of Sevlievo, Bulgaria.
1963 Started his scientific career at the National Centre of Infectious and
Parasitic Diseases (NCIPD) as a Research Fellow and founded the first
laboratory of allergy in Bulgaria which aimed at studying the allergizing factors
in the country and producing allergen preparations for specific diagnosis and
treatment.
1964-65 Carried out a 6-month post-graduate study of allergology and immunology in

Czechoslovakia under the guidance of Prof. I. Liska and Prof. I. Sercl.
1965 Organized the production of allergen preparations in Bulgaria - a base

for the development of modern clinical allergology in this country. Presently,
the Laboratory of Allergy at the NCIPD produces over 180 types of allergens
of all major groups and absolutely satisfies the needs of the country's clinical
allergological practice.
1968-72 Participated in a joint research project together with specialists from "
BAYER" on investigating the effect of proteinase inhibitors (Trazilol) on
immunological and allergic reactions.
1969 Defended a thesis on the chemical, immunological and biological

properties of the domestic dust allergen and was awarded the academic
distinction PhD.
1972-73 Performed a 6-month specialization, having won a WHO scholarship in the

field of experimental and applied allergology in England (Prof. Pepis, Prof.
Augustin), France (prof. Alpern, Pasteur Institute) and the Netherlands (prof.
Berens, Prof. Worhorst).
1973 Elected Associate Professor and commenced giving lectures on

allergology and immunology to post-graduate medical students.
1974 Awarded the badge of honour of the State Committee for Research and
Technology for contribution in the scientific research work.
1975 Selected and confirmed as a WHO expert on the problems of allergen

products.
1976 Awarded the "Cyril and Methodius" medal for scientific research and
production achievements.
1978 Doctor of Medical Sciences - "The mechanism of activity of atopic

allergens".
1978 Organized a laboratory for producing allergen preparations in New

Delhi, India, and gave lectures to the local allergologists.
1979-89 Chosen to be a chief of the scientific programme of the countries members at

the ex - Council for Mutual Economic Assistance (COMECON) on the
problems concerning allergen preparations - production and standardization.
1979 on Member of a sub-committee dealing with allergen control and standardization

within the Committee of Biological Standardization at the WHO.
1979 on General Secretary of the Bulgarian Society of Allergology.
1980 Awarded the Robert Koch badge of honour of the GDR's Society of
Allergology.
1980 Visited Canada on the occasion of the "Days of Bulgarian Science and
Technology" and delivered lectures in MacGil University, Montreal and the
University of Otawa.
1980 Appointed Scientific Secretary of the NCIPD.
1981-82 Participated actively in the work of the sub-committee of allergen control and
standardization at the WHO for development and evaluation of the First
International Allergen Reference Preparations.
1983 Elected member of the Specialized Scientific Council of Immunology

and Allergology at the High Accreditation Committee (HIC).
1985 Elected Professor of immunology and allergology at the Medical

Faculty, Sofia.
1985 Visited the USA, the National Health Institute near Bethesda for
participation in the 4th International Seminar on Allergen Control and
Standardization.
1985 Appointed Vice Director of the NCIPD in charge of scientific problems.
1986-89 Appointed National Coordinator of the Research Work on the problem

"Biotechnology and Medicine" developed in the COMECON countries.
1987 Organized in Havana the first Cuban laboratory for studying the
allergizing factors and producing allergen preparations. Delivered lectures for
training Cuban specialists in the field of allergology. Became an honorary
member of the Cuban Society of Allergology.
1988 Appointed President of the Medico-Biological Committee at the HAC
of the Republic of Bulgaria.
1989 Participated with his associates in the First International Study "HLA
System and Allergy", organized by the USA and Japan.
1990 Elected member of the Bulgarian Selection Committee at the Fogarty

Foundation in charge of selecting scholarship students in the USA on the
problems of medico-biological sciences by the executive body of the National
Health Institute, the USA.
1991 Awarded a special prize of the World Exhibition of Inventors in Plovdiv,

Bulgaria, for the first Bulgarian bacterial immunostimulant for oral
administration RESPIVAX, developed and produced by his team.
1993 Appointed Director of the National Centre of Infectious and Parasitic

Diseases, Sofia.
CURRICULUM VITAE
Name: Professor Dimiter Kirilov Todorov, MD, PhD, DSc.
Address: Department of Oncopharmacology

National Oncological Centre
Medical Academy
Sofia 1156 - Bulgaria
Tel.: 00359 2 - 72 06 54 and - 7123 ext.307 and 329
Education: 1956 - High School, Sofia distinguished by a silver medal; Languages:

English, Russian, French.
1962 - Medical education, Medical University, Sofia; MD.
1965 - 1967 - Postgraduate Assistant, Institute of Pharmacology and
Toxicology, Medical University, Sofia.
1969 - Diploma for Specialization in Pharmacology and Toxicology.
1967 - 1970 Assistant, Institute of Pharmacology and Toxicology,
Medical University, Medical Academy, Sofia.
1970 - PhD. Thesis on experimental pharmacologyand toxicology:
Pharmacological Studies on Some Pyrimidine Derivatives, especially on
their Influence on the Central Nervous System, under
the guidance of Professor Dr. D. Paskov.
1984 - DSc. Thesis on experimental oncopharmacology and toxicology:
Some Pharmacological Approaches to the Modification of the Effects
of Antitumour Agents.
Work: 1971 till now: Head of Department of Oncopharmacology at the

National Oncological Centre, Medical Academy, Sofia
1974 - Assistant Professor of Experimental Therapy and for 8 years
lecturer at the Institute of Pharmacology and Toxicology, Medical
University, Sofia: gave full courses of lectures on pharmacology
and toxicology to students in medicine, dentistry and pharmacy.
1976 - 1977 - Eleanor Roosevelt International Cancer Fellowship at the
Chester Beatty Research Institute, London: Pharmaco - biochemical
Studies on the Mechanisms of Action of Thaliblastine(Non- myelotoxic
Antitumour Drug of Plant Origin with Novel Chemical Structure) under
the guidance of Prof. Dr. T. A. Connors.
1987 - Professor of Oncopharmacology
1987 till now - Appointed Director of Research
Activities, National Oncological Centre, Medical Academy, Sofia
1990 - Appointed Executive Director, National Oncological Centre,
Sofia 1991 - Visiting Scientist at the Institute of Toxicology and
Chemotherapy, German Cancer Research Centre, Heidelberg in the
group of Professor Dr. W.J. Zeller: In vitro and in vivo Studies on
Some New Approaches to the Treatment of Human Gliomas and
Human Ovary Tumours.
1991 - Visiting Scientist at the Institute of Clinical Immunology,
University of Erlangen, Germany (DFG Fellow) in the group of
Ass. Prof. Dr. M. Gramatzki : In vivo studies on the overcoming of
MDR in the human cell line CEM.
Scientific Subjects:
Models and screening of new antitumour agents in vitro and in vivo,
preclinical pharmacology and toxicology, molecular mechanisms of
action, carriers of antitumour drugs (liposomes, nanoparticles,
polymers, proteins, lectines), evaluation of drugs in metastatic models,
studies on enhancing the selectivity of antitumour agents.
Scientific publications:
Total number: 262, comprising 138 publications in scientific journals
(97 in Bulgarian, 41 in foreign languages), 26 Bulgarian patents, 98
reports at congresses, symposia, conferences (abstracts); more than 130
references by Science Citation Index.
Scientific Lectures and Seminars

abroad: England, USSR, Belgium, Germany (F.R.G. and former
G.D.R.), Hungary, Pakistan, India, Poland, Greece.
Popular Lectures and Seminars

in Bulgaria: As a member of the Bulgarian Society for Distribution of Scientific
Knowledge: Etiology and epidemiology of cancer, carcinogenesis,
primary and secondary prophylaxis, combined modality of treatment,
palliative treatment of cancer (including especially cancer pain relief).
Memberships: UICC, EACR (Treasurer for Bulgaria), European Society for

Photobiology, Bulgarian Society for Oncology, Bulgarian Society for
Pharmacology, International Union of Scientific Workers, Member of
the Bulgarian Commission for Drugs (Ministry of Public Health),
Member of the Editorial Board of "Problems of Oncology"(Bulgarian)
and of the Referative Bulletin "Oncology, Radiology and
Roentgenology" (Bulgarian); "Oncologia" (Oncology) Bulgarian.
CURRICULUM VITAE
of Prof. PLAMEN NIKOLOV NENKOV, MD, DSc,

Chief of Laboratory "Bacterial vaccines"
Deputy Director of National Centre of Infectious and Parasitic Diseases,
Sofia.
1965 Finished the German Language High School in Sofia.
1971 Graduated from the Higher Institute of Hygiene and Medicine in Sankt
Peterburg, Russia.
1971 Started working as an ordinator at the Institute of Infectious and

Parasitic Diseases in Sofia.
1973 Started his scientific career by winning a Junior Research Fellowship

competition.
1980 PhD, thesis: "Enteral Immunization with live cholera vaccine in

experiment".
1986 Appointed Chief of Bacterial Vaccines Laboratory.
1987 Elected Senior Research Fellow, 2nd rank.
1989 Elected Deputy Director of the National Centre of Infectious and

Parasitic Diseases, Sofia, in charge of production.
1990 DSc, thesis: "Production of live and killed vaccines by means of

cultivation in a bioreactor and immunological characteristics of the
biopreparations received".
1991 Elected Senior Research Fellow, 1st rank.

CURRICULUM VITAE
of Prof.RAHAMIN DANIEL SHEKERDJIISKI, PhD

Head of Department of Industrial Pharmacy,
Faculty of Pharmacy Director of
Pharmaceutical, Scientific and Production Enterprise, Sofia
1956 Mag.Pharm., Faculty of Pharmacy, Sofia, Bulgaria
1956 Appointed production manager, then head of division "New

Pharmaceuticals" at the Pharmaceutical Factory in Dupnitsa.
1968 Postgraduate work at the Faculty of Pharmacy,

department"Technology of Pharmaceutical Preparations".
1972 PhD in pharmacy, thesis on "Tablets with Sustained

Release Based on the Principle of Extended Diffusion".
1973 Appointed assistant of technology ofpreparations, Department

"Technology of Pharmaceutical Preparations", Faculty of Pharmacy,Sofia.
1980 Assoc.Prof. at the Department "Technology of Pharmaceutical

Preparations", Faculty of Pharmacy, Sofia.
1986 Head of Department "Industrial Pharmacy".
1988 DSc, thesis on "Technological and Biopharmaceutical

Research on the Creation of Tablet Preparations".
1991 Professor of Technology of Pharmaceutical Preparations.
1992 Manager of Pharmaceutical,Scientific and Production Enterprise.
Prof. R. Shekerdjiiski has given lectures on "Technology of Pharmaceutical

Preparations " to undergraduate and postgraduate students studying pharmacy,as well as to
students from the Biological Faculty. He has published some books on Technology of
Pharmaceutical Preparations and above 100 research papers in our country and abroad. He has
also taken part in many conferences and symposia.
Prof. Shekerdjiiski is interested in the creation of new preparations with controlled
release and quickly disintegrating tablets.
He has participated in international experiments for investigation of the behaviour of
some receptors in the cosmos. Prof. Shekerdjiiski's scientific research is directed to
creation, biopharmaceutical characterization and realization of the most widely used in the
medical practice solid dosage preparations. The main contribution to the pharmaceutical
theory and practice is the creation of preparations with controlled release so that a prolonged
therapeutic effect is achieved. He is the author of a therapeutical model of a medication with
sustained release through which the necessary release speed and degree that guarantee the
desired biological availability are attained.
On the basis of established by Prof. Shekerdjiiski regularities in the creation of quickly
disintegrating tablets maximum release speed, pharmaceutical and biological activity are
guaranteed. As a result of this bioequivalent preparations are produced. Thus some basic
problems of pharmaceutical technology are solved.
A great part of his researches is associated with the influence of the auxiliary substances and
the technological regime on the stability, the pharmaceutical and biological availability of new
preparations which are of great importance for the clinical practice - tablets, suspensions, etc.
His scientific work led to the creation of Factor-R - one of the first peroral vaccines in the
form of tablets. In the course of the experiments several technological problems connected
with the physical and chemical stabilization of the product and the possible changes during the
years of storage were solved.
He takes part in a programme realized in cosmic conditions with a test - a series of
tablets for investigation of the change of the gustation. Prof. Shekerdjiiski has supervised 2
PhD theses. At present he gives lectures in specialized courses to students studying pharmacy.
Languages: English, Russian.
Addresses:
1. Sofia 1000
"Dunav" Str.No 2
Faculty of Pharmacy,
Department Industrial Pharmacy
2. Sofia
"Traiko Stanoev" Blv.
NPSK of Pharmacy, phone: 706 259, fax. 705 253
CURRICULUM VITAE
of Prof. Dia Mihailova, DSc.

Head of Department of Chemistry
Dean of Faculty of Pharmacy
Higher Medical School, Sofia
1955 M.S. in Chemistry, University of Sofia, Bulgaria.
1956 Appointed Assistant of physical chemistry at the Department of

Chemistry, Faculty of Pharmacy, Medical Academy, Sofia.
1968 PhD in pharmacy; thesis: "Physicochemical properties of drugs relative

to their absorption, distribution and elimination".
1970-90 Post-doctoral studies at the Department of Pharmacy, Chelsea College, London

University (during different periods).
1972 Appointed Associate Professor of Physical Chemistry, Department of

Chemistry, Faculty of Pharmacy.
1978 Head of Department of Chemistry.
1988 DSc, thesis: "Pharmacokinetic approaches to the complex evaluation of

drugs".
1989 Appointed Professor of Physical Chemistry.
1989 Head of the newly established Department of Chemistry (Inorganic,

Physical and Analytical).
1991 Appointed Dean of the Faculty of Pharmacy.
MAIN NATIONAL AND INTERNATIONAL ACTIVITY
Prof. Mihailova has been invited to lectures in Austria, Germany, Greece, Poland, Russia and
Switzerland. She has published two books: Textbook of Physical Chemistry, for which she was
given two awards and The Bases of Pharmacokinetics. She has published more than 150
research papers and has supervised more than 10 PhD theses in the field of pharmacokinetics,
drug metabolism and drug design. Her major present interests are in the field of
pharmacokinetics, QSAR analysis and molecular design.
Languages: English, Russian, German.

GLOSSARY OF TERMS
AGGLUTINATION: Accumulation and sedimentation of corpuscular

particles, such as bacteria, erythrocytes and other cellular
elements.
AIDS: Acquired Immune Deficiency Syndrome. A

severe viral disease of the immune system leading to other lethal
infections and malignancies.
ALBUMIN: Protein; a group name of the simple proteins

which are the main part of proteins of animal and plant tissues.
ALLERGEN: A substance causing allergy, bringing about the

formation of antibodies and sensitized cells.
AM: Alveolar macrophages - macrophages

situated in the lungs.
ANTIBODY: A protein produced by certain white blood cells

in humans and animals in response to a substance seen as non-
self, that is a foreign antigen (such as a virus or bacteria). An
antibody binds specifically to a single antigen.
ANTIGEN: Any substance seen as foreign by the immune

system and which triggers an antibody or cell-mediated response
by the body's immune system.
ASTHMA: An chronic or acute lung disorder. It is

characterized by congestion and contraction of the lungs and
difficulty in breathing. It is believed to be a autoimmune
disorder.
BACTERIA: Unicellular microorganisms, many of which

cause disease or help dead animals and plants to decay.
B-LYMPHOCYTE: B-Cell-a type of lymphocyte which produces antibodies

in response to antigens.
BRONCHIOLES: The smallest branches of the bronchi in the lung lobules.
BRONCHITIS: Inflammation of the mucous membrane of the bronchi.
BRONCHOPNEUMONIA: Inflammatory process in a restricted part of the lung tissue.
BRONCHODILATING
PRODUCTS: Applied for prophylaxis and treatment of
bronchospamsms (spasmodic bronchitis, bronchial asthma) and
are an important component in the complex therapy of these
diseases.
C3 The 3rd part of the complement system.
CANCER: A group of diseases characterized by the

uncontrolled growth and spread of abnormal cells. If the spread
cannot be controlled, it results in death.
CANNULA: A tube inserted in a body's cavity.
CHEMOTHERAPY: Treatment of infectious diseases and tumours with

chemotherapeutic prepations: antibiotics, sulphonamides,
antitumour medications, etc.
COMPLEMENT: A system of serum proteins which is activated by the

antigen - antibody complex with a formation of biologically
active substances capable of causing irreversible damages to the
cellular membranes; one of the factors of the body's natural
immunity.
CYTOSTATIC: A drug that kills tumour cells.
CYTOTOXICITY: Killing of cells.
DIABETES: A disease of the pancreas in which sugar and

starchy foods cannot be properly absorbed.
EDEMA: Increased accumulation of liquids in the body's

tissues, swelling of a tissue as a result of accumulation of a
liquid in the tissue areas.
EFFECTOR CELLULAR
POPULATION: (in this case) Spleen NK cells.
EFFICACY: Strict definition is positive or negative biological

activity. In practice efficacy refers to how well a drug produces
the intended effect.
ENDOTOXIN: Toxins produced inside the microorganisms which are

released after the destruction of the bacterial cell.
E-RFC REACTION:
Rea
ctio
n of
pro
vin
g T-
lym
pho
cyt
es.
ERYTHROCYTE: Red blood cell.
ETD;EMD50;EMD75;
EMD25: Expiratory top debit; expiratory maximal debit-
50% of FVC; expiratory maximal debit -75% of FVC;
expiratory maximal debit - 25% debit of FVC(forced vital
capacity).
EXUDATE: The liquid (rich in proteins and containing

forming elements of the blood) coming out of the walls of the
small vessels when there is an inflammatory process.
FEV1; VC: Forced monosecond expiratory volume; Vital

capacity - parameters for the assessment of the functional level
of the lung.
FIBROBRONCHOSCOPY: Studying of the bronchi by insertion of a thin tube of fibre glass.
GAMMAGLOBULIN: Immunoglobulin fraction of the blood serum containing

the greater part of antibodies.
GINGIVITIS
CATARRHALIS
CHRONICA: Chronic inflammation of the gums.
HEMOAGGLUTINATION: Agglutination of the red blood cells.
HIV: Human Immunodeficiency Virus. A group

of viruses believed to be responsible for AIDS and AIDS related
diseases.
HUMORAL IMMUNE
RESPONSE: Immune response in which the identification of
the antigen is realized by B-cells.
HYBRID: An animal or plant produced from two different

kinds.
HYPERPLASIA: Quantitative increase of the component parts of separate

tissues through reproduction of their cells, increased formation
of cellular elements.
IgA, IgG, IgM: Immunoglobulin A, Immunoglobulin G, Immunoglobulin
M - Proteins in the normal blood serum related to the humoral
immune response.
I.M. Intramuscular - inside the muscles.
IMMUNODEFICIENCY,
ACQUIRED: A generalized diminution of the immune response
to antigenic stimuli due to a wide variety of conditions including
aging, AIDS, amyotrophic lateral sclerosis, burns, radiation, etc.
IMMUNOSTIMULANT: A preparation which activates and stimulates the functions of

the immune system.
IMMUNE RESPONSE: A chain of molecular and cellular events starting with an

identification of the antigen and ending with an accumulation of
effector immune cells and molecules.
INFECTION: A disease that can be spread by means of bacteria carried

in the air or in water.
INOCULATION: Application of microorganisms or tumour cells in the

body.
INTRADERMAL: In the skin.
INSPECTORATING
PRODUCTS: Lead to liquefaction of the bronchial secretion
and facilitate its excretion from the respiratory pathways.
INTRAGASTRIC: Inside the stomach.
I.P. Intraperitoneal - inside the peritoneal

cavity.
I.V. Intravenous - inside the vein.
IN VITRO: Studies or phenomena that take place outside the

body.
IN VIVO: Studies and phenomena that take place inside the

body.
LAMINA PROPRIA A layer of the mucous membrane made up of

MUCOSAE lamina of loose connective tissue.
LATENT: Not manifest, concealed.
LARYNGITIS: Inflammation of the larynx.

LAVAGE: Taking material from living cells by introduction
of liquid.
LESION: Hurt, injury, damage.
LETHAL: Causing death.
LEUKOCYTES: White blood cells
LLC: Lewis Lung carcinoma - mice tumour

model.
LYMPH FOLLICLE: A small lymph nodule.
LYMPHOCYTE: A type of white blood cell divided into two classes, B-

cells and T-cells.
LYSOZYME: A class of hydrolytic enzymes responsible for
hydrolysis of mucopolysaccharides and mucoproteins, found in
tears, milk, saliva and serum as well as neutrophils and cells of
the monocyte phagocytic system.
MACROPHAGE: A cell found in the body that has the ability to kill the
viruses, bacteria, fungi and cancer cells, often by engulfing the
targeted organism or cell.
MEMD25-75: Mean expiratory maximal debit - 25-75% of

FVC.
METASTASIS: The spread of malignant cells throughout the body that

induces secondary tumours. When a cancer treatment fails,
metastasis is the primary cause of death. These secondary
tumours are called metastases.
METASTATIC FOCI: Groups of tumour cells far from the primary tumour.
MORBUS
BRONCHOECTATICUS: A disease which results in destruction of the elastic tissue of the
lung.
MYCOSIS: A general name of diseases caused by pathogenic

fungi.
NEOPLASM: New growth tumour.
NK CELLS: Natural killer cells - lymphoid cells of the spleen,

lymph nodes and peripheral blood which have the natural ability
to kill tumour, infected with viruses or bacteria target cells.
OTITIS: Inflammation of the ear.
PARENCHYMA: A totality of the basic functional elements of a given

organ, e.g. the specific tissue elements of the lung, liver,
kidneys, etc.
PATHOGENETIC: Pathogenic - causing disease.
PERITONEAL
MACROPHAGES: Macrophages of the peritoneal cavity.
PER OS: Through the mouth, by mouth.
PEYER'S PATCHES: Cellular substrate of the immune system - a lymphoid organ in

which the B-cells are situated.
PHAGOCYTES: Cells (leucocytes) capable of swallowing up and

processing bacteria, foreign particles and other cells.
PHAGOCYTIC INDEX: A measurement of non-specific hyperreactivity of the immune

system, manifested by an increased clearance of colloidal
carbon, which is accelerated in graft-versus-host disease.
PHAGOCYTOSIS: The ability of phagocytes to swallow up and make

harmless bacteria and foreign cells.
PHARYNGITIS: Inflammation of the mucous membrane of the pharynx.
PLANTAR EDEMA: Swelling of the sole of the foot.
PNEUMOLOGY: Lung diseases.
PNEUMONIA: Inflammatory process in the tissues of the lung starting

as a separate disease or as a manifestation or complication of
another disease.
PNEUMOSCLEROSIS: A lung disease.
PRIMARY ANTIBODY
RESPONSE: The response that the immune system displays
when it is first exposed to an antigen.
PROPERDIN: Protein in the normal blood serum of the group of

globulins having bactericidal and viral-neutralizing properties,
one of the natural (inborn) factors of the immunity.
PROPHYLAXIS: Prevention of disease.
PROTEASE
INHIBITORS: Substances suppressing the activity of the proteolytic
enzyme protease.
RESPIRATORY
SYNDROME: A
relatively specific
immune response
to high-dose
rifampin therapy.
RHINITIS: Inflammation of the mucous membrane of the

nose.
RIBOSOME: A nucleoprotein-rich organelle that is critical to

the translation of a mature mRNA transcript into a protein;
RIF: Reaction of immunofluorescence.
SALINE: Physiological solution
S.C.: Subcutaneous - under the skin.

SECONDARY ANTIBODY
RESPONSE: The enhanced immune response of an organism
when it is re-exposed to an antigen, after it has had sufficient
time to generate an immune recognition "cascade".
STAPHYLOCOCCUS
AUREUS: Grampositive bacteria gathered in the form of
clusters causing suppurative inflammatory processes.
SURFACTANT: A mixture of lipids and proteins lining the alveoli,

without which the alveoli would collapse upon expiration in
accordance with the laws of Laplace.
SUSPENSION: A mixture (disperse system) of fragmented particles of a

solid substance (disperse phase) in a liquid (disperse
environment).
SYSTEMIC: Related to the whole organism.
TARGET YAC-1
CELLS: Specific cell line used in cancerology.
T-LYMPHOCYTES: A type of lymphocyte which will amplify or suppress

antibody formation by B-cells, and can also directly destroy
"foreign" cells by activating "killer cells".
TONSILLITIS: Inflammation of the tonsils.

TRACHEOBRONCHITIS: Simultaneous inflammation of the mucous membrane of the
trachea and the bronchi.
TRACHEOTOMY: Operative opening of the trachea and insertion in it of a

special tube if there is danger of suffocation.
TUBERCULOSIS: An infectious disease caused by the tuberculosis bacteria

Mycobacterium tuberculosis; a frequent disease of the lungs,
lymph nodes, etc.
TUMOUR: A diseased growth in some part of the body.
VACCINE: A preparation made from live or dead cultures of

microorganisms, their toxins or antigens intended for active
immunization of humans and animals.
VIRULENCE: The pathogenic power of a given strain of

microorganisms, the degree of their pathogenicity with respect
to a certain animal type or to a human being.
VIRUS: Non-cellular life forms possessing chromosome

hereditary factors (DNA or RNA), but lacking their own
synthesizing apparatus, causing typical infectious diseases.
LIST OF PUBLICATIONS CONCERNING

FACTOR-R
1. Petrunov B., P.Nenkov, B.Dragulev, J.Tzvetanov. A study on Respivax - Polybacterial

preparation for oral immunotherapy and immunoprophylaxis of non-specific
respiratory diseases. - presented at 8th International Biotechnology Symposium, Paris,
July 17 -22, 1988.
2. Dragulev B., B.Petrunov, P.Nenkov, J.Tzvetanov. Physicochemical analysis and

immunological activity of the fractions of the drug "Respivax". - Workshop on
"Respivax", Sofia, 1988.
3. Josifov J., Sv.Bakalova, M.Kolarova, Sn.Stankova. Use of Respivax for prophylaxis of

bronchopulmonary infections in children. - "Pneumologia & Phthisiathria", v.26, No.1,
1989, p.20-23.
4. Dobrev P., P.Nikolova, Sn.Stankova, Vl.Maksimov, B.Petrunov, V.Radanova,

D.Minchev, V.Popov, Z.Chang. Prophylaxis of bronchopulmonary infections with the
Bulgarian immunostimulator Respivax - "Pneumologia & Phthisiathria", v.26, No.2,
1989, p.27-31.
5. Josifov J., Sv.Bakalova, M.Kolarova, Sn.Stankova. Application of Respivax in the

treatment of some acute lung infections in children using double blind trial. -
"Pediatria", v.27, No.3, 1989, p.110-112.
6. Tzetanov J., B.Petrunov, P.Nenkov, B.Dragulev. Immunomorphologic changes in the
lymphnodes and parenchymal organs of mice, subcutaneously and orally treated with
Respivax.- "Problems of Infectious and Parasitic Diseases", v.16, 1989, p.81-89.
7. Iliev I., V.Radanova, P.Petrova, Y.Yosifov. Clinico-immunological results from the

administration of Respivax in children with different pulmonary diseases. - "Pediatria",
v.29, No.1, 1990, p.55-61.
8. Garov S., Clinical results from the administration of the new Bulgarian
immunostimulating preparation Respivax in complex treatment of gingivitis catarrhalis
chronica.- "Stomatologia", No.4, 1990, p.55-61.
9. Petrovska J., L.Tzvetkova. Clinical - immunological study on patients with infectious -

allergic asthma treated with polybacterial immunostimulator Respivax - "Therapeutic
Archives, No.3, 1990, p.72-75.
10. Tzvetanov J., E.Janev, B.Petrunov, P.Nenkov, A.Momchilev, T.Markovska. Changes in

the pulmonary surfactant system in rats stimulated with polybacterial
immunostimulator Respivax - "Problems Infectious and Parasitic Diseases", v.18,
1991.
11 Petrunov B., P.Nenkov, J.Tzvetanov, B.Dragulev. A study on the effect of Respivax -

polyvalent vaccine for peroral immunotherapy and immunoprophylaxis of non-specific
infections of the respiratory tract - on the immune system. - JMEI, 1991, ( in press)
12 Kassabov K., Y.Stoychkov. Inhibition of spontaneous pulmonary metastases of Lewis

lung carcinoma by oral treatment with Respivax - Reports of BAS, v.43, 1990, No.12,
p.117-119.
13 Kassabov K., J.Stoychkov. Inhibition of spontaneous pulmonary metastases of Lewis

lung carcinoma by oral treatment with Respivax and Broncho-Vaxom -"Cancer
Immunology Immunotherapy", Springer-Verlag, 1991.
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Optimisation of Respivax's theraupetical scheme by determining the titer of the specific
antibodies to its bacterial components. - "Epidemol. Microbiol. Infec. Dis.", No.1,
1991.
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Evaluation of immunostimulants used in pulmologic practice. - "Internal medicine",
No.1, 1989, p.85-90.
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K.Jankov. Immunostimulators in clinical practice and the results of their application in
the treatment of the chest diseases. - "Drug Information", Varna, 1990, p.59-69.
17. Kisyova K., D.Petkova, K.Yankov, J.Radkov. Clinical effectiveness of the Bulgarian
immunostimulant Respivax in patients with inflammatory lung disorders. Proceedings
of the Simposium on Lung Diseases, 1990, Varna, p.7-10.
18. Vassileva M., Immunoprophylaxis and immunotherapy with Respivax of children up to
3 years. 2nd National Congress of Allergology, 1989, Sofia.
19. Klinkova M., Ts.Ljutskanova, M.Bosheva. Immunotherapy of infectious asthma. 2nd

National Congress of Allergology, 1989, Sofia.
20. Kassabov K., Immunotherapy with respivax and DEC of some experimental tumours,
Doctoral thesis, 1991, Sofia.
21. Damyanova-Surneva M., Kassabov K., Vassilev P.,Stoychkov J. Experimental research

into immunomodulating and antitumour properties of diethyleditiocarbamate-NIFF. 7th
Congress on microbiology, Varna, p.27-29, October 1989, Resumes of reports, p. 135.
22. Kassabov K., J.Stoychkov: Antimetastatic action of the new polybacterial

vaccine Respivax in mice bearing Lewic Lung carcinoma: Third Congress of the
Bulgarian Pharmacological Society, Sofia, 17-20 May, 1990, Abstracts, p.118.
22. Kassabov K., J.Stoychkov, B.Minev, T.Sedloev: Chemo - immuno prevention of solid
tumour metastases in mice. 1st International Conference on Chemo-Immuno
Prevention of Cancer (CCPC- 90), Vienna, Austria, August 24-25, 1990, Abstracts,
p.34
23. Kassabov K., J.Stoychkov: Immunotherapie orale des metastases pulmonaires par le
vaccin bacterial Respivax. XXI-e Semaine medicale balkanique, Varna, 2-5 Sept.,
1990. Resumes, p.136.
24. Kassabov K.,Damyanova-Surneva M., Stoychkov J.: Experimental research into

immunorestoration properties of diethyleditiocarbamate - NIFF. Annual research
session of NIFF, Sofia, December 14th, 1990.
25. Kassabov K., Damyanova-Surneva M., Stoychkov J.: Research into the effect of
diethyleditiocarbarmate - NIFF on the immune response of normal and
immunosuppressed with cyclophosphamide mice. Youth research session: Problems in
the creation of preparations, Panichishte, Bulgaria, February 25-27, 1991.
26. Kassabov K., Stoychkov J.: Effect of Respivax and Broncho-Vaxom on the function of
mice macrophages. Second national conference on immunomodulators, Sofia, May
31st-June 1st 1991, Resumes of reports, p.13
27. Stoychkov J., Kassabov K.:Comparative research on Respivax and Broncho-Vaxom in

tumour model.Second national conference on immunomodulators, Sofia, May 31st-
June 1st 1991, Resumes of reports, p.33
28. Minev B., Kassabov K., Stoychkov J., Neichev H.:Effect of Respivax on the
production of interleukin-1 in vitro.Second national conference on immunomodulators,
Sofia, May 31st-June 1st 1991, Resumes of reports, p.21.
29. Kassabov K.,Stoychkov J.:Combined therapy with DEC and Respivax-experimental

data. Second national conference on immunomodulators, Sofia, May 31st-June 1st
1991, Resumes of reports, p.13.
30. Christine Gorman, Are Some People Immune to AIDS?, Time, March 22nd, 1993.
31. Prof. As.Toshkov, Prof. V. Denchev, Immune System(in norm
and in pathology),1987.

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LifeChoice FACTOR-R Immunostimulant

Antibiotics, chemotherapy, cold medicines, antihistamines and a wealth of other products.

This created an unregulated subculture of vitamin gurus and natural/holistic medicine

Being non-medically trained, I have attempted to write the following in an understandable

Admittedly these compounds are a preferred alternative in most instances to no treatment at

1.1. Setting up of the problem

The treatments of those infections necessitate the administration of antimicrobial drugs

Immunoprophylaxis refers to effective control and removal of epidemic processes through

Vaccination - an Absolute Weapon

Original Antigenic Sin

Immunoregulation is not, however, the exclusive attribute of these endogenous parameters of

The Future of Immunomodulation

Therapeutic application of immunomodulation will lead to the discovery of the involvement of

1.2. Presentation of Factor-R

Factor-R is a polybacterial immunostimulant intended for oral immunotherapy and

HOW FACTOR-R WORKS AS AN ANTI-AIDS TREATMENT

a. acute, chronic and recurrent bronchitis and

b. acute and chronic tonsillitis, pharyngitis, laryngitis;

c. acute and chronic rhinitis, sinusitis, otitis;

e. infectious bronchial asthma.

Factor-R acts in synergy

2.1. Establishing the Immunostimulating Activity of Factor-R

2.1.1. Action on Antibody Formation

2.1.2. Determination of the spleen index in immunized mice

2.1.3. Protective action on infections in white mice

It is evident that when applied orally and subcutaneously

No. 1, 2, 5 are control groups of mice not treated with Factor-R.

In the Peyer's patches a hyperplasia, an enlargement of the T- dependent zone and a

No thickened alveolar septa, peribronchial mononuclear infiltrations and lymphoid

Bronchiole-alveolar inflammatory processes owing to different respiratory infections affect the

Materials and Methods:

Results and Conclusions:

1. Significant immunomorphological changes were observed in the Peyer's patches. The

4. Important immunomorphological changes were established in the lung in the parenchyma of

3.2. Examination of the effect of Factor-R on non-specific respiratory diseases in humans.

3.2.1. Application of Factor-R for prophylaxis of broncho-pulmonary infections in children

A basic problem of the medical practice in cases of

The children were divided into two groups:

(1) A group of 30 children treated with Factor-R

(1) The rate of secretory IgA in saliva

Before 10th 30th 60th 90th

Control 8,92 10,18

1.The application of Factor-R for prophylaxis of broncho-pulmonary infections in frequently

3.2.2. Prophylaxis of broncho-pulmonary infections with Factor-R in adults

In case of oral administration of Factor-R a protection of the respiratory tract is realized as a

4.The preparation has a very good tolerability.

3.3. Examination of the effect of Factor-R on mice

A significant increase (P<0.001) of DHR was established in the injected with

*p<0.05; **p<0.01; ***p<0.001

*p<0.05; **p<0.01; ***p<0.001

3.3.2. Effect of Factor-R and DEC on animals with implanted tumours.

Animals - normal and tumour-bearing mice.

3.3.2.1. Combined prophylaxis with cyclophosphamide and Factor-R

Significant difference from the group treated with CY only:

3.4 Immune mechanisms in the activity of Factor-R

2. In tumour-bearing mice oral administration of Factor-R caused an increase in

1. The activation of AM is the basic mechanism through which the peroral

2. The peroral medication has antimetastatic activity in animals with spontaneous

3. The combined therapy with Factor-R and cyclophosphamide led to more

Fig.28 Effect of Factor-R on the composition of the broncho-alveolar cellular

In a separate experiment we examined the effect of Factor-R on the peritoneal macrophages

Stability data of Factor-R

p<0.05; p<0.01; p<0.001

p<0.05; p<0.01; p<0.001