Safety issues

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Safety issues related to the possible transmission of xenoses.

German government submitted in 1997 to the German Supreme Court reports about possible transmission of zoonoses via ‘frischzellentherapie’, including infections allegedly caused by prions. The court discovery process showed that the sole case of ‘possible’ serious complication directly related to the fresh cell therapy was that of a patient who died of post-infectious encephalitis many years after fresh cell therapy in 1983, many years before the SBE panic, and the appearance of prions. As a result of the decision of the German Supreme Court on February 16, 2000, and since Germany is a scrapie-free country, the members of the Association of German Physicians for Fresh Cell Therapy have continued to use sheep as a source of fresh cell therapeutica.

P. Niehans, both a human and veterinary surgeon of high reputation earned in military during WW1, selected in the 30-ies sheep as an animal source for cell xeno-transplantation (that he named ‘cell therapy’), because sheep had been known as the healthiest of all domestic farm animals in Europe. VI.BIBLIOGRAPHY [157] He took an advice of a major Australian sheep producer, that advised him that he has not seen a single case of cancer in 40,000 mountain black sheep in three decades VI.BIBLIOGRAPHY [157], and set-up a farm near his clinic in Vevey, Switzerland, where he raised that breed of sheep to serve as the animal source for fresh cell therapy, and to the end of his days argued that patients treated by the implantation of black sheep cells are resistant to cancer. Despite his convictions P. Niehans did not hesitate to use pigs as animal sources of certain, in particular endocrine, organs and tissues, when he started an industrial production of lyophilized celltherapeutica in 50-ies, and the tests showed that clinical effectiveness of some of the pig cells was superior to his favored sheep.

In 50-ies when P. Niehans decided to widen the impact of cell therapy by offering preserved cells to the medical profession, his veterinarian, J. Miller, disagreed with his choice of lyophilization as the best method for cell preservation, and created a company that used quick freezing for the same purpose. J. Miller preferred horse fetuses for the production of cryopreserved ‘cell-therapeutica’. Some smaller companies used cattle fetuses instead. Thus the ‘grand-fathers’ proved the point, that as long an animal source fulfills the criteria of AAALAC, many different animals could be used for the manufacture of cell xeno-transplants, and when new animal comes onto the scene, it is not necessary to start the research all over again from the ‘big bang’.

In U.S.S.R./Russia the reason for a switch to rabbits was an economic disaster. In U.S. it may be an ecologic disaster: a discovery of a transmissible-to-man retro-virus in pigs may cause elimination of pigs from consideration. But then, the recent attempt in Australia to eliminate rabbits on a grand scale by introduction of viruses into rabbit populations may lead to another ecologic disaster that may disqualify rabbits as an animal source of cell xeno-transplants, too, whereby guinea pigs, rats, or mice, or fowl, or fish, become an animal source of fetal precursor cell transplants in the future. But it makes no diference: in all instances the rules of cell biology, including that of organospecificity, are the same, and all clinical experience collected to-date with cell transplantation using fetal precursor cells containing tissue fragments originating from animal or human fetuses still apply. If cell xeno-transplantation is to become a widespread method, ‘practical considerations and out-right cost-effectiveness’ VI.BIBLIOGRAPHY [37] come into play.

Safety data related to immune reactions

An experience with fetal cell xeno-transplantation was reviewed by the German Supreme Court over many years, and the Court ruled in February 2000 that ‘fresh cell therapy’ is safe. German medicine continues to be one of the best in the world, and Germans, the exemplary bureaucrats, tightly control everything, nothing ever happens ‘under the table’, so that German data are very reliable. Review of the court documents from Germany, as provided by Prof. Dr. Wimmer, top German constitutional lawyer, that represented the Association of German Physicians for Fresh Cell Therapy in the lawsuit against the German government, shows that of the estimated 800,000 patients treated worldwide by fresh cell therapy over the period of 70+ years there was only one serious complication ‘possibly’ directly related to fresh cell therapy. VI.BIBLIOGRAPHY [104] These statistics are remarkable, because the method of preparation of cell xeno-transplants by the school of fresh cell therapy has not changed for the past 85+ years, and is in the author’s opinion scientifically outdated. Method of fresh cell therapy exposes a patient / recipient to unnecessarily large antigen load, and it does not permit testing of cell xeno-transplants for the possible presence of zoonotic infectious agents.

Let's analyze these two issues.

German government submitted to the German Supreme Court reports of German ‘official’ immunologists describing dangerous acute rejection reactions as a logical consequence of fetal cell xeno-transplantation, but the specialists in fresh cell therapy have not seen such reactions in their clinical practices whatsoever, although the immunosuppression that they have used has consisted of no more than one small oral dose of cortison/antihistamine combination given to the patient 20 minutes before treatment. VI.BIBLIOGRAPHY [104] This is a fact that must be explained. U.S. immunologists are starting to publish data about ‘anergy’, ‘tolerance’, etc., and those terms express what they have recognized in their work, i.e. minimal reactions after discordant cell xeno-transplantation.

If there have been no serious immune reactions after fresh cell therapy, with all the deficiencies of the old method of preparation of fresh cell implants, it is not surprising that modern methods of preparation of fetal precursor cell xeno-transplants by tissue culture have eliminated them completely, which permitted Ministry of Health of U.S.S.R. to state already in 1984 in the ‘Regulations on cell transplantation’ that immunosuppression is not necessary with fetal cell transplantation, including when intraportal implantations are used, etc., if a correct method of tissue culture is used in the preparation of fetal precursor cell transplants.

From 1991 until 1997 the IIBM team under the leadership of the author never used immunosuppression with cell transplantation, even in newborns and small children, treated every 4 months, several times in a sequence, and reported during its December 1995 symposium in Moscow a complete lack of overt immune reactions in the treatment of around 3,000 private patients and many other patients included in multiplicity of clinical trials carried out at 15 top governmetal medical research centers..

Among the practitioners of cell therapy VI.BIBLIOGRAPHY [184] the lack of success of fresh cell therapy in the treatment of certain diseases, and diabetes mellitus was one of them, was well known. There are legends about the obsession of P. Niehans to solve the problem of treatment of diabetes mellitus, but despite his genius, he did not succeed. RITAOMH team proved that it could not have been done without the preparation of cell transplants by tissue culture. Despite the lack of overt immune reactions there are apparently some other kinds of reactions, not detectable by the current laboratory tests, perhaps autoimmune, that destroy implanted cell transplants prepared by the outdated method of fresh cell therapy to such a degree that their overall clinical effect is minimal to none, as for example in IDDM. With the continued improvement of methods of preparation of cell xeno-transplants, an area in which our team earned a major victory, the results of treatment of complications of IDDM have markedly improved as well. VI.BIBLIOGRAPHY [146, 147]

As the preparation of fresh cell therapeutica in Germany triggered an instant criticism let’s analyze the facts by comparing BCRO method of fetal precursor cell xeno-transplantation and fresh cell therapy.

The scientific principle behind fetal precursor cell xeno-transplantation (‘FPCXT’) and fresh cell therapy (‘FCT’) is the same. In both instances live cells of any & all animal organs and tissues from animal fetuses are implanted in a patient for the treatment of those disease(s), where such therapeutic method is indicated, essentially for a direct stimulation of regeneration of diseased organ systems, organs and tissues of the recipient.

However, there is a vast difference in the safety between FCT as still practiced today, and that of FPCXT when transplants are prepared by the method described in this book.

Preparation of fresh tissue fragments for FCT has not changed for the past 90 years, while fetal precursor cell xeno-transplants prepared by the described method from fetal and newborn rabbits follows the European Community Council Directive 2001/83/EC, and filed for U.S. Patent (U.S. Patent pending) and know-how includes pertinent parts of “PHS Guidelines on Infectious Disease Issues in Xenotransplantation”of January 19, 2001 (Federal Register, Volume 66, Number 19, pages 8120 – 1).

The key goal of the U.S. PHS regulations is to increase the safety of FPCXT for the benefit of the recipient patient, but also to minimize, or abolish, the medico-legal exposure of the treating physician as well as of manufacturer.

The above U.S. PHS regulations demand that the link between rabbit females as the sources of the fetal and newborn rabbit cadavers used for procurement of fetal precursor cell xeno-transplants, and a patient / recipient of FPCXT, is not interrupted throughout the entire preparation and treatment cycle, i.e. that it is forever known that fetal precursor cell xeno-transplants implanted in a body of a specific named patient were obtained from a pre-determined, well identified, group of fetal and newborn rabbits, with a documented genetic lineage, bred and reared in captivity, that in turn originate from a specific, well characterized group of rabbit females, bred and reared in captivity in a well established, licenses, closed colony of rabbits.

This link is thoroughly and permanently documented, and such documentation, as well as tissue samples from each such rabbit female, and samples of each fetal precursor cell xeno-transplant used for the treatment of a named patient, are stored for five years, also in liquid nitrogen. These frozen samples can be at any time compared with various specimens obtained from the recipient patient. In this way any doubts about a possible origin of any new illness in the patient / recipient of FPCXT can be completely and quickly eliminated.

FCT has not followed such regulations, and for that reason it has always had great difficulty to defend against accusations of transmission of zoonoses while under the attack by the pharmaceutical industry media campaigns.

Specifically the differences between FPCXT and FCT are:

A/ All BCRO fetal precursor cell xeno-transplants are prepared by a primary tissue culture, whereby there is an ample time for a close observation, i.e. eleven days, to ascertain that each primary tissue culture is free of any disease.

The tissue culture is not required by EC Directive 2103/83/EC, or by U.S. PHS regulations, it is a part of of BCRO’s patented procedure (U.S. Patent Pending) and know-how.

In FCT the dissection of the sheep (or other animal source) is carried out in a hurry, the tissue fragments are immediately loaded in syringes, and implanted within two hours from the time of hysterotomy; so that there is no time to pay attention to the quality and safety of the implanted tissue fragments whatsoever.

B/ The most important feature of BCRO’s procedure of preparation of fetal precursor cell xeno-transplants is an attainment of an almost complete immunological tolerance of fetal precursor cell xeno-transplants by the recipient as a result of which there is no need for an immunosuppression whatsoever, or even a premedication, as practiced by FCT, since clinically detectable reactions of patient’s immune system to FPCXT are not observable or measurable.

With BCRO’s method of preparation of cell xeno-transplants an elimination of 99% of cellular ballast of each cell xeno-transplant takes place, whereby the patient’s immunological load is substantially decreased, and then antigenicity of cell xeno-transplants is cut to a minimum by the described in this book manufacturing steps.

None of this happens with FCT, and that’s why immune reactions to the implantation of ‘frischzellen’ are unavoidable. Because of that the ‘official’ immunologists cannot be convinced of the safety of FCT.

C/ In FPCXT prepared by the described in this text method all fetal and newborn rabbits used as animal sources of cell xeno-transplants originate from a closed colony.

Closed colony is an enclosed unit, suitably ecologically located, where rabbits, with selected genetic lineages, are bred and reared for generations, in order to be protected from the dangers of the surrounding world to the highest degree possible by ecological means. They cannot get infected from other rabbits, or other animals, or by insects or vermin, or by humans: only a minimum number of rabbit handlers, and a veterinarian, are permitted an entry into the closed colony, and all these humans are subjected to regular medical examinations, are properly attired, and are excluded from entry when they become ill. Feed is pasteurized, prepared by a certified manufacturer. If a numerical expansion of the colony is necessary by intake of new rabbits, they have to come from a similar closed colony, and pass through a quarantine room, where they are observed and medically tested for 4 weeks to ascertain their good health. Once a rabbit is taken out of colony it is never allowed to return. When a new closed colony is established, the group of rabbits with pure genetic lineages, from similar colonies, has to be bred and reared together for at least 25 generations, i.e. around 24 months, before the colony can receive a designation ‘closed’. During this time of observation any genetic abnormalities, a carrier-state of some dormant infections, and other pathological conditions, etc., become noticeable in the new rabbit colony, and the affected animals can be eliminated. FCT has never used source animals from closed colony.

D/ The rabbits are observed daily by an experienced personnel, and at least once a week by a veterinarian. The medical records of each rabbit are kept indefinitely, and are linked to those of its predecessors for generations back. Thus the health status of the whole colony can be evaluated instantly, also historically during its entire existence.

The blood and excreta of each rabbit female are tested every 6 months, and the blood samples kept frozen for 5 years.

Upon death each rabbit female undergoes a full autopsy, samples of blood and four organs are obtained and kept frozen for 5 years.

As the first step of the manufacturing, each fetal and newborn rabbit cadaver, the source of cell xeno-transplants, is dissected by an experienced veterinary pathologist, and discarded if even the slightest abnormality is observed.

None of the above has ever been done with FCT.

E/ During the procurement, each tissue culture is inspected daily macro- and micro-scopically by a tissue culture expert.

Parallel with each tissue culture, another culture is grown in Layton flasks which is processed histologically to verify that each tissue culture included in the final (released) fetal cell xeno-transplant originates from a correct organ or tissue, and such histological preparations are kept for 5 years.

At the time of harvesting of a final fetal cell xeno-transplant a small sample of a supernatant of each cell xeno-transplant is placed in a vial and stored in liquid nitrogen for 5 years.

At the same time a bacteriological testing and a test for bacterial endotoxins are carried out for each fetal cell xeno-transplant.

The manufacturing facility, equipment, supplies, personnel, and the entire manufacturing process, packaging, labeling, and release of each batch of fetal cell xeno-transplant to be used for a treatment of a named patient, etc., are supervised by Quality Control department, and compared with standard procedures.

There is a full documentation of the preparation of each fetal cell xeno-transplant, as required by GMP (‘Good Manufacturing Practice’) standards, which is kept indefinitely.

None of the above is carried out with FCT.

F/ Clinical practice of FPCXT by BCRO method.

The BCRO procedure of preparation of fetal precursor cell xenotransplants by a primary tissue culture procedure, that is the final step in obtaining a nearly complete loss of immunogenicity, permits implantation of fetal precursor cell xenotransplant directly into the blood circulation, or into various parts of any organ, including brain, cerebrospinal fluid, without immunosuppression(!), that markedly widens therapeutic possibilities.

One of the key reasons for the high therapeutic success rate of FPCXT carried out by our clinical method is the fact that no immunosuppression has to be used with implantation. But a better understanding of what happens in the organism of the recipient after FPCXT, or of interrelationships of various simultaneously implanted fetal precursor cell xeno-transplants, plays a decisive role in such success, too. Some 25 years ago BCRO took the clinical experience of ‘zellentherapie’ as the basis for further study, and its current state-of-art clinical method is the result of many years of research and of diligent clinical observation.

Toxicological studies

No toxicological studies of fetal cell xeno-transplants have ever been carried out as they would be meaningless. Incidentally, studies of acute, subacute and chronic toxicity were carried out a few decades ago with lyophilized preparations of variety of organs by Prof.Dr. Neuman in Germany, and even 50-times higher than therapeutic doses did not cause any harm. VI.BIBLIOGRAPHY [95]