NOTE: This material is very likely superseded to some extent by The China Study, but is still very valuable.
by Hans Nieper, M.D.
I feel preventive medicine is the most important guideline at the moment to come to with less effort and less money to better results in the prevention and the protection of our health. So far as emerges out of my limited understanding of the American situation, my feeling is that if people would go more often for a preventative check-up they would, less frequently, run into trouble.
I think a few of you have already heard of the concepts of active mineral transports in directed therapy. I will give you a tour of horizons of what active mineral transport is and what it can do and how it is to be explained.
Late in the 1950's it was discovered that cells of the female breasts becoming malignant are going to lose magnesium so we thought why not conceive an extra-active transport of principle to take magnesium into these cells with the help of phenylalanine and paraminobenzoic acid. At the same time, Hans Selye's book on the prevention of myocardial necrosis with the help of potassium and magnesium chloride was published and so we developed, in fulfilling the requirements of more active transport of potassium and magnesium into the cell, the potassium-magnesium aspartate in 1957-1958. This became quite successful world-wide as a medicament for the protection of myocardial necrosis, enhancement of liver functions and the detoxification of digitalis. Since this has been so successful, we followed this concept of active mineral transport and we changed as well the mineral which had to be transported as also the molecules which are suitable to transport mineral into a cell by means of artificially created active transport. So the most important transporters we have today are aspartic acid, 2-aminoethylphosphoric acid and orotic acid; 2-aminoethylphosphoric acid (AEP) is a substance which plays a role as a component in the cell membrane and at the same time has the property to form a complex with minerals. You may replace the calcium by magnesium, potassium, iron or whatever. This substance goes into the outer layer of cell membrane, is decomposed there, incorporated into the cell membrane and releases the ion upon metabolization. The second substance, the aspartates, especially the L-aspartate, goes to the inner layer of the outer cell membrane and there, upon metabolization, releases the mineral to become the ion. The third substance which interests us enormously is orotic acid which forms a high complex salt with any mineral and which has no metabolic affinity to the outer cell membrane but penetrates the outer cell membrane even in the form of a complex salt and is only metabolized at the site of the membranes of the mitochondria and of the structures found in the cell plasma. Only here, the mineral will be released to the form of an ion.
So we have three different kinds of transporters: The AEPs (outer layer of the outer cell membrane), the aspartates (inner layer of the outer cell membrane) and the orotates (cell plasma organelles). All three substances are officially on the market in Germany and they play an important role in cardiology and hepatology for the aspartates. In the prevention and the treatment of multiple sclerosis, for the AEP, calcium potassium magnesium AEP is officially declared in Germany as the only active substance in the treatment of multiple sclerosis. The myelin is a multilayer of cell membrane and AEP goes there, fits as a membrane component in the damaged membrane in the case of multiple sclerosis, releases the calcium at the same time which shields against aggression by antibodies. The orotates are officially on the market for the treatment of numerous diseases, especially decalcification and immune aggression toward the cell. Keep this in mind: different transporters go to different structures inside the cell.
We will direct ourselves to calcium orotate. Calcium orotate really performs clinical effects in various diseases connected with decalcification and injury of bones which can rapidly be improved by means of the application of calcium orotate by using this new concept of active mineral transport since we know, especially in studies run in Zurich, that all formation of bone, more or less, is controlled by cell membrane and that the microgranules of apatit have to be formed inside the osteoblast and then released through the cell membrane again.
A patient's leg was sliced off with all attendant injuries of vessels. It was almost impossible to heal him by conventional means. He received calcium orotate for two years and he is now able to walk around. He telephoned me recently and said he is in excellent shape. This is one of the accidents and injuries which really needs calcium orotate to achieve the best results which obtained today in my opinion.
Bone fractures have been treated unsuccessfully for several months and years without formation of callus or healing. The bone fractures were due, in one case, to an immune arteriolitis. Upon application of calcium orotate, within six weeks the patient returned to normal functions and had no more complaints.
Especially in Europe, more than in this country, decalcification has to do with the higher carbohydrate intake. In Germany we have a tremendous amount of, more or less, severe damages in the dorsal spine. A 28-year-old patient suffered with juvenile decalcification and severe osteochondrosis. There was no help for this patient, not by hormones or conventional calcium. However, upon treatment with calcium diorotate he became normal in every respect within a few weeks and is still without any complaints.
Now here I have to stress a little bit the aspects of the transport by the orotates. The orotic molecule is mostly taken up by mesenchymal tissue and by bradytrophic tissue, especially by cartilage tissue and also by the vessel walls, by the blood-brain barrier and by the matrix of the bone. It is much less taken up by epithelial tissue such as liver epithelium glands, and so on, or mucous, in contrast to the AEP, for instance. We learned, during the months and years, that the improvement which we observed in dorsal spine complaints upon the application of calcium orotate, obviously had not so much to do with an improvement of the recalcification, or the improvement of the density of the bone tissue, but with the protection given to the tissue and cartilage surface by means of active calcium transport into cartilage tissue with the help of orotic carrying molecule. The orotic acid plays a very important role in so-called pentose pathway metabolism which accounts for the metabolism in cartilage tissue and especially for all organs which account for aging. There, the ribose coupling needs orotic acid and therefore obviously the orotic carrying molecule has a high affinity to this kind of tissue, like cartilage which, so far, we were unable to influence and which experienced even more damage under the influence of cortisone. Therefore, calcium orotate seems to me to be one of the most important substances to prevent cortisone side effects in, eg, rheumatoid arthritis. This is very important.
I could speak much longer on this problem. However I want you to have a certain impression. During the following years in which you will stay healthy with the help of orotates, you will be able to learn more and more about this. A 14-year-old girl unsuccessfully treated so far with every imaginable medication, was entirely relieved with calcium orotate, because the calcium orotate goes into this connective tissue which develops in the frame of this disease, as well as in the Perthes disease, as in Schlatter disease and in Recklinghausen's disease.
By the way, I have quite a few patients who after the intake of contraceptive pills developed cartilage damage. The application of calcium orotate allows the continuation of the intake of baby pills.
A patient with a severe osteochondrosis was almost entirely immobilized. After six weeks of treatment, there were no more complaints. Astonishingly enough, there is no parallel between the lack of increasing density of bone tissue and improvement, which again points into the direction that the origin of pain in spinal syndrome has to do with cartilage behavior less so with osteoporosis as such. A 64-year-old lady with severe decalcification and in severe pain had a disc slipped off a vertebra. She was treated unsuccessfully for years and is now without any complaints for two years. Although without any radiological improvements, she is fine. In the case of severe osteochondrosis in an 18-year-old patient, she was almost immobilized two years ago. She has now absolutely no complaints and is mobile, despite the fact that there is no change roentgenologic finding.
What we see in Europe in dorsal spine deformation is alarming. I do not know if you have a parallel in the United States. From the literature, I learned that decalcification problems in Europe play a much more important role than in this country because in the United States the protein intake is, on the average, higher.
We learned recently that Bechterew disease is an autoimmune disease related to rheumatoid form and astonishingly enough as well as the intravenous application of calcium AEP as the application of calcium orotate gives very important relief in these patients. We have the feeling that the application of the orotates blocks the immune processes which lead to an abnormal and ectopic calcification in these patients. They become partly remobilized and we have patients who gained about 20 degrees in upright positlon. Especially, there is no more pain. I have quite a series of Bechterew disease patients and they were always very much helped by this kind of treatment, where previously all other imaginable treatment failed. One patient had this disease for about 13 years and after 11 years of ailing we started the treatment with calcium AEP intravenously and calcium orotate; there were no more complalnts, she resumed normal housekeeping and gained about 20 degrees of an upright position. Another patient was an 82-year-old lady with excellent activity. Only in upright position she had unbearable pain and when lying down had no pain at all. This is a typical symptom for chondrosis. Upon impact on the cartilage the pain developed. After the treatment with calcium diorotate (3 gm/day) she had no more pain at all. She is going around in a Fiat sports car at 82 years of age.
Arthrosis of the hip shows good results with the treatment of calcium orotate. Of course, you cannot replace damage and lesion. However, we have the feeling that once the first signs of osteochondrosis develop, the long-time treatment with calcium orotate helps a lot and at least stretches out the time until eventually the arthrosis will have developed to become a surgical problem. The protection of the cartilage layer really is the mechanism which accounts for the prevention of osteochrondosls and of arthrosis.
We have quite a series of patients with severe osteoporosis with arthrosis on both sides who underwent operations and were previously, for about six months, treated with calcium AEP and calcium orotate. Surgeons reported a very important hardening of the spongiosal structure of the bone and all over it seems that the results, especially upon the implantation of the metal, seem to be much better after such a pretreatment than without it.
In Houston, Texas, four years ago at the Cancer Congress, I presented a series of patients who had developed metastatic disease, mostly breast cancers with bone metastases. We started about five years ago. This was the first clinical step with calcium orotate to try to recalcify these metastases. We found that calcium orotate has no side effects at all. It is more successful than sodium fluoride in the calcification of bone metastases, and we had excellent and reliable success in about 40% of all metastatic disease in the bone system. One patient had very severe lesions in the left hip. After treatment with calcium orotate for about eight weeks this patient was free from any complaints, the lesions were mostly recalcified. This patient, too, went around in a Fiat sports car without having any complaints.
Another patient came with 200 parts per million of serum calcium pretreatment with important doses of conventional calcium which resulted in hypercalcemia, a dangerous situation concerning the heart rate and heart metabolism, with thousands of metastases and practically in a terminal situation. After about four months of treatment with calcium orotate there was almost entire recalcification. The results speak for themselves: no more complaints.
This is calcium orotate, its effect on recalcification of bone metastases, on cartilage tissue and also on osteoporosis. Without any doubt, clinically, it is obvious that there is no calcium compound known which affects cartilage tissue and which prevents damage on pentose pathway tisssue such as cartilage. I feel this is quite a bit of progress in preserving our health and especially in preventing aging of tissue.
Another mineral transporter is the zinc aspartate which is officially on the market in Germany and offered as a medicament for the improvement in diabetes and of immune defense. It seems that the production of insulin is enhanced by actively transported zinc. Heinitz made quite an extensive report on this. In his study, diabetlcs received 40 units of insulin alone and in combination with zinc aspartate. The sugar tolerance becomes much better in the combination of 40 units of insulin and zinc aspartate than without the zinc aspartate. In the problem of diabetes, this is an important observation.
In a study out of our hospital, there are borderline diabetics, mostly early detected. They are treated exclusively with zinc orotate, no insulin. I feel that in the management of diabetes, a basic treatment with an actively transported zinc preparation, such as zinc orotate should be a must because it takes off the peaks of the ups and downs in the control of the diabetes. We have zinc orotate officially on the market in Germany as a substance which helps to overcome immune fatigue in cancer patients because zinc orotate activates the thymus gland and the formation of T informed lymphocytes. Zinc plays the role of a spark plug in cell bound desaminases which are actually the tool of the T lymphocyte to fight cancer cells. Therefore, we test all cancer patients for zinc levels. All cancer patients get actively transported zinc to protect the immune system from fatigue.
Now, again, let us come to another field, to cardiology. As I have pointed out, potassium-magnesium-aspartate, in many countries, with the exception of the United States, plays a very important role in the management of metabolic heart disease. Here is an outlook on the mortality from heart infarct or coronary disease at different times. We now have in Germany about 105,000 people who die each year from heart attack, much increased since the late 1950's (7,000 deaths per year). This was from a study by Bansi in Hamburg, Germany. However, it was found that the arteriosclerotic lesions stayed static, so obviously there is no important or no essential interrelationship between arteriosclerotic behavior of the vessel and death rate from cardiac infarct and cardiac necrosis.
We had a very interesting cardiological congress in Baden-Baden, Germany, last year, with participants including Laboris of Paris, France, and Baroldi of Milan, Italy, and from Houston, and Erhardt from Stockholm, who pointed out that the coronary thrombus develops only after the cardiac necrosis and not before in practically all cases. One came to the conclusion that occlusion in coronary vessels accounts for, at the most, 20% of the different factors which cause myocardial necrosis, and that they are mostly metabolic factors which lead to heart attack and cardiac necrosis. Baroldi, the former pathologist who worked with Dr. Denton Cooley in Houston, pointed out that despite occlusion of the coronary system there is sufficient collateral supply of all cardiac tissue so that there is no major reason to expect a necrosis to develop from insufficient blood supply.
We feel that there are other factors than arteriosclerosis and occlusion which account for the high incidence of cardiac infarcts. We know by now that potassium magnesium aspartate decreases very much the death rate from cardiac infarct. Our own study, taken over seven years time, shows a decrease of about 84%. This seems to be in line with an Australian study. In other words, under constant treatment with potassium magnesium aspartate we come back to the death rate from cardiac infarct that we had 20 years ago in Germany. Also, magnesium orotate prevents cardiac necrosis and so does potassium orotate, as Bujust pointed out. However, potassium orotate is not available on the market, for reasons of stability.
In a study of magnesium orotate, it was seen that magnesium goes into vessel walls, as I pointed out, with the help of the orotic molecule. We just recently completed a study which shows that increasing of vessel elasticity is best after treatment with magnesium orotate after one year or 1 1/2 years treatment. This substance is followed by the so-called EPL which means "Essential Phospholipid Substances," which are on the market in Germany. In arteriosclerosis we found a 94% success rate with magnesium orotate, about 60% success rate with EPL substances and almost no improving effect of clofibrate on vessei elasticity!
I conclude that just a laboratory cosmetic effect in decreasing cholesterol has nothing to do with improvement of vessel elasticity. On the other hand, magnesium orotate activates cholesterol esterases and mobilizes cholesterol. We observe quite often that in the beginning the cholesterol levels increase as the vessels are cleaned more and more, and only after 1 1/2 years do they go down to normal. In a study done in Munich, Germany, with magnesium orotate, there was an improvement in cholesterol lipids levels. Also, iron orotate is sold on the market in Germany now, it is a cell going ion transporter, and by the way it is manufactured by an American firm in Germany.
One of the most important factors in overcoming muscular fatigue and potential risk of muscular necrosis in the myocardium and to overcome an overspill of the lactate pool is to increase the formation of ATP. In a Japanese study it was shown that potassium magnesium aspartate enhances ATPases before and after potassium aspartate. In the gastroenemic muscle, the formation of ATP is very much enhanced upon the application of potassium magnesium aspartate. For the same reason, potassium magnesium aspartate today plays an important role in the enhancement of the host defense in the cancer patient: more formation of ATP. The Japanese thought of a decrease in the use of ATP but we found recently that we have to deal with more formation of ATP. This is very important, it is a key phenomenon in the understanding of the effect of potassium magnesium aspartate. The ions potassium and magnesium transported to the inner layer of the outer cell membrane activate the respective enzymes, which then result in the formation of more ATP.
Potassium magnesium aspartate was given to improve abnormal levels of alpha-keto-glutaric acid and lactic acid which develop upon the application of glycosides such as ouabain and Digoxin. This was one of our first studies and is now 14 years old. This study resulted in the fact that today many big firms in Germany, including Bayer, offer digitalis in combination with potassium magnesium aspartate in order to improve the tolerance of digitalis. This has been a very important observation. In several patients with a history of cardiac necrosis and respective complaints the lactate level is mostly improved by the application of potassium magnesium aspartate.
Now we come to a very important observation. A few years ago it was reported in Germany that the oral intake of ouabain resulted in a decrease in angina and, obviously, an important decrease in the death rate from heart attack. This observation was very controversial. This again resulted in very extensive studies which are mostly carried out in Dresden by the cooperative of Manfred von Ardenne. It came out of these studies that the decrease of the pH in the myocardium as a result of metabolic deficiencies and of metabolic damage and increase of lactate due to a decrease of blood supply and many other different factors, that this decrease of the pH results sooner or later in the labilization of lysosomes. As a matter of fact, the big myocardial necrosis develops only upon the release of lysozymes in the form of a chain reaction, in which lysosome enzymes again labilize other lysosomes so that an important release of the lysosomal enzymes results in a big necrosis. The Ardenne people were able to really point out that this mechanism has a very high likelihood. Or, on the other hand, that the increasing of the pH and the decreasing of the acidity, by decreasing lactate, for instance, results in a potential protection of lysosomes and therefore results in protection from cardiac necrosis. As a matter of fact these chain reactions, which develop by the lysosomal enzyme mediated labilization of other lysosomes, manifolds the lysosomal activity, and this has been shown experimentally. I refer you to the original papers which came out, especially in Germany, in Acta Cardiologica.
A very interesting experiment has been widely reported. The Ardenne people have special electrodes to measure in vivo the pH levels in myocardial tissue in the rat. Upon a ligation of a coronary artery, there is a decrease of the pH, which, as I said previously, may result in lysozymal activity. And upon the application of oral ouabain, there is again an increase of the pH, which may result in better protection. This is an experiment which may explain the observation that oral ouabain as well as potassium magnesium aspartate as well as magnesium aspartate protect one from potential cardiac necrosis.
Minerals, electrolytes and eletrolyte transport play a role in sustaining the normal function of the myocardium. In contrast to skeletal muscle, the cardiac muscle gets about 48% of its energy from fat. That’s why it survives in famine and hunger. The mobilization of energy from fat is performed by enzymes which are mostly controlled by calcium. Therefore, an active transport of calcium is very important to the myocardial muscle. We know by now that in the aging muscle there is a deficiency in transit of calcium. This has been shown by Fleckenstein and by Kaufmann. We know that calcium orotate in the aging heart muscle very importantly activates the release of energy from fat and from triglycerides. Therefore, it decreases triglycerides, converts them into energy. Most importantly, since there is no release of calcium ions from calcium orotate in the cell membrane, there is no electric disturbance on the myocardium upon the application of calcium orotate. This is a very important observation. There is not even a complication from toxic side effects when digitalis is given at the same time. However, in Switzerland, studies on 14-year-old dogs were done on a 14% slope. These dogs had on the average about 14 meters of walking way, then they had to arrest. Upon treatment with digitalis, these 14 meters increased to 15 or 16 meters. A combination of digitalis and potassium magnesium aspartate resulted in about 40 meters of running. And the combination of digitalis and potassium magnesium aspartate plus calcium orotate resulted in no arrest after more than 500 meters. This was a very important observation which has to do with the improvement of defective calcium transit into aging myocardium or into hypertrophic myocardium. This may give you a certain idea of how ions which work a spark plug in an automobile engine play a role in sustaining normal function of myocardium metabolism.
Potassium magnesium aspartate has an effect on supraventricular extrasystoles. This therapy very often results in an improvement of the clinical finding.
The ductile system of the myocardium is not a nerve system but rather a transformed muscle, cardiac muscle system, which is mainly based on pentose pathway or direct oxidation metabolism. This is exactly the tissue where the orotates go. I have the feeling that the prevention of potential danger to the ductile system of the myocardium will be one of the major indications of the orotate therapy. A patient had tachyarrhythmia, more than 1,000 mg% of triglycerides. Upon treatment of 4 gm of calcium orotate together with digitalis, there was a striking improvement. First, no complication of the combination of digitalis and calcium carrier because there is no membrane calcium deliberated. Second, the decrease of the triglycerides down to 400 because the conversion of the triglycerides to energy was very much improved. I think that this is a very modern aspect of protective myocardiology, very new and very recent. I have not read of this elsewhere so far.
In another study from a hospital in Mannheim, Germany, a patient with posterior wall infarct received potassium magnesium aspartate. A few days later they ran out of their magnesium potassium aspartate supply. The infarct pattern reappeared. And then they got a new supply into the hospital. And, again there was improvement.
You can substitute minerals and ions to either become active factors in enzyme metabolism or to become a component of structure, cell membrane, or bone. We can also think of using the release of ions in order to protect membranes and surfaces from immune aggression. This is a very old theory. Injection of calcium for the treatment of allergies. This mechanism of course can be manifolded by the application of an active transport principle. The Buchi cell membrane model shows two different pores. One is the active transport pore which accounts for the active transmembranal transport of nutritive substances like amino acids, sugars, hormones, etc. The other one is the free lipid pore which may allow the entry of unwanted material like infective agents, antibodies, toxins, especially when insufficient electrostatic compression of the cell membrane keeps these pores open. The 2-amino-ethylphosphate complex salts react with the membrane at the entrance of the free lipid pores and there release their ion, eg, calcium. We feel that this is an imaginable mechanism which explains the powerful shielding effect of calcium AEP of membranes against immune aggression. This is so in gastritis, multiple sclerosis nephritis, blood-brain barrier encephalitis disseminata and in pancreatitis.
An electron microscopy study performed In Muenster, Germany, by Moeminghoft, works with peroxidase injected into capillaries.
Granules, oxidase granules, are released into the micro villi. They penetrate the capillary membrane and penetrate into the micro villi. This shows that there is no sufficient shielding of the membrane to prevent the transit of peroxidase granules of active peroxidase.
For the test the system has been pretreated with calcium AEP. Thereafter there is no more transit of peroxidase into the micro villi. However, the exchange of nutritive substances is unchanged. Therefore, only the unwanted transit of unwanted substances will be blocked, but nutritive substances will not be kept out. This has to do with the phenomenon that the cell membranes have two different pores, one active transport pore, which accounts for the active transport and which is not affected by the release of calcium ion and of AEP, and then an uncontrolled exhaust, which can be controlled by calcium AEP in order to prevent the transit of unwanted material - viruses, antibodies, or, as in this particular case, peroxidase.
The same thing can be achieved, by the way, with the aspartates. It is lesser, but it is also effective for shielding of the capillary membrane against transit of unwanted materials.
Today the application of active calcium carriers is playing an increasing role in the treatment and management of immune disease. There was a three-year study of the effect of calcium orotate on chronic aggressive hepatitis. Some of these people were terminal cases. Included also are 12 cases of cirrhosis of the liver with ascites. The result is that after a treatment of about six weeks or up to 1 1/2 years, all aggressive hepatitis and all liver cirrhosis showed normal function and had no more sign of effective aggression. You are the first to learn about this because this is the first time that I have released this information to the public. We have at this moment a Volkswagen Grant to look into this problem further. The mechanism seems to be the following: According to the research done especially by Deborah Doniach, the mechanism of chronic aggressive hepatitis and practically all forms of liver cirrhosis is based upon the aggression by antimitochondrial antibodies, not on cell antimembrane antibodies. The calcium ion out of calcium orotate is released on the membrane of the mitochondria; at least this seems likely. The constant release of calcium ions at this specific site in the cells, and especially of the liver mesenchyma, results in an inhibition which slowly turns down the vicious circle of immune aggression and antigen release. After a certain time there is no more effective humoral aggression against the liver. This seems to be very effective and in addition to this since calcium orotate prevents side effects from cortisone, the combination of cortisone and calcium orotate gives an even better aspect.
Now, a few months ago, we started research work using lithium orotate. Lithlum orotate, also of course, goes in the blood-brain barrier and into pentose pathway tissue, especially into the glia, but also into the membranes of mitochondria and especially of lysosomes. What we have observed is the following: the release of the lithium in the membranes of lysosomes results in a depletion of sodium and the dehydration of lysosomal membranes. This means stabilization of lysosomal membranes so that there is no more release of aggressive enzymes. With the help of the combination of calcium orotate and lithium orotate, we are able to perform, within about four days, what we formerly were able to see in about one year using calcium orotate alone. Obviously, the treatment with lithium orotate results in an entire stop of the release of aggressive enzymes in chronic hepatitis. And after about four days or one week, or two weeks, the patients report healthy behavior and healthy feeling and there is no more sign of hepatitis. This problem is now being further studied in various hospitals and clinics in Germany. My feeling is that the continuous aggression of antimitochondrial antibodies may result in the labilization of these membranes. And once the labilization has developed, another principle becomes active: the release of aggressive enzymes. Chronic hepatitis is a two-step phenomenon. With the help of calcium orotate, in addition to lithium orotate, we probably will be able to control both situations and both conditions. I feel that we have made quite a step foward in the control of this disease, which, in Germany, plays a very important role.
I would like to make it perfectly clear how the mineral transport substances work. They release an ion at a site where we want it to be released. Hans Selye said once ten years ago in Hannover, Germany: We are able to write an address on the mineral, on the potential ion, and have it go where we want it to go so that it can exert its function. Either by activation of enzymes or by restoring structure or by sealing against potential aggression. It is a very simple, extremely harmless, but yet active principle.
Hans Nieper, MD, The Silbersee Hospital, Hannover, West Germany.