The remarkable role of peptide bioregulators for human health
(An interview with Professor Vladimir Khavinson)
In this interview, the current President of the International Association of Gerontology and Geriatrics, (European Region) and Head of the St. Petersburg Institute of Bioregulation and Gerontology, Professor Vladimir Khavinson, discusses with Phil Micans the role of peptide bioregulators and their ability to create a protective biological reserve for health and aging.
PM: “Professor Khavinson, it’s a privilege to talk with you today about the peptide bioregulators that you have discovered.”
VK: “Thank you Phil, of course this discovery was the result of much research.”
PM: “Indeed, I have read many of your papers and listened to your lectures. But for our readers, could you please describe how it all began?”
VK: “The journey began in the 1980s when I was a medical Colonel in the then Soviet army. The Kremlin was concerned about new American weapons such as a battlefield laser that would blind troops, or the fact that our submariners’ and missile silo operators were being exposed to low levels of radiation for long periods. They wanted answers that would help protect and maintain the troops’ health and indeed reverse various conditions. In fact, because of their jobs, some of these individuals were literally showing signs of premature aging; so we could say we were developing an antiaging medicine.”
PM: “Fascinating and presumably the resources of the State were behind you?”
VK: “Yes they were, and of course it was all a military secret then. I have to say that I don’t believe it would be possible to repeat much of our research today, because then we could virtually ask for what we wanted and it was made available. Today the cost would be very great for pure research- without a known goal.”
PM: “So what did you discover?”
VK: “We discovered and have widely published that short-chain peptides have a very important role. They are a short-cut to protein synthesis, that each gland/ organ uses a very specific peptide that acts like a gene switch; reinvigorating, triggering if you will a biological reserve. Accordingly, we have named them peptide bioregulators. Importantly we have shown that these peptides can be taken by mouth and make their way into the bloodstream.”
PM: “So, by assumption if one was to ingest the peptide bioregulator for the testes, could a man expect more testosterone release, is that the idea?”
VK: “Yes and often there are more functions beside, so in your example there is also increased spermogenesis.”
PM: “I am aware that these peptide bioregulators today have been patented and are registered on the Russian market as food supplements, how many do you have today and what areas do they cover?”
VK: “Regarding the bovine extracted peptides we currently have 17 manufactured on a regular basis; these are peptide extracts from blood vessels, thymus, cartilage, liver, brain, pancreas, pineal, bladder, stomach, eye, testes, heart, ovaries, prostate, adrenals, muscles and kidneys. Naturally we intend to add more as our research continues.”
PM: “Have any of these in particular proved to be outstanding in anyway?”
VK: “The pineal extract has had many outstanding results as can be seen in our publications, but all peptides to date have been effective.”
PM: “I know that the dosing of these peptides is quite unique, for example they don’t have to be taken every day. What do you normally recommend?”
VK: “Of course it depends on the need, but the biological reserve is created after a cycled dose and can be maintained for some time thereafter. In nearly every case the biological reserve is improved by 42%. Some individuals who are healthy and wish to maintain health can use as little as 2 capsules daily for 10-days and repeat it 6-months later. Others who require more than just maintenance may need 2 capsules daily for 30-days and repeat bi-monthly, however a lot of patients find their stabilizing dose between those two regimes.”
PM: “Have you used peptides in combination and found any synergistic effects?”
VK: “We have recently designed up to three peptides for various disorders to make these synergistic combinations. In all cases, the addition of the vascular peptide - Ventfort® - is a useful addition; obviously by improving blood supply this can have wide benefits.”
PM: “That’s very useful; IAS will print off that recommended combination list and include it with this interview. Clearly Professor, you have been involved in this fascinating project for many decades, in all that time how many patients do you think it has been applied to and what side effects or contraindications have there been?”
VK: “There are no known side-effects, or contraindications and our methods have been applied millions of times in tens of thousands of patients over decades.”
PM: “What are your thoughts today about these peptide bioregulators and where they might take the future of medicine and health?”
VK: “I think it may improve everyday life of seniors, who constitute the most vulnerable group of population. Europeans and America are getting older and living longer than ever before, nearly 10 years more than in 1960. Increased longevity is a great achievement and a great challenge. It is our task to turn challenges into opportunities and to make the most of the chances offered by the scientific community. Peptides will bring medicine and health systems to a new level with an accent to preventive medicine which will help to enhance human vital resource and add life to years.”
PM: “Professor Khavinson thank you very much for your insight into this remarkable research. I firmly believe that peptides are going to become a major focus in our field. Congratulations on your intriguing research.”
Introducing The Peptide Revolution - A video about the development of Peptides during the cold war. Russian leadership noted 'Premature Aging Syndrome' in personnel working in certain dangerous conditions and provided the resources for Professors Khavinson and Anisimov to make groundbreaking discoveries. Today Peptides are routinely sold over the counter in Russia and it has taken the West many years to understand and take note of it's interesting properties and effects of the Peptide Revolution.
Vladonix® A report of the results of clinical study of the biologically active peptide bioregulator of thymus origin: The biologically active peptide bioregulator Vladonix® contains a complex of low-molecular peptides with molecular weight up to 10000 Da, isolated from thymus of young animals - calves aged up to 12 months.
INDICATION FOR USE
immune system regenerator and regulator
Recovery from Cancer
Recovery from Stroke and Heart Attack
The thymus gland primarily serves a significant role in the maintenance and preparation of T-lymphocytes which is an important type of white blood cell. It is in control of the proper function of the immune system, which protects the body against harmful diseases, viruses and bacteria.
Bioregulator Vladonix - is a thymus extract and contains all the most important thymus peptides. For the extraction of peptides only thymus tissue are used derived from calves and pigs younger than 11 months old. All young animals come from farms in which no diseases were registered, which are dangerous to humans, including BSE.
By taking the bioregulator Vladonix in the body is an enrichment of the pool of regulatory peptides of the thymus tissue. Thus, the use of the bioregulator Vladonix promotes the normalization of the levels of the peptides in the thymus tissue cells. This in turn leads to normalization of metabolism in thymus cells and regulate their functions. Thus, the preparation helps to normalize cellular metabolism in the cells of the immune system and restore the body's defenses.Vladonix - clinical studies
Clinical studies revealed the efficiency of bioregulator Vladonix in the complex restoration of the immunity after different diseases, in case of pathological states causing disorders of immune system functions, in case of extreme factors impact, malnutrition and also in aging. No side effects.
Cerluten®A report of the results of clinical study of the biologically active peptide bioregulator of brain origin:
On the basis of the data received it is justifiably to draw a conclusion that activation of reserve capacity of the brain cortex using Cerluten® helps to improve integral functions of the brain.
Thus the results of clinical study testify the efficiency and expediency of use of Cerluten® for complex treatment and prophylaxis of the diseases of the central nervous system of various origins.
Cerluten® does not result in side effects, complications and drug dependence; there were no contraindications for carrying out of clinical studies.
Cerluten® can be used for treatment and prophylaxis, including in combination with any means of symptomatic therapy, used for neurological practice (vascular, nootropic, resolving, anticonvulsants, vitamins etc.)
Recommendations for use
Cerluten® is recommended for acceleration of restoration of the brain functions after the craniocerebral injury, stroke, intellectual disorders and the influence on the organism of various extreme factors. It’s also indicated to elderly people for maintenance of the mental capacity.
It is recommended to take Cerluten® per os 10-15 minutes before meals 1-2 capsules 2-3 times a day for 10-20 days.
It may be desired to have one more course in 3-6 months.
There are no contraindications and side effects for Cerluten® administration.
1. Kovalev G.V. Nootropic medicines. - Volgograd: Nizh.-Volzh. publishing house, 1990. - 368 pages
2. Treatment of nervous diseases: Translated from English/ Edited by V.K.Viderholt. - M.: Medicine, 1984. - 560 pages
3. Mashkovsky M.D. Medicines: Pharmacotherapy for doctors, manual: 2 parts. - Vilnius: ZAO “Gamta”, 1993.
The biologically active peptide bioregulator Cerluten® contains a complex of low-molecular peptides with molecular weight up to 10 000 Da, isolated from CNS of young animals - calves aged up to 12 months.
Cerluten® is manufactured in the form of capsules with a content of active substances of 10 mg.
Experimental studies have shown that the peptides possess tissue-specific action on the cells of the tissues from which they were isolated. Cerluten ® peptides regulate metabolism processes in the brain cells, increase brain safety margins, having a favorable effect on the organism adaptation processes in extreme conditions, the possess anti-oxidative properties, regulating peroxide oxidation processes in the brain cortex. So it is possible to extrapolate an efficiency of administration of Cerluten ® for restoration of the function of the central nervous system and its disorders of various origins.
Treatment of central nervous system diseases is of specific urgency, because they lead to social adaptation disorder and invalidation of patients (2).
Now the treatment of patients with disease of central nervous system diseases in view of pathogenetic mechanisms is carried out using the following traditional therapeutic agents of various action types: (1, 3)
The control group consisted of 37 similar patients, which have only general purpose treatment.
All the patients have been taking symptomatic and pathogenetic drugs, these drugs have resulted in short-term therapeutic effect, which required increase in a dose of the drugs per treatment course and duration of their administration.
Visoluten, vision and retina peptide complex supports vision health and performance by enhancing the quality of the retina, the cornea and the eye blood vessels. Visoluten® is the retina peptide bioregulator.
Prevents spasms, glaucoma, and cataracts
Angiopathy of the Retina
Prevent Retinal Degeneration and Detachment
Maintain the Functions of the Visual Analyzer
Spasm of Accommodation
The optimal function of the human visual organ is directly related to the state of the cells of the eye tissues - retina, lens, vitreous body and cornea. For the optimal function of the cells is their optimal supply of nutrients such as vitamins, minerals, and with peptides required. The peptides are components of the protein molecules and are released during protein metabolism (Disintegration of the protein into smaller fractions = peptides). The peptides are information molecules, which influence gene expression and start the process of protein synthesis. Formation of proteins is a vital process. This is necessary for the growth of the cells and performing its key features.
Visoluten includes the peptides obtained from the eye of young animal that improve the health of the visual analyzer by interacting directly with the retinal cells, the ciliary muscle and the conjunctiva. Peptides activate the synthesis of the specific proteins, capable of restoring tissues, damaged by a disease or with ageing. Treatment by Visoluten allows to reduce severity of complicated high myopia, pseudophakia and achieve significant positive dynamic in visual functions.
Visoluten eye extract contains natural peptides. These are molecules that play a key role in various biological processes in our body. They take care of information processing and transfer, as do hormones, by carrying messages from one tissue to another.
Fig. 3. Expression of transcription proteins (PAX 1) in human thymus epithelial cells (the study was conducted in cooperation with Prince Philippe Biomedical Research Center, Valencia, Spain).
In the 1970-ies we began investigation in the mechanism of immuno-depression both experimentally and clinically. We found out that with ageing there takes place an involution of the central organ of the immune system — thymus (Fig. 2, 3) and that of the neuroendocrine system — pineal gland. We also registered definite decrease of protein synthesis in cells of different organism tissues (Fig. 4).
To restore functions of thymus, pineal gland and other organs we developed a special method for isolation and fractionating of low-molecular peptides from extracts of these organs [24, 25].
On the organism level we have registered in different animals a significant variety of biologic effects exerted by small peptides especially by peptides of thymus (pharmaceutical “Thymalin”) and pineal gland (pharmaceutical “Epithalamin”) [3, 8, 13, 15, 36, 45, 46, 53, 57].
Fig. 1. Potential increase in the average human lifespan up to the specific limit (biological reserve).
genes which regulate mechanisms of individual development and the onset of diseases .
The influence produced on gene expression permits correction of cell proliferation and differentiation decreased with age [26, 49]. The study of genetic mechanisms of ageing and development of age-related pathology underlies regulatory therapy — the employment of modulators of transcription, deterring and restoring genetically conditioned alterations occurring with age. It is important to know the genome, occurring disorders and to use substances producing selective effect on gene expression .
Designing of effective bioregulators which would contribute to the achievement of special life span limit and maintain major physiological functions constitutes a vital issue in modern biogerontology. Investigations in the problem focus on the role of peptides in prevention of premature ageing [36, 49].
Peptidergic regulation of homeostasis occupies an important place in a complex chain of physiological processes leading to the ageing of cells, tissues, organs and an organism in whole.
Morphological and functional equivalent of ageing consists in the involution of organs and tissues, primarily those referred to major regulatory systems — nervous, endocrine and immune ones. The data available suggest occurrence of age-associated hypoplasia, and in some cases even an atrophy of the pineal gland, thymus, brain cortex neurons and subcortical structures, retina, vascular wall, genital organs .
Fig. 6. Effect of pineal gland preparation on the frequency of tumor incidence in animals.
spontaneous and induced by irradiation or carcinogens (Fig. 6) [5, 9, 10, 16, 87]. It should be emphasized that this unprecedented decrease of tumour incidence was found in the majority of experiments (Table 1). Taking into consideration the general mechanism of carcinogenesis in all mammalians the results of these investigation have a great practical significance for tumour prevention in humans [10, 52].
Small peptides isolated from different organs and tissues as well as their synthesized analogues (di-, tri-, tetrapeptides) revealed a pronounced tissue specific (gene specific) activity both in cell cultures and in young and old experimental animals (Fig. 7).
Peptide tissue specific activity manifested in stimulation of protein synthesis in cells of those organs they had been isolated from. The enhancement of protein synthesis under the effect of peptide has been registered in young and old animals (Fig. 8).
Especially significant appeared restoration of reproductive function in old female rats subjected to the pineal peptide preparation treatment . Thus, estrus phase in animals, analogous to menopause in women, lowered from the initial 95% down to
52% after the drug administration, while other phases of the cycle, typical of the normal estrus, increased from the initial 5% up to 48%. Another experiment revealed that none of the old female rats got pregnant after mating with young males. Repeated mating after the administration of the pineal gland peptide preparation entailed pregnancy in 4 out of 16 animals which gave birth to 5–9 healthy off-springs each. Thus there were ascertained main advantages of low-molecular peptides as compared to high-molecular protein regulators: they possess high biological activity, reveal tissue specificity and are
For many years the phenomenon of ageing had been studied within the framework of ethics and social issues. Only in the last century the society realized that the process of ageing should be studied from a different viewpoint, that is, as a special physiologic mechanism bearing a certain evolutionary significance [26,30,67].
Ageing is the most complicate issue in medicine and biology. The process of ageing is a gradual involution of tissues and development of organism malfunctioning. Its symptoms appear already at the end of the reproductive period and become more pronounced with ageing .
At the end of the XIX century I. Mechnikov showed that enhancement of cellular immunity contributed to a lifespan increase. He developed a phagocytic theory of immunity and considered human organism capable of combating pathologic ageing . In 1908 he was awarded the Nobel Prize in Physiology or Medicine together with P. Ehrlich. And only one century later, P. Doherty and R. Zinkernagel conducted detailed studies in specificity of cellular immunity in case of viral infection (the Nobel Prize in Physiology or Medicine 1996).
J. Watson and F. Crick jointly with M. Wilkins were awarded the Nobel Prize in Physiology or Medicine in 1962 “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”.
In 1961 F. Jacob and J. Monod suggested a model of genetic regulation of protein synthesis with the participation of low molecular ligand, which ousts repressor and triggers allosteric conformational transition in the DNA structure of bacterial cell . In 1965 they were awarded the Nobel Prize in Physiology or Medicine along with A. Lwoff. Many years of scientific work by M. Nirenberg and G. Khorana resulted in deciphering genetic code and defining codons (triplets of nucleotides) for each of twenty amino acids (the Nobel Prize in Physiology or Medicine, along with R. Holley, 1968).
Fundamental investigation in nucleic acids biochemistry and identification of RNA and DNA bases sequence were conducted in the 60-ies and 70-ies of the XX century by P. Berg, W. Gilbert and F. Sanger (the Nobel Prize in Chemistry, 1980).
Experimental and clinical studies in gerontology evidenced that immunity of the organism is among the first systemic functions to reveal disorders with ageing [22, 31]. Thymus peptide extracts and peptides, isolated from these extracts, were the first preparations suggested for immune deficit correction [21, 27, 29]. The origin of small regulatory peptides pool in a young organism became evident after the discovery of ubiquitin-mediated protein degradation in proteasomes made by A. Ciechanover, A. Hershko, I. Rose (The Nobel Prize in Chemistry, 2004). Small peptides were shown to play an important role for transmission of biologic information, as for example autocrine hormones and neuropeptides do. A high molecular protein can be hydrolyzed in different ways, degradating into several small peptides. Due to this mechanism there can be produced peptides with completely different biologic functions as compared to the maternal macromolecule . S. Karlin and S. Altschul proved in their works that there are several types of recurring blocks of amino acid residues with charged side chains in protein macromolecules. Nuclear proteins: transcription factors, centromere proteins, and HMG proteins — reliably contain the greatest number of such blocks . Proteasome hydrolysis of these proteins in the nucleus can provide presence of the sufficient amount of peptides with charged side chains.
However, the regulating role of small peptides had never been discussed in the concepts of gene control of protein synthesis in higher organisms before we started the research.
Alongside with immunity decrease associated with age there occur other alterations on cellular level. In particular, there take place changes in the inner structure of cellular nucleus. DNAprotein complex of cellular nucleus (chromatin) gets organized into chromosomes only in case of cell division. In stationary state chromatin is found in two forms: euchromatin and heterochromatin . Heterochromatin is usually localized in the nucleus periphery and contains generally inactive part of genome: genes blocked by repressors. The ratio euchromatin/heterochromatin changes with ageing due to reduction of active euchromatin. This leads to the decrease of protein synthesis in a cell .
Thus ageing phase of the organism reveals several levels of dysfunction and may be classified as a systemic syndrome. Promising results of immunodeficiency correction by endogenous regulatory peptides testified the necessity of further enhanced studies [27, 29, 31].
Discovery of peptide regulation of ageing
It is known that specific limit of animal and human lifespan is approximately 30-40% higher than their mean lifespan. It could be referred to the impact of adverse factors causing changes in the gene structure and expression accompanied by disorders in the protein synthesis and organism functioning (Fig. 1).
Specific limit of human lifespan — 110–120 years.
Recent achievements in theoretical and applied gerontology allowed goal-seeking regulation of ageing-associated alterations. Therefore, one of the priorities of gerontology today consists in prevention of premature ageing and age-associated pathology, finally aimed at the increase in an average lifespan, maintaining active longevity and reaching an upper limit of human life [30,51].
The integration of findings made by fundamental research into medicine resulted in a better understanding that clinical progress largely depends on molecular medicine, i.e. investigations conducted in genes and biologically active molecules. The achievements in genetics, molecular and cell biology often underlie molecular medicine in designing new pharmaceuticals and technologies.
The studying of genetic mechanisms of ageing is in the forefront of molecular medicine today. There have been defined
Peptide regulation of aging
Fig. 5. Peptide preparations effect on mean lifespan andreactionof blast-transformation of lymphocytes with phytohaemagglutinin in mice.
In numerous experiments, these peptide preparations contributed to a reliable increase in animal mean lifespan up to 25–30% as compared to control [4, 5, 9, 16, 24, 25]. The majority of experiments registered some increase in the maximum life span. The most significant effect in the increase of the maximum life span was noted in CBA mice administered with peptide Ala-Glu-Asp-Gly. It made 42.3% . Of particular importance is a correlation between mean lifespan and the main index of cellular immunity
(reaction of blast-transformation of lymphocytes with phytohaemagglutinin) determining T-lymphocytes function in animals exposed to the effect of thymus and pineal gland preparations (Fig. 5) .
A significant increase in the mean lifespan of animals was evidently caused by a reliable anti-tumour activity of low-molecular peptides isolated from thymus and pineal gland which is confirmed throughout 55 experiments during 35 years. The animals manifested a sharp 1,4–7-fold decrease in malignant tumour incidence, both
Fig. 8. Effect of the liver and pineal peptide preparations on protein
synthesis intensity in hepatocyte monolayer culture in rats of different age.
On the level of cellular structures, small peptides activate heterochromatin in the cell nuclei in senile patients and facilitate the “release” of genes suppressed as a result of heterochromatinization of chromosome euchromatin areas (Table 2) [48, 74]. Structural condensation of chromatin is in close correlation with functional heterogeneity. Heterochromatinization is known to increase with age and correlate with inactivation of genes which were formerly active . Tightly condensed heterochromatin areas of chromosomes are genetically inactivated and replicate lately.
Decondensed (euchromatin) areas of chromosomes function actively. Active chromatin is obviously a necessary factor for gene transcription activity . As it was said above there are two forms of chromatin in the cellular nucleus: light euchromatin and dense heterochromatin located near nuclear membrane. Gene transcription takes place in the light phase, that’s in euchromatin. The amount of heterochromatin in the nucleus increases with ageing on average from 63% to 80%. Regulatory peptides entail the increase in the
Fig. 11. Overcoming human somatic cell division limit due to introduction of the peptide into the culture of the pulmonic fibroblasts.
Fig. 9. Induction effect of retinal peptides on the polypotent cells of Xenopus laevis early gastrula ectoderm.
Addition of small peptides to ectoderm polypotent cells in the same experimental model led to the onset of various tissues. These experiments showed that peptides are able to induce cell differentiation in regard to the structure of the substance added. The analysis of results obtained gives every ground to conclude that it is quite possible to induce deliberately differentiation of polypotent cells and to use biological reserve of various organs and tissues of the organism contributing to prolongation of life up to species limit.
The number of chromosome aberrations is used as a marker of DNA damages in an ageing organism. Somatic mutations can occur due to accumulation of stable aberrations and underlie age-related pathology, including malignant neoplasia . Reliable antimutagenic and reparative activity of thymus and pineal gland peptides have been confirmed by a reduction in the number of chromosome aberrations in the bone marrow cells and cornea epithelium cells in animals revealing accelerated ageing [14, 19, 49, 69].
On the level of gene activity regulation it was established that administration of peptides Lys-Glu and Ala-Glu-Asp-Gly to transgenic mice caused a 2—3.6-fold suppression of HER-2/neu gene expression (human breast cancer) as compared to the control group. This suppression is accompanied by a reliable reduction of the tumor diameter (Fig. 10) [15, 49].
It was revealed that addition of tetrapeptide Ala-Glu-Asp-Gly to the cultural medium of human lung fibroblasts induces telomerase gene expression and contributes to a 2.4-fold lengthening of telomeres. Activation of gene expression is accompanied by a growing number of cell divisions (by 42.5%), which is the evidence of Hayflick’s limit overcoming (Fig. 11) [40, 41]. This fact fully correlates with earlier stated maximum increase of animal life span (42.3%) after administration of this peptide .
Fig. 7. Peptide tissue-specific (gene-specific) regulation.
neither species specific nor immunogenic. These features make regulatory peptides similar to peptide hormones [1, 4, 18].
A detailed study of molecular weight, chemical properties, amino acid composition and sequence of low-molecular peptides isolated from thymus, pineal gland and other organs had been carried out for many years [77, 78, 79, 80, 81]. The obtained data were used for chemical synthesis of several small peptides. A comparative analysis showed that biological activity of natural and synthetic preparations was largely identical. Thus, for example, thymus dipeptide Glu-Trp stimulated immunity, decreased ageing rate and suppressed occurrence of spontaneous tumours in animals [78, 80].
Biological activity of natural and synthetic peptides appeared to be similar in standard testing in tissue cultures and in animals [11, 12, 17, 42]. These results demonstrate prospects for application of these peptides as geroprotectors [37, 64, 71]. The necessity of searching for new drugs — geroprotectors dictated the onset of preclinical studies of these preparations on different structural levels.
Fig. 10. Peptides effect on the development of mammary adenocarcinoma and HER-2/neu oncogene expression in transgenic mice (the study was conducted in cooperation with the National Research Centre on Ageing, Ancona, Italy).
The effect of di- and tetrapeptides Lys-Glu, Glu-Trp, Ala-Glu- Asp-Gly, Ala-Glu-Asp-Pro on the expression of 15 247 murine heart and brain genes before and after peptides administration was studied with the employment of DNA-microarray technology .
In this experiment, there were used clones from the library of the National Institute on Aging, USA. This experiment provided unique data on alteration in the expression of different genes under the effect of peptide preparations (Fig. 12). An important conclusion driven from the experiment was that every peptide specifically regulates particular genes. Results of this experiment testify to the existing mechanism of peptide regulation of gene activity. It was also registered that dipeptide Lys-Glu, showing immunomodulating
amount of euchromatin in the nucleus. This means that more genes become available for transcription factors, and transcription of gene information goes on more intensively as well as protein synthesis.
In other words the more euchromatin there is in the nucleus, the more intensive the protein synthesis goes on in the cell [48, 74, 75].
These experimental results brought us to a conclusion that chromatin heterochromatinization is a reversible process which confirms a possibility of restoring protein synthesis, hence, organism functions .
The capability of peptides to induce polypotential cells differentiation is of special significance (Fig. 9) . Thus addition of retinal peptides to polypotential cells of Xenopus laevis early gastrula ectoderm led to the emergence of retinal and pigment epithelium cells. This outstanding result explains a pronounced clinical effect of the preparation of the retina in patients with retinal degenerations  and in animals with genetically determined retinitis pigmentosa .
Fig. 12. Peptide effect on gene expression in the heart of mice (the study was conducted in cooperation with the National Institute on Aging, Baltimore, USA).
activity, regulates gene interleukin-2 expression in blood lymphocytes .
On the molecular level, there was an obvious gap between multiple evidence of specific effects, caused by regulatory peptides in activation of gene transcription [6, 14, 23, 47, 52, 60, 69, 72, 84], and limited schemes of the process underlying the selective binding of the transcription factor with specific DNA sites. Meanwhile nonspecific binding of proteins with the DNA double helix was proved by physicochemical methods . Activation of gene transcription in cells of higher organisms as a rule needs dozens of macromolecular activators and transcription factors.
We proposed a molecular model of interaction between regulatory peptides and DNA double helix in gene promoter region (Fig. 13, 14, 15, 16) [63, 65].
Geometrical and chemical complementarity of peptide amino acid sequence and DNA nucleotide pairs sequence was assumed as a basis for the molecular model. Regulatory peptide recognizes a specific site in the DNA double helix if its own amino acid sequence is complementary to the DNA nucleotide sequence for a sufficient
Fig. 13. Unfolded peptide Ala-Glu-Asp-Gly conformation (plane projection). There are shown end and side functional groups, capable of complementary interaction with DNA.
length. In other words their interaction is specific due to matching
sequences. Each sequence of the DNA double helix nucleotide pairs forms a unique pattern of functional groups on the surface of the DNA double helix major groove. A peptide in the unfolded - conformation can complimentary fit into the DNA major groove along the double helix axis. We used data on molecular geometry of the DNA double-helix and peptide -thread from scientific
Fig. 14. Metric location of functional groups exposed onto the surface
of the DNA major groove in case of embedding of each nucleotide pai
into DNA double helix. Dash line - perpendicular plane, where
aromatic structures of nucleic bases are located.
—NH2 - proton donors groups;
=7N – proton acceptors groups;
—CH3 – hydrophobic (methyl) group.
publications in order to identify nucleotide pairs sequence for specific binding of the DNA and peptide Ala-Glu-Asp-Gly. The screening conducted showed that this tetrapeptide can be located in the DNA major groove with the ATTTG (or ATTTC) nucleotide sequence on the main chain in compliance with the complementarity of disposition of their functional groups .
For experimental testing of the molecular model there were used synthetic preparations: DNA [poly(dA-dT):poly(dA-dT)] (double helix) and tetrapeptide Ala-Glu-Asp-Gly. Gel chromatography helped to prove that peptide Ala-Glu-Asp-Gly forms stable intermolecular complex with the DNA double helix (Fig. 17) .
Complementary binding of the peptide with nucleotides sequence on the leading strand TATATA of the double helix can be conducted by six hydrogenous and one hydrophobic bonds between functional groups of both participants.
Fig. 16. Scheme of complementary interaction of tetrapeptide Ala-Glu-Asp-Gly with DNA double helix (“DNA-tetrapeptide” complex on the promoter segment of telomerase gene).
Under normal physiological conditions DNA exists in the form of a double helix two polymeric strands of which are kept together by hydrogenous bindings between pairs of bases of each chain.
Most of the biological processes with DNA participation (transcription, replications) need the double helix to undergo disjunction into separate strands. In particular, it is known, that local separation of double helix strands precedes gene transcription by RNA polymerase. For the transcription onset (synthesis of the matrix RNA) the DNA double helix has to be freed from histones,
Fig. 17. HPLC of peptide and DNA on sefadex G-25 in physiological solution at room temperature.
Fig. 18. The scheme of local separation of strands [poly (dA-dT) : poly (dA-dT)] as a result of peptide Ala-Glu-Asp-Gly binding in DNA double helix major groove.
and in the place where the matrix RNA synthesis starts, the strands of the double helix should be separated (Fig. 18).
Concentration dependent hyperchromic effect (increased optic density 260 nm) was found by spectrophotometery of solutions containing synthetic DNA double helix and tetrapeptide Ala-Glu-Asp-Gly. The hyperchromic effect points out a partial destruction of hydrogen bonds between nucleotide pairs of the double helix and local separation of its strands (allosteric conformational changes) .
It was experimentally revealed that separation (melting) of free DNA strands occurs at the temperature +69.5°С. In the “DNAtetrapeptide” system melting of the double helix occurred at the temperature +28°С and was characterized by approximately 2-fold decrease in the values of entropy and enthalpy . This fact points out a thermodynamically simplified way of the DNA strands separation in temperature settings typical of biochemical processes of the majority of living organisms. Thus, DNA strands separation under physiological temperature is not a denaturation but a typical feature of protein synthesis initiation. In vitro experiments show that a small peptide of the definite structure and amino acid sequence can participate in activation of genes transcription on the stage of strands separation in the DNA double helix. Biochemical aspect of this phenomenon consists in similarity of structure and amino acid sequence of a regulatory peptide and a specific segment of the peptide chain of the macromolecular transcription factor.
Thus, the studies of peptides biological activity on different structural levels and of physicochemical processes of their interaction proved an indubitably high physiologic activity of peptide regulators and prospects for their further use. Major conclusion reads that peptides are capable of regulating gene expression. Pre-clinical trials demonstrated high biological activity and safety of synthesized peptides [35, 43, 56, 58].
Thus, the administration of peptides Lys-Glu, Ala-Glu-Asp-Gly to animals contributed to a reduced incidence of tumours and an increase in their mean lifespan [39, 82, 88]. Peptide Ala-Glu-Asp-Pro stimulated nerve regeneration , peptide Lys-Glu-Asp-Trp decreased blood glucose level in animals with experimental diabetes mellitus , peptide Ala-Glu-Asp increased osseus tissue density, peptide Ala-Glu-Asp-Leu contributed to the restoration of bronchial epithelium cells functions , peptide Ala-Glu-Asp-Arg restored myocardic cells functional activity .
There are still in progress studies of peptide preparations isolated from the cartilage, testes, liver, vessels, urinary bladder, thyroid, as well as synthesized peptides regulating functions of the brain, retina, immune system, proliferation and differentiation of polypotent cells. These physiologically active substances possess, as a rule, a substantial tissue specific effect and are obviously useful for designing new drugs on their basis applicable in bioregulation therapy .
Application of peptide bioregulators in monkeys. Taking into consideration a reliable biological activity of peptides we found it reasonable to study the effect of regulatory peptides in monkeys (Macaca mulatta) . Restoration of the melatonin level in old monkeys (20-26 years old) up to normal (typical for young animals 6-8 years old) following administration of the peptide preparation was among the most significant achievements (Fig. 19) .
The same old monkeys revealed restoring to normal indices of a daily rhythm of secretion of the main hormone of adrenal gland — cortisol (Fig. 20). Administration of the peptide or pineal preparation to old animals led also to restoration of glucose tolerance disturbed with ageing. Restoring effect of pineal peptides in respect to the function of the islet apparatus of the pancreas and
Fig. 19. The peptide effect on melatonin productionin monkeys of different age.
Fig. 20. The peptide effect on cortisol production in monkeys of different age (in the morning and in the evening).
glucose metabolism is probably related to the restoration of both β-cells sensitivity to the glucose level in the blood and peripheral tissues to insulin) . Due to full correlation of mechanisms of ageing in primates and humans its seems reasonable to use pineal peptides in order to correct functions of the pineal gland producing melatonin, islet apparatus of the pancreas, and hypothalamushypophysis adrenal system in older people.
Application of peptide bioregulators in humans. Taking into consideration the encouraging data testifying to a high geroprotective activity of both natural tissue specific and synthetic peptide preparations we have been concentrating our attention on studies of geroprotective activity of peptides in old and senile people in recent years [7, 28, 36, 49, 52, 68, 70, 73]. Thus, annual treatment course with thymus and pineal preparations led to a reliable decrease in mortality during the period of observation (6–12 years) (Table 3), due to improvement of brain function and that of immune, endocrine, cardio-vascular systems, increased density
Peptide preparation effect on mortality rate in elderly and old patients
of osseous tissue (Fig. 21, 22) [36, 52, 68, 73]. It is noteworthy that application of preparation of the thymus led to a 2-fold decrease in frequency of acute respiratory disease (Fig. 23) . The restoration of melatonin secretion level in patients subjected to administration of preparation of the pineal gland is of special significance (Fig. 24) [68, 73].
Application of the pineal preparation in patients led to significant increase of anti-oxidation activity , organism resistance to stress factors, produced normalizing effect on carbohydrate metabolism.
Hypoglycemic action of the pineal preparation was conditioned by the increased insulin secretion
which combined with elevated sensitivity of peripheral tissues to insulin. Modulatory effect of the pineal peptide on the level of glycemia decreased along compensation of the disease. The patients suffering insulin-independent diabetes mellitus complicated by hypertension and treated with this drug revealed reduced arterial pressure and restoration of diastolic function of myocardium .
Women suffering climacteric myocardiodystrophy showed a significant therapeutic effect after administration of the pineal preparation which correlated with normalization of their immune and endocrine systems indices . The efficacy of the pineal preparation was registered in treatment of patients suffering aspirin asthma. They showed initially low content of melatonin, as well as patients with asthenia syndrome .
Thymus preparation revealed its efficacy in patients subject to thymectomy for thymus tumour. In 6-18 months after surgery, they
Fig. 22. Dynamics of reaction of blast-transformation of lymphocytes with phytohaemagglutinin index in elderly patients in 3 years after 6 courses of peptide preparations.
developed severe immunodeficiency which was evidenced by high incidence of respiratory viral infections, recurrent pneumonia, furunculosis, reduced ability of tissues to regeneration, signs of premature ageing (weakened skin turgor, intense graying, increased mass of fat tissue, disturbed functions of endocrine system, etc.).
These patients were treated with thymus preparation only. Following the course of treatment they revealed restoration of cell immunity, disappearance of furunculosis, increased muscular tonus. Later on there were registered lower incidence of viral infections and pneumonia. The treatment courses were repeated in 6-8 months.
These patients received thymus peptides both of the natural origin (drug “Thymalin”), and the synthesized one (drug “Thymogen”) during 15-20 years. It should be emphasized that application of thymus peptides appeared to be vital for them . Special value of this investigation consisted in identifying correlation of positive results with administration of thymus peptides to thymectomized animals.
Fig. 23. ARD incidence in elderly and old people treated with thymus preparation
The employment of thymus peptide preparations (drugs“Thymalin”, Thymogen”, “Vilon”) appeared efficient in treatment of many diseases and conditions associated with the decrease of cell immunity and phagocytosis: radiotherapy and chemotherapy in cancer patients, acute and chronic inflammatory diseases, massive utilization of antibiotics, in case of suppressed regeneration in posttraumatic period and in cases of various complications, in obliterating diseases of limb arteries, in chronic diseases of the liver, prostate gland, complex treatment of some forms of tuberculosis, leprosy .
Peptide preparation “Cortexin”, isolated from brain cortex produces considerable neuroprotection effect. This drug improves memory, stimulates brain repair and accelerates restoration of its functions after stress. The drug is used effectively in case of craniocerebral injury, cerebral circulation, viral and bacterial
Fig. 24. Effect of the pineal gland preparation on melatonin level in elderly people.
neuroinfections, encephalopathy of various genesis, acute and chronic encephalitis and encephalomyelitis. The most pronounced efficiency of the brain peptide preparation is marked in old and senile patients .
Peptide preparation “Retinalamin” isolated from the animal eye retina shows vivid clinical efficacy. This unique preparation was created for the first time in medical practice and used in patients with various degenerative diseases of the retina, including diabetic retinopathy, involution dystrophy, pigmented degeneration of the retina, etc. The ability of the drug to restore electric activity of the retina correlated with the improvement of vision and appeared to be its great value .
A distinct effect was registered in patients after administration of a peptide preparation “Prostatilen” (“Samprost”), isolated from the prostate gland of animals. The drug proved to be effective in chronic prostatitis, adenoma, post-surgery complications and other age-associated urogenital dysfunctions.
Long-term studies and application of peptide preparations of the pineal gland, thymus, brain, retina of the eye, prostate proved their high therapeutic effect in patients of various age, however their strongest effect was observed in patients over 60. An obvious advantage of these peptide bioregulators-geroprotectors is an absence of any side effects. It is noteworthy that over 15 mln. people with different pathologies were treated with peptide preparations during the period of 26 years. Therapeutic effect was equal to 75-85% on average.
The results of clinical studies obviously prompt prospects for tackling demographic issues [51, 64].
Conclusion The mechanisms of ageing studies showed that an involution of the main organs and tissues of the organism accompanied by a decrease of protein synthesis in cells underlies the process of ageing. Peptide preparations isolated from organs of young animals when introduced into an old organism are capable of stimulating protein synthesis, followed by restoration of the main functions. Long-term application of peptides, both isolated from organs and synthesized from amino acid, was registered to lead to a reliable increase in animal mean lifespan by 20—40% i.e. up to their
specific limit (when peptide application started as a rule from the second half of their life). Small peptides (di-, tri- and tetrapeptides) revealed capability of complementary interaction with the DNA specific binding site on the promoter segment of genes, inducing separation of double helix strands and RNA polymerase activation.
Discovery of the phenomenon of peptide activation of gene transcription points out the natural mechanism of organism to maintain physiologic functions, which is based on the complementary interaction of the DNA and regulatory peptides.
This process is fundamental for the development and functioning of the living substance (Fig. 25, 26). Experimental data obtained
Fig. 25. The role of peptides in the cycle of DNA, RNA and protein biosynthesis.
serve as a confirmation hereto. Peptide incubation with the DNA leads to separation of its strands at 28°C and is accompanied with twice less values of enthalpy and entropy. Activation of telomerase gene expression was reached by incubation with the same peptide at temperature 30° C, and was accompanied by the increased fibroblasts divisions by 42.5%. Administration of this peptide to animals resulted in an utmost increase in their mean life span by 42.3%, which correlated with the phenomenon of increased division of fibroblasts.
Application of peptide bioregulators in humans for preventive purposes led to a significant rehabilitation of the main physiological functions and a reliable mortality decrease in different age groups during the period of 6—12 years.
It should be emphasized that this approach to the prevention of ageing is based not only on experimental and clinical data, but also
VENTFORT is a blood vessel peptide bioregulator used to purify, repair and boost vascular system's health and performance. It increases blood flow and strengthens the cells of the vascular walls. With age, the blood vessels become more rigid and are affected by atherosclerosis. As a result, vessels often cannot provide sufficient blood circulation to all tissues. Nowadays, coronary artery disease (hardening of the arteries in the heart) is the leading cause of death in both men and women. Moreover, in every case, there is some lack of blood supply involved. In order to heal the disease, blood supply must be restored, which is why supporting blood vessels is important.
The biologically active peptide bioregulator Ventfort provides regulation of blood cholesterol and lipoproteins contents and promotes improvement of vascular wall condition. Ventfort is well tolerated at oral administration, does not have any side effects, does not have any contraindication and can be used as an adjunct to complex treatment and prophylaxis of vascular disorders of various geneses.
Ventfort is recommended for improvement of the function of vascular wall in case of atherosclerosis, microcirculation disorders in the bodies and tissues art various diseases, influence on the organism of various extreme factors. It is also recommended to elderly people for maintenance of the vascular system function.
A report of the results of clinical study of the biologically active peptide bioregulator of blood vessel origin:
The biologically active peptide bioregulator Ventfort® contains a complex of low-molecular peptides with molecular weight up to 10000 Da, isolated from the vascular (aorta) tissue of young animals - calves aged up to 12 months.
Ventfort® is manufactured in the form of tablets or capsules with a content of active substances 10 mg.
Experimental studies have shown that the peptides possess tissue-specific action on the cells of the tissues from which they were isolated. They improve trophism of the vascular wall cells and provide regulating action on the metabolic processes in them, provide normalization of functional and morphological changes in the vascular wall, they regulate blood content of cholesterol and lipoproteins, thus decreasing a risk of various vascular defects. So it is possible to extrapolate an efficiency of use of Ventfort® for recovery of vascular function at various diseases, including vascular atherosclerosis.
Atherosclerosis and its consequences is one of the main causes of invalidation and death in developed countries. Age related changes of vascular wall and hemodynamic disorders results in decrease of peripheral blood flow, vascularization of bodies and tissues, development of various components of oxygen insufficiency and trophesies. (2, 3, 4, 6).
Drug treatment of atherosclerosis is aimed at normalization of lipid metabolism, blood coagulation processes and metabolism in the vascular walls (1, 5).
The clinical studies of Ventfort® were carried out at the Medical Center of the Saint Petersburg Institute of Bioregulation and Gerontology in patients with atherosclerosis of various arteries and senile purpura during the period from November 2003 till February 2004.
Clinical characteristic of the patients
The subjects of the clinical studies were 49 patients with arterial atherosclerosis and senile purpura, 27 of them were the main group (15 men and 12 women) - they were additionally prescribed Ventfort® per os 10-15 minutes before meal 1-2 capsules 2-3 times a day for 10-15 days depending on a degree of pathological process. 22 patients (11 men and 11 women) in the control group have been taking only general purpose medicines. The age of both groups of patients has made from 52 up to 84 years old (Table 1).
The patients of both groups have various clinical signs depending on affection of various caliber vessels: essential hypertension, ischemic heart disease, cerebrovascular disorders with memory impairment, clouded sensorium and affective liability. All the patients had progressive dynamics of pathogenic pathway.
All the patients have been taking symptomatic and pathogenic therapy for specific clinical signs of vascular pathology.
Distribution of the patients by clinical entities, sex and age
The patient complaints were assessed and compared, general clinical studies of blood and urine were carried out together with blood biochemical test using “REFLOTRON” device (Boehringer Mannheim, Germany). Blood coagulogram and tourniquet Hesse testing were carried out with a purpose of homeostasis assessment.
It was established that Ventfort® administration in patients with arterial atherosclerosis has resulted in improvement of general state of health, especially in patients with cerebrovascular disorders.
As you can see in the table 2, Ventfort® administration has resulted in reliable decrease in the level of general blood cholesterol. There were also a tendency towards decrease in the content of very little density lipoproteins, being most atherogenic.
The patients with senile purpura after Ventfort® administration had an increase in strength of capillary walls according to the results of Hesse testing, the frequency of hemorrhages has decreased. In most patients the skin and hair condition has improved.
Ventfort® administration has not resulted in any side effects, complications, contraindications and drug dependence.
Ventfort® is convenient for administration in hospital, out-patient conditions and at home.
Ventfort® can be used as medical and preventive mean in the form of biologicall active food additive in the form of adjunct for complex therapy of vascular atherosclerosis and improvement of microcirculation in different tissues in combination with any means of symptomatic and pathogenetic therapy.
The biologically active peptide bioregulator Ventfort® provides regulation of blood cholesterol and lipoproteins contents and promotes improvement of vascular wall condition.
Ventfort® is well tolerated at oral administration, does not have any side effects, does not have any contraindication and can be used as an adjunct to complex treatment and prophylaxis of vascular disorders of various geneses.
Ventfort® is recommended for improvement of the function of vascular wall in case of atherosclerosis, microcirculation disorders in the bodies and tissues art various diseases, influence on the organism of various extreme factors. It is also recommended to elderly people for maintenance of the vascular system function.
Thyreogen acts as a tissue specific bioregulator to regenerate, repair and restore organ functions. Thyreogen has been shown to help treat both hyperthyroidism, (weight loss, anxiety, heat loss etc) and hypothyroidism (weight gain, lethargy, cold intolerance etc). Also a poorly performing thyroid gland can lead to autoimmune thyroiditis.
Bioregulator Thyreogen - is a thyroid gland extract and contains the major peptides of the thyroid gland. For the extraction of peptides only thyroid gland tissue are used derived from calves and pigs younger than 11 months old. All young animals come from farms in which no diseases were registered, which are dangerous to humans, including BSE.
Remove Metabolic Disorders
Prevent the Thyroid Diseases
Treat Hyperthyroidism and Hypothyroidism
Erradicate Thyroid Nodules
Remove Autoimmune Diseases
Professor KhavisoInterview with Vladimir Khavinsonn is president of the European Academy of Gerontology and Geriatrics (IAGG), advisor to various Ministries of Health and holds honorary distinctions from several universities.
Thyreogen - is a peptide complex, isolated from the thyroid gland of young, healthy animals. The isolated thyroid gland peptides have a selective effect on different cells of the human thyroid gland, normalize metabolism in these cells, regulate their functional activity and thus contribute to the regulation of the thyroid gland.
The optimal function of the human endocrine system is directly related to the state of the thyroid cells. For the optimal function of the cells is their optimal supply of nutrients such as vitamins, minerals, and with peptides required. The peptides are components of the protein molecules and are released during protein metabolism (Disintegration of the protein into smaller fractions = peptides). The peptides are information molecules, which influence gene expression and start the process of protein synthesis. Formation of proteins is a vital process. This is necessary for the growth of the cells and performing its key features.
Safety of natural peptide bioregulators
Figure 1. Gel chromatography of Cortexin solution.
Edited by Prof. Vladimir Kh. Khavinson,
Associate Member of the Russian Academy of Medical Sciences
Written by G.A. Ryzhak
Safety of Natural Peptide Bioregulators. – St. Petersburg: IKF Foliant, 2002. – 20 p.
The proposed scientific publication presents the results of a detailed study on peptide bioregulators isolated from animal organs and tissues and on the risk of their contamination with infectious agents, functionally active protooncogenes, nucleic acids, and prion proteins. The medical application of this class of pharmaceuticals has been proven entirely safe.
Introduction The contemporary epoch is marked by an extraordinary diversity of unfavourable factors affecting the human organism: natural conditions, unbalanced nutrition, environmental factors, external damaging agents including ionising and microwave radiation and toxic substances. It results in the depletion of adaptation and compensation mechanisms, occurrence of various diseases and pathologic states, and, finally, in premature ageing.
The above problems necessitate the development and clinical implementation of new effective therapeutic agents and the methods of functional correction, intensification of resistance to adverse factors, inhibition of ageing, and prolongation of life span.
Long-term experience of applying peptide bioregulators extracted from the organs and tissues of young animals has confirmed the high efficacy of this class of substances in various diseases and pathologic states including those not responsive to the treatment with other medications.
However, the active application of animal-derived peptide bioregulators in medicine requires special control over the quality and safety of these substances, since raw material used in their production can contain components hazardous for the human organism. In this view, it becomes ever more significant to devise technologies securing the safety of such substances and to work out effective control methods proving the absence of infectious agents, protooncogenes, prion proteins or other objectionable components in them.
natural peptide bioregulators The concept of bioregulation therapy based on the pathogenetic application of peptide bioregulators in various diseases, pathologic states, and ageing has been proposed and grounded in the course of 30-years’ research conducted at the Military Medical Academy (St. Petersburg) and St. Petersburg Institute of Bioregulation and Gerontology. Vyacheslav Morozov and Vladimir Khavinson were the first to isolate peptide bioregulators of multicellular systems from the hypothalamus, epiphysis, and vessel walls in 1971 . These substances have been brand-named cytomedins.
The technology of obtaining cytomedins includes acetic extraction of polypeptide fractions from cattle and pig tissues, their precipitation and subsequent multistage purification. The final product is in the form of lyophilised powder for injection solutions.
These developments have enabled the creation of new pharmaceuticals – peptide bioregulators, which form a group of pharmacologically active substances with molecular weight within 1-10 kDa. Their administration to the organism results in the functional restoration of the very organs, which the cytomedins have been isolated from.
The Institute possesses 15 pharmaceuticals. All of them have undergone thorough trials. Some cytomedins have been approved for clinical use over 15 years before (Epithalamin® – the endocrine system bioregulator, Thymalin® – the thymus bioregulator, and Prostatilen® – the prostate bioregulator) . In 1999, the Russian Ministry of Health certified the clinical application of Cortexin® (the cerebral cortex bioregulator) and Retinalamin® (the retina bioregulator) [15, 4]. Other bioregulators are undergoing various stages of clinical and experimental studies.
The technology of bioregulators manufacture and the methods of treatment with their use are covered by 70 licenses and USSR, Russian, and foreign patents. The majority of the developments have no analogues in the world.
Long-term experience of applying peptide bioregulators in healthcare has revealed their high effectiveness in various diseases and pathologic states including those not responsive to the treatment by other therapeutic means.
A new class of parapharmaceuticals – cytamins – has been created to expand the sphere for the application of bioregulators. Cytamins are balanced tissue-specific nucleoprotein complexes isolated from animal organs and tissues .
Today, 17 Cytamins are produced: extracted from the brain, liver, prostate, heart, thymus, bronchi, cartilages, pancreas, vessels, stomach, testes, epiphysis, thyroid, adrenal glands, kidneys, ovaries, and eye tissues.
Cytamins exert a targeted (organotropic) effect immediately upon the organs and tissues they have been isolated from. Being not drugs per se they produce a mild physiological regulatory influence on various functional systems of the organism, which enables their use as natural adaptogenes. Cytamins promote optimal functioning and full-value nourishment of organs and tissues, they do not contain any conservatives or other alien substances, produce no side effects, have no contraindications, and are compatible with any other nutrients and medications.
The patented technology of cytamins manufacture includes alkaline hydrolysis from tissue cells, consecutive precipitation of nucleoprotein complexes, their purification from ballast substances, and manufacture of the ready form as enterosoluble tablets or capsules.
Thus, two new classes of peptide bioregulators have been developed: pharmaceuticals cytomedins and parapharmaceuticals cytamins applied on a wide scale in medical practice to prevent various disease and pathologic states and treat for them.
safety of cytomedins and cytamins Historical background of the prion diseases concept
The history of the prion diseases concept is set forth in detail in monograph by V.A. Zuev et al. “Prion diseases in humans and animals” . Below we resort to some excerpts from this book.
The problem of prion diseases arose within the framework of the slow developing infections theory on the basis of the results of long-term investigations on mass diseases in sheep imported to Iceland from Germany in 1933. Despite some obvious clinical differences and uneven localisation of lesions in the animals’ organs and tissues, a principal similarity was revealed. This similarity can be summed up in four major signs of slow developing infections:
Among the studied sheep pathologies, scrapie was investigated. This disease of sheep and goats was well known in many countries.
Three years later, in a geographically opposite region – New Guinea – a new disease, now known as kuru, was revealed among Papua cannibals and described. Its mass development pointed at its infectious nature.
These and a number of other diseases were united by a common typical symptom. All of them were manifested only as lesions to the central nervous system: a typical picture of so-called spongiform transformation of the grey and/or white brain substances and, sometimes, of the spinal marrow based upon primary degenerative processes (without inflammation signs) and, in some cases, accompanied by the formation of amyloid plaques and expressed gliosis.
This peculiarity of the pathomorphologic picture marked out the name for the entire group of diseases – transmissible spongiform encephalopathies. Their pathognomonic feature consisted in the transmissibility of spongiform alterations solely within the central nervous system.
For decades, any attempts to discover pathogenes of these diseases ended in a failure though their infectious nature was convincingly confirmed. Yet, in early 80s Stanley Prusiner, an American biochemist from the California University, claimed that this pathogene was a nucleon-free low molecular protein (27-30 kDa), which he named “the infectious prion protein” . Prusiner proposed the term “prion” – an anagram from “proteinaceous infectious (particle)” as an infectious unit consisting of the infectious prion protein molecules. Prusiner was awarded a Nobel Prize in Biology or Medicine in 1997 for his prolonged investigations on slow developing prion infections.
Results of the studies carried out over the recent 15 years confirmed the prion nature of transmissible spongiform encephalopathy pathogenes completely. Consequently, these diseases were defined as prion ones.
The non-infectious (cellular) prion protein is vitally important. It is found in all mammals including humans. Among its distinguishing features is its high sensitivity to the digestive activity of protease K, which destroys this protein.
The infectious prion protein is preserved after the digestive impact of protease K. Its molecular weight equals 27-30 kDa.
The mechanism of accumulating the infectious prion protein in an infected organism has not been defined by now. At the same time, it is obvious that in a healthy organism the infectious prion protein entails the transformation of the normal prion protein into its infectious form due to the conformation changes of the normal prion protein. Therefore, the infectious prion protein is accumulated not via de novo synthesis of its molecules in an infected organism, but due to the conformation alterations of already synthesised normal molecules of a prion protein under the effect of the infectious prion protein.
The modern classification of prion diseases distinguishes human and animal pathologies and includes four human and six animal ones.
The list of human prion pathologies starts with Creutzfeldt-Jacob disease – the main in this group, while kuru and Herstmann-Streussler-Scheinker syndrome are considered to be its variants.
Scrapie is the main animal prion disease viewed as the prototype for all human and animal prion diseases.
In 1986, the United Kingdom was struck by an epizootic of bovine spongiform encephalopathy. As it turned out, the infectious prion protein originated from meat/bone flour. The technological process of its manufacture in early 80s implied a considerably reduced process of carbohydrate dissolving extraction of fat from bones, pluck, and heads of caws and sheep. This technological modification enabled the preservation of the infectious prion protein in raw material and caused mass contamination of ruminants after adding meat/bone flour to their forage as a protein supplement.
Started with two cases in 1986, the epizootic developed rather intensively and reached the peak of 1,000 cases in caws in 1992. Then the rate of new occurrences decreased notably and progressively.
Over this period, 23 sporadic cases of the so-called the new variant of Creutzfeldt-Jacob disease were registered, chiefly in the United Kingdom. The disease broke out among young patients, which was untypical.
Creutzfeldt-Jacob’s is a rare and fatal disease of worldwide distribution. Its total annual incidence in different regions is nearly equal and makes 0.3-1 case per 1,000,000 people. There has been revealed no correlation between Creutzfeldt-Jacob disease and the development of scrapie as the most frequent animal prion pathology. Creutzfeldt-Jacob disease has the same incidence in the scrapie-endemic United Kingdom and in Australia and New Zealand where scrapie has not been registered for years.
Wide-scale research was conducted in the United Kingdom in response to the epizootic of bovine spongiform encephalopathy in this country. Results of these investigations revealed the principal risk of infecting humans with prions from contaminated animals. It must be noted that the epizootic did not influence the total incidence of Creutzfeldt-Jacob disease in the United Kingdom as compared to other countries where no cases of the pathology in cattle were observed. Only the young age of all patients with the new variant of Creutzfeldt-Jacob disease attracts attention: all these people were less than 40 years of age. At the same time, young patients with this diseases constituted as little as 2 % of the total population (usually it was registered in the older age group, its peak striking the 60-65-year-olds).
Consequently, natural raw material of animal origin can potentially include infectious agents, protooncogenes, and nucleic acids. That is why, in the manufacture of preparations from animal organs and tissues a special attention is to be given to the purification of the active substance from objectionable admixtures and, first of all, to the infectious safety of such preparations.
Technological aspects of peptide bioregulators safety
In the manufacture of peptide bioregulators only the Russian-raised cattle is employed – calves and pigs under 12 months of age from the regions and farms where no human-endangering infectious diseases including transmissive bovine spongiform encephalopathy has been registered. It is to emphasise that Russia is known for its epizootological and epidemiological safety in respect to prion diseases.
The technology of obtaining cytomedins implies the acetic extraction of polypeptide fractions from calf and pig tissues, their precipitation and subsequent multistage purification until the outcome of active fractions with the molecular weight of 1-10 kDa. The final product is in the form of lyophilised powder intended for injection solutions.
The technology of extracting Cytamins includes alkaline hydrolysis of tissue cells, subsequent precipitation of nucleic complexes and their purification from ballast substances, drying of the half-product and manufacture of the ready form as enterosoluble tablets or capsules.
Thus, the patented methods of obtaining cytomedins and cytamins secure the maximal protection of these preparations from the interference of infectious agents. The active substance is extracted from animal organs and tissues at 3-7°C, pH 3.0 (cytomedins) or 11.0 (cytamins) for 6 days. These conditions are sufficient to fully inactivate all microbes and viruses even if no extra impacts are applied [8, 10].
Analysis of peptide bioregulators molecular weight
Molecular weight of cytomedins was studied by two methods – gel chromatography in Sefadex G-25 and electrophoresis in 15 % polyacrylamide gel. The results of gel chromatography revealed one peak in each chromatograms of the Cytomedins in the region of molecular weight under 10 kDa (Figures 1, 2, 3).
Testoluten acts as a tissue specific bioregulator to regenerate, repair and restore organ functions.
Low testosterone can result in depressed libido, erectile dysfunction, decreases muscle mass, depression, and depleted haemoglobin levels in the blood.
Testoluten - is a peptide complex, isolated from the testes of young, healthy animals. The isolated testes peptides have a selective effect on different cells of the male testes, participate in their cellular metabolism, support the regulation of their functional activity and thus contribute to the regulation of the functions of the testes and to increase the mobility of the sperm.
Influence of peptide bioregulators on morphology of parenchymatous organs
TABLE OF CONTENTS
Chapter 1. Ultrasound diagnosis. Method capacities
Chapter 2. Effect of Peptide Bioregulators on thyroid gland morphology
2.1. Summary on thyroid gland structure and functions
2.2. Thyroid gland disorders
2.3. Current diagnosis methods of thyroid gland disorders
2.4. Thyroid gland ultrasound diagnosis
2.5. Structural changes in the thyroid gland at peptide bioregulators
Chapter 3. Effect of peptide bioregulators on the prostatic gland morphology
3.1. Summary on the prostate structure and functions
3.2. Prostate age-related changes
3.3. Prostatic gland disorders
3.4. Current methods of diagnosis of the prostatic gland disorders
3.5. Prostatic gland ultrasound diagnosis
3.6. Structural changes in the prostatic gland at peptide bioregulators
Chapter 4. Effect of peptide bioregulators on morphology of other glandular
4.1. Pineal gland (epiphysis)
4.1.1. Summary on the pineal gland structure and functions
4.1.2. Pineal gland disorders
4.1.3. Current diagnostic methods of pineal gland disorders
4.1.4. Structural changes in the pineal gland at peptide bioregulators
4.2.1. Summary on the pancreas structure and functions
4.2.2. Pancreas disorders
4.2.3. Current diagnostic methods of pancreas disorders
4.2.4. Pancreas ultrasound diagnosis
4.2.5. Structural changes in the pancreas at peptide bioregulators
4.3. Mammary gland (breast)
4.3.1. Summary on the breast structure and functions
4.3.2. Breast disorders
4.3.3. Current diagnosis methods of breast disorders
4.3.4. Breast ultrasound diagnosis
4.3.5. Structural changes in the breast at peptide
Extension of human life span is the most important objective of modern science. With ageing body regulating functions deteriorate and are accompanied by the immunity disorders and development of age-related diseases [1, 2, 7, 21, 33, 35, 37]. The ageing process is characterized with a complex of alterations due to impairments in many body functions, diminution of adaptive capacities, progressive growth of abnormal alterations and death probability. The causes and mechanisms of ageing are not quite clear as yet. A great deal of theories were suggested to explain some or other ageing mechanisms [30, 34]. According to one of them ageing is caused by accumulation of pathologic alterations in the body, and the rate for such an accumulation might be influenced by genetic factors as well as by environmental conditions [11, 12]. An issue of health maintenance and longevity consists mainly in utilization of natural body reserve capacities. Therefore, issues regarding implementation of the very own body biological potential are still of current interest being key objectives for gerontology in general and geriatrics, in particular . One of the priority trends of current research in gerontology is a concept of biological regulation (bioregulation) suggested and proved by V. Kh. Khavinson and V. G. Morozov [25, 26, 27]. The bioregulation as per up-to-date notions proceeds on several levels such as supracellular, intercellular, intracellular and molecular. The bioregulation mechanisms in spite of multilevel hierarchy perform a single task to coordinate processes of biosynthesis, interchanging and reproduction of genetic information. The bioregulation unites all control mechanisms in a pluricellular organism .
Multiplicity and complexity of the regulating processes suggest presence of universal mediators for information transmission to a cell. Such mediators are peptide bioregulators that exist in different tissues and reveal a wide range of biological activity. They participate in intercellular interactions by transmitting information recorded through corresponding amino acid sequence from one cell to another . Another and not-the-least objective for gerontology is to pursue for new means of the ageing inhibition and life-span extension (the so-called geroprotectors). Development of new therapeutics based on endogenous physiologic active substances produced by a body is a novel approach for restitution of functions lost with ageing .
One of the recent discoveries consists in obtaining from animal organs and tissues of the peptide bioregulators, cytomedins . Firstly the cytomedins were obtained from hypothalamic area of the cerebral cortex, pineal gland, thymus and vascular wall [25, 26]. Later peptides similar in origin and physical-chemical properties but different regarding functional activity were found in other body tissues, as well [23, 41, 42]. At present class of peptide bioregulators enumerates several dozens of known compounds and their number increases constantly. As per chemical composition they are complexes of polypeptides having molecular weight of 1000 to 10000 daltons. After experimental and clinical studies of cytomedins there appeared possibility for preventive and therapeutic application of peptide agents to enhance body resistance to impact of negative environmental factors. These researches admit development of new therapeutic agents containing peptide bioregulators of pineal gland (Epithalamin®), thymus (Thymalin®), prostate (Prostatilen®), brain cortex (Cortexin®), retina (Retinalamin®), etc. [23, 25, 26, 42].
Last years among the agents of bioregulation therapy another new class of therapeutics generally named as cytamins and being biologically active nucleoprotein complexes extracted from animal organs and tissues appeared. The said medicines relate to parapharmaceuticals and can effectively restore altered functions in organs they were extracted from [22, 43].
Normalizing effect of peptide bioregulators on the functions of various organs and tissues was found. One can note one of the mechanisms of <> activity of peptides, namely, participation of cytomedins in regulation of cell proliferation and differentiation, as well as capacity of the self-regulation regarding the number and functional activity of cell elements in population [18, 27]. Therefore, one can suggest that peptide bioregulators might affect tissue morphology restituting their altered structure.
To prove the aforementioned mechanism of action for the peptide agents the clinical study of influence of cytomedins and cytamins on normalization in structure of abnormally altered tissues in parenchymatous organs.
Taxorest supports the performance of the respiratory system, helps regenerate lung tissue, regulates lung function and is recommended for those suffering or recovering from lung issues. Taxorest is a nutritive supplement with natural bronchial mucous peptides. The respiratory system provides oxygen to your blood, which then brings oxygen to the rest of the tissues in your body. The respiratory system is also responsible for carbon dioxide removal. If the respiratory system and any of these functions are compromised, it can lead to debilitating and even fatal conditions.
Taxorest is a complex of peptide fractions extracted from the bronchial mucous membrane of young animals. These extracted peptides selectively interacts with the bronchial mucous membrane cells thus regulating their metabolism and increasing their functional activity.
The respiratory system transfers oxygen into the blood and removes carbon dioxide. In order to function properly, the body needs a sufficient supply of oxygen. Only four minutes without it can cause permanent damage to the brain. Thus, it is crucial to keep the respiratory system healthy by avoiding injuries, inflammation, and infections, as well as supporting the bronchial mucous.
Taxorest is recommended for everyone whose bronchi may be compromised, especially people with chronic bronchitis, bronchial asthma, smoker’s cough, chronic obstructive pulmonary disease, and chronic cardiac failure.
Physiological Role of Short Peptides in Nutrition
V.A. Tutel’yan, V. Kh. Khavinson*, and V. V. Malinin*
Translated from Byulleten’ Eksperimental ‘noi Biologii i Meditsiny, Vol. 135, No. 1, pp. 4-10,
Here we review new data about the physiological role of short peptides and their use as biologically active food additives (parapharmaceutics). Some approaches to the development of peptide preparations for peroral administrations are considered and the mechanisms of non-specific and tissue-specific effects produced by peroral peptide parapharmaceutics are discussed. Particular attention is given to biological properties of short peptides synthesized at the St. Petersburg Institute of Bioregulation and Gerontology. These peptides hold much promise for the synthesis of parapharmaceutics increasing organism’s resistance to extreme factors and preventing accelerated aging and age-related diseases.
Endogenous peptides are involved in the compensatory and adaptive response of the organism to stress and disturbances in homeostasis. The peptide system plays a major role in neuroimmunoendocrine interactions .
Despite multilevel hierarchy, the main functions of homeostasis-regulating systems are coordination of biosynthesis and maintenance of stable genetic composition of cells in organs and tissues. Disturbances in the peptide-mediated regulation and transfer of informational molecules between cells lead to the development of pathological states associated with decreased organism’s resistance to destabilizing exogenous and endogenous factors.
Much progress was recently achieved in the synthesis of complex peptide-based preparations. Clinical efficiency of these drugs is extensively studied to substantiate their use in combination therapy of various diseases and disorders [11,13,20]. This approach is based on the fact that bioregulation in the organism is mediated by various oligopeptides selectively transferring information between the immune, nervous, and other cells. These oligopeptides are formed during partial proteolysis of precursor proteins (e.g., cytokines, growth and thymic factors, and immunoglobulins) in the immediate proximity to the corresponding receptors.
The general principle underlying organization of the protein molecule is that higher structures are determined by lower structures. Therefore, the primary sequence of amino acids includes information required for the formation of the protein molecule . According to modern views, information can be transferred by molecules consisting of 2-4 amino acid residues with polar side radicals.
Homology of protein sequences of most peptide hormones of the gastrointestinal tract (GIT), insulin, calcitonin, and pituitary hormones attests to their common origin. For example, the study of the evolution of these hormones showed that insulin is synthesized in gastrointestinal mucosa in mollusks. Insulin and insulin-like growth factor have the same evolutionary origin. Moreover, insulin is evolutionarily similar to nerve growth factors. It was shown that the amino acid sequence of the peptide with insulin-like activity is similar to that of trypsin inhibitor, somatomedin, and relaxin. Comparative structural analysis of biologically active substances (BAS) secreted by cells of the diffuse neuroendocrine system showed common origin of peptide hormones [12,36].
Institute of Nutrition, Russian Academy of Medical Sciences, Moscow;
*St. Petersburg Institute of Bioregulation and Gerontology, Northwestern Division of the Russian Academy of Medical Sciences
Not only the whole molecule can affect physiological processes. Sometimes fragments of 3-4 amino acid residues are more effective than native compounds. Therefore, the regulation and coordination of functions can be realized via processing of polypeptides. During this process fragments with different activity, specificity, and effects on various physiological systems are cleaved from relatively long chains depending on the needs of organisms. Processing regulation is characterized by considerable plasticity. This process results in rapid and local formation of required regulators from preexistent precursors due to activation of specific peptidases. The mechanism of processing determines the sequence of activation of regulators. Processing regulation is most typical of peptide compounds with the linear structure. Their molecules can undergo considerable conformational changes even after cleavage of a single amino- or carboxyl-terminal amino acid residue. This cleavage is followed by changes in various properties of molecules, e.g., their hydrophobicity and the blood-tissue barriers .
A growing body of evidence indicates that regulatory oligopeptides are involved in the growth, development, and regeneration. Many oligopeptides are well-studied compounds regulating various physiological functions, coordination of homeostasis, and adaptation of functional systems to the environment was revised after studies of regulatory peptides performed over the past 2-3 decades.
Nutrition is the major environmental factor that affects the organism over the whole life. Nutrients are metabolized into structural elements of cells, provide physical and mental activity, and determine the health and lifetime. Inadequate nutrition is always followed by negative consequences. Nutrition adequate to the age, professional activity, and state of health is an important factor preventing various human diseases, including cardiovascular (atherosclerosis, myocardial infarction, insult, and hypertension) and gastrointestinal pathologies, metabolic disorders (obesity and osteochondrosis), and tumors.
In developed countries people consume considerable amounts of industrially manufactured food. Technological treatment markedly reduces the contents of vitamins, mineral elements, and other BAS that regulate metabolism and functional activity of various organs and systems in the organism. In modern urbanized society, people receiving traditional nutrient products are extremely predisposed to the development of nutrient deficiency. This determines inability of protective systems in the body to respond adequately to adverse environmental factors and increases the risk of various disorders. The experience of economically developed countries indicates that it is impossible to improve the structure and quality of nutrition by traditional methods. This problem can be solved via development of new alternative methods for the production of chemically pure BAS from natural sources .
A long search and use of BAS in practice showed that various chemical compounds with a completely or partially known structure possess biological activity. BAS were efficient during the therapy of diseases and correction of mental and physical disturbances. Recent lines of research involve the analysis of BAS effectiveness in traditional spheres and other fields that develop after the appearance of compounds with new action on living matter.
There is a good reason to introduce the term “systemic preparation”, whose components participate in the regulation of various stages of the same key process. They not only initiate certain stages of this process but also attenuate negative consequences of this activation.
Apart from products of molecular biology, medicinal preparations are synthesized from traditionally used plant and animal products (even with an unknown mechanism of action). A wide use of natural medicinal preparations makes them similar to food products .
The theory of functional systems proposed by P. K. Anokhin extended and refined the notion on the mechanisms regulating homeostasis . Functional systems are involved in the regulation of a balance between nutrient substances and removal of xenobiotics and foreign antigens. The theory suggests that they recognize exogenous substrates or metabolites and transfer information to other elements of the regulatory system. After reception of the exogenous substance or metabolite and integration of information from other regulatory systems, the controlling element of this regulatory system generates a signal that triggers the operated or effector component. Information about reception of substances is transferred by hormones or mediators differing from nutrients in their chemical structure. Therefore, regulatory systems can differentiate food substrates and signals. This pathway of information transfer allows the organism to maintain the required signal at a high level even under conditions of pronounced nutrient deficiency. Many secondary messengers of signals are formed from essential compounds present in food products, but not synthesized in the body.
Information about the metabolic state is perceived by ancient (intracellular) and evolutionarily young regulatory systems (endocrine and nervous systems). Allosteric modulation is performed by the ancient regulatory system and responsible for fine adaptive reactions. The regulation of gene activation and repression contributes to the organism's adaptation to changes in food supply from the environment.
It cannot be excluded that endogenous and exogenous metabolic states are perceived similarly. Information is disintegrated into components, whose intensity is determined by receptors of the nervous and other regulatory systems at the main stages of metabolic processes. Undoubtedly, information transfer is impaired under pathological conditions. The release and accumulation of endogenous compounds (e.g., peptides) transferring abnormal information violate functional activity of regulatory systems. Therefore, consumption of BAS with food products prevents informational chaos in the regulatory systems of patients.
According to Anokhin's theory attainment of the beneficial result is characteristic of all regulatory systems. It should be emphasized that the effectiveness of regulatory systems developed during long evolution. There is a close relationship between phylogenetically developed systems and certain environmental conditions. The beneficial result can not be achieved under other conditions. Therefore, various anthropogenic factors produce a negative impact on coordinated activity of regulatory systems.
Compounds transducing signals in regulatory systems in organisms at the lower level of food chains enter the organisms of the next levels with food. If the systems in organisms of these coupled elements of the food chain are similar, these compounds can directionally affect the regulatory systems in the consumer organism. The food chain transfers not only energy, nutrients and toxins, but also information .
The regulatory systems of the intestine transfer peptides formed from proteins during digestion more rapidly than absorb the amino acid mixture, which are unusual for this organism. The small intestine contains di- and tripeptide transporters that provide absorption of short peptides [22,38]. The rate of transport for dipeptides surpasses that for amino acids. Peptidases in the brush-border membrane of enterocytes cleave 40-60% short peptides to di- and tripeptides. This fact also confirms high nutritive value of BAS and the possibility of regulation and coordination of the functions of regulatory systems in the organism with these BAS.
It should be emphasized that short peptides, including dipeptides, have different sensitivity to hydrolysis with peptidases. Some peptides are weakly hydrolyzed in enterocyte brush border. Other dipeptides, including glycyl-glycyl, proline and hydroxyproline dipeptides, glycyl- sarcosine, carnosine and tripeptide glycyl-sarcosyl-sarcosine, do not undergo complete intracellular hydrolysis and enter the portal vein .
It is interesting that insulin, vasopressin, and other hormones include peptide fragments stimulating the growth of microorganisms. Initially these observations produced a conclusion that hormonal regulation in higher animals is similar to regulation of cell division in microorganisms. Since these fragments differ in the amino acid sequence, it was hypothesized that peptides are characterized by the common steric configuration with stimulatory activity . Further studies showed that in bacteria these fragments were formed from amino acids absent in the medium and making the composition more balanced . The stimulatory effect of casein di- and tripeptides on the growth of nematodes was explained similarly . It was concluded that these peptides do not belong to endogenous growth-regulating factors.
Addition of Gln-containing dipeptides Ala-Gln and Gly-Gln to parenteral nutrition prevents disturbances during stress and malnutrition [24,27]. Parenteral nutrition enriched with Gly-Gln dipeptide prevents atrophy of the lymphoid tissue in the small intestine and promotes the recovery of secretory immunity (as differentiated from standard parenteral nutrition), which is related to the increase in IgA content in the intestinal and upper respiratory tract mucosa after intranasal infection of mice with influenza virus H1N1 . Parenteral nutrition enriched with Ala-Gln dipeptide normalizes the nitrogen balance, maintains intracellular Gln content, restores the total lymphocyte count in the peripheral blood, provides intestinal permeability and absorption, and shortens hospitalization period for surgical patients (42-86 years) after abdominal operations .
Peroral peptide preparations with different pharmacological activity are now synthesized and intensively studied [23,39,41]. However, these peptides are characterized by low resistance to enzyme hydrolysis in the stomach and small intestine. The synthesis of modified peptides or enzyme-resistant polymer conjugates would solve this problem [25,26,28,29,31]. Pharmacokinetics of peroral peptide preparations and the role of peptide transport in the small intestine were extensively studied [35,40,42].
Progressive involution of the gastrointestinal mucosa during aging is associated with changes in the rate of regeneration and dystrophic, and atrophic processes. They are characterized by shortening and thickening of villi, decrease in the number of microvilli, and structural impairment of the glicocalix [5,6] Activity of enzymes involved in final cleavage of disaccharides, dipeptides, and esters of phosphoric acid is modified .
Age-related changes in the intestinal mucosa and peculiarities of short peptide absorption provided the basis for synthesizing biologically active food additive from carnosine (β-Ala-His), whose gero-protective effects are primarily related to antioxidant activity of the peptide .
Peroral administration of tetrapeptide Asn-Leu-Pro-Arg (NLPR) to rats with memory disturbances enhances perceptivity, induces behavioral response, and promotes expression of nerve growth factor (NGF) in the brain. NLPR improves memory via initiation of NGF expression and holds much promise for the therapy of memory disturbances .
Studies of structural and functional characteristics of peptides elucidated the mechanism of their effects. Amino acid analysis of polypeptide preparations performed at the St. Petersburg Institute of Bioregulation and Gerontology resulted in the synthesis of their structural analogues. The dipeptide Vilon (Lys-Glu) was synthesized after amino acid analysis of a complex thymic preparation Thymalin and studies of immunobiological and physicochemical properties of amino acids. The tetrapeptide Epithalon (Ala-Glu-Asp-Gly) was constructed after amino acid analysis of the polypeptide preparation from the pituitary gland Epithalamin.
Computer analysis of amino acid sequence of polypeptides (Eucaryotae databank) presented in the PIR bank showed that fragments Lys-Glu and Ala-Glu-Asp-Gly are present in various endogenous regulatory peptides. Lys-Glu is a fragment of interleukin-1β (IL-1β), IL-2, IL-3, IL-4, IL-5, IL-6, interferon-γ, splenin, splenopentin, thymosins α1 β4, and β7-β14, thymopoietins I and II, motilin, parathyroid hormone, and somatoliberin. Ala-Glu-Asp-Gly enters the composition of prothymosin, parathymosin, cytostatin, troponin, thyroglobulin, neuron adhesion molecules, glyceraldehyde-3-phosphate dehydrogenase, and calmodulin-binding proteins GAP-43 and P-57. The data suggest that peptides Lys-Glu and Ala-Glu-Asp-Gly are formed in the organism from various precursor proteins during proteolysis. A comparative study of biological activity of polypeptide preparations and synthetic peptides revealed that they produce similar effects on various organs and tissues under normal and pathological conditions. Evaluation of the pharmacological effect produced by short peptides during peroral administration is of special interest. Cleavage of Vilon and Epithalon proceeding in media with various pH or induced by proteases of the stomach and contents or homogenate of the small intestine indicates that these preparations are low hydrolyzable or hydrolysis-resistant peptides. These properties of Vilon and Epithalon allowed synthesizing peroral medicinal preparations of peptides for the prevention and correction of immunodeficiency and accelerated aging.
Peroral treatment of male and female Wistar rats aging 3 and 11 months with Vilon and Epithalon affected activity of digestive enzymes (invertase, maltase, alkaline phosphatase, and amino- and dipeptidases) hydrolyzing carbohydrates, proteins, and esters of phosphoric acid in various portions of GIT (stomach, duodenum, ileum, and large intestine). Enzyme activity increased most significantly in 11-month-old animals. Therefore, the differences between enzyme activities in rats of various ages became less pronounced. These data indicate that Vilon and Epithalon regulate enzyme activity in GIT during aging [19,21].
Peroral treatment with Vilon and Epithalon (for 1 month) improved transport in the small intestine in old rats. It should be emphasized that these preparations produced a strong effect on passive and active transport of glucose. Passive accumulation of glucose in the serous fluid of the diverticulum increased in distal (Vilon) and medial portions of the small intestine (Epithalon) by 1.6 and 2.2 times, respectively. Vilon and Epithalon enhanced active absorption of glucose. Vilon 2-fold increased active accumulation of glucose in the serous fluid of the diverticulum in the medial portion of the small intestine. Epithalon intensified this process in the proximal and medial portions of the small intestine by 6 and 8 times, respectively. Peptides had no effect on passive absorption of glycine. Epithalon increased only active absorption of glycine in the proximal and medial portions of the small intestine .
Vilon and Epithalon affect activity of digestive enzymes and absorption of glucose and glycine in the small intestine of old rats. Peptides improve functions of enzyme and transport systems in the small intestine, which probably promotes food assimilation and normalizes digestion during aging.
Modern notions about nutrition and effects of nutrient substances on regulatory systems in the organism, studies of the mechanisms underlying the influence of short peptides, and synthesis of peroral medicinal preparations and parapharmaceutics indicate that the composition of therapeutic and preventive diets should be improved. Short peptides possess geroprotective properties and can be used as parapharmaceutics . Probably, exogenous peptide preparations temporally substitute the impaired element of physiological regulation. This process allows the organism to restore the diminished or lost function and to maintain it for a long time. These data confirm the view that functional compensatory systems can be formed in old organisms . We hypothesize that peptides normalize and maintain protein synthesis in the corresponding organ at a level typical of young individuals. The recovery of proteins in cell receptors normalizes their sensitivity to other humoral regulators.
Physiologically active short peptides should be used as biologically active food additives at any age for the maintenance of metabolic processes, prevention and therapy of various diseases, rehabilitation after severe disorders, traumas, and surgeries, and deceleration of aging.
The appropriate and substantiated use of biologically active food additives from short peptides opens up fresh opportunities for a new field of science, “integral medicine”. Pharmaconutrition in combination with modern diagnostic and procedures holds much promise as an effective and harmless method for the maintenance of health and increase in the lifetime.
Clinical studies revealed the efficiency of bioregulator Svetinorm in the complex improvement of the digestive system functions after different diseases, in case of pathological states causing disorders of the functions of gastrointestinal tract, in case of extreme factors impact, disturbances in lipoprotein metabolism, malnutrition and also in aging. No side effects.
The optimal function of the human digestive system is mainly associated with the optimal interaction of the endocrine and hepatobiliary systems. The key organ of these functions is the liver. Of all the organs, the liver plays the leading role in the metabolism of proteins, fats, carbohydrates, vitamins, hormones, and other substances. The optimum functioning of the human liver is connected directly to the state of the liver cells. For the optimal function of the cells is their optimal supply of nutrients such as vitamins, minerals, and with peptides required.
A report of the results of clinical study of the biologically active peptide bioregulator of liver origin:
Biologically Active Food Additive Svetinorm® is a complex of low-molecular peptides with molecular weight up to 10 000 Da, isolated from liver of young animals - calves aged up to 12 months. Isolated peptides possess tissue-specific action to liver cells, thus restoring metabolism and normalizing their functional activity.
Svetinorm® is manufactured in the form of capsules, containing 10 mg of active peptides.
The clinical studies of Svetinorm® were carried out at the Medical Center of the Saint Petersburg Institute of Bioregulation and Gerontology of the Northwest Branch of the Russian Academy of Medical Sciences in patients with chronic hepatitis and oncological patients after the course of radiation and chemotherapy during the period from October 2003 till January 2004.
Svetinorm® was administered per os 10-15 minutes before meal 1-2 capsules 2 times a day for 10-20 days depending on severity of the pathological process.
Now we see an increase in the number of patients with chronic liver diseases, which affect mostly able-bodies persons. They are mainly caused by unfavorable social and environmental factors. Chronic hepatitis is not an outcome of acute infectious process, but the form of clinical course of infectious process (2, 3).
Now the treatment of patients with chronic hepatitis in view of pathogenic mechanisms is carried out using the following traditional therapeutic agents (1):
· Drugs, which improve metabolism of hepatic cells (hepatoprotectors, essentiale, legalon, sirepar)
· bile secretion stimulators (Liv-52)
· B group vitamins (B1, B6, B12), ascorbic acid etc.)
Clinical characteristic of the patients
The clinical studies were carried out in 47 patient with chronic hepatitis and oncological patients after the course of chemotherapy, including 30 men and 17 women in the age from 35 to 68 years (table 1). The disease period has made from 3 to 10 years old. The patients of the main group have also been taking Svetinorm® in addition to the general purpose medicines - 2 capsules, 2 times a day before meal for 15-20 days.
The control groups consisted of 38 similar patients, which have only general purpose treatment.
The complaints were assessed subjectively at different times. The following tests were carried out: general clinical test of blood and urine, biochemical and immunological blood test (determination of immunoglobulins using Mancini method), liver ultrasound.
After treatment using Svetinorm®, most patients noticed elimination of fatigability, improvement of appetite and working capacity. 53% of patients have noticed considerable decrease in intensity of pain syndrome.
Oncological patients have noticed condition improvement, decrease in fatigability, decrease in intensity of dyspeptic disorders.
Recommendations for use
Svetinorm® is recommended for acceleration of restoration of liver function at acute and chronic affection, at treatment with antibiotics and other medicines with unfavorable liver effect, at hypoalimentation, in oncological patients after radiation and chemotherapy, at influence on the organism of various factors. It is also indicated to elderly people for maintenance of the liver function.
It is recommended to take Svetinorm® per os 10-15 minutes before meal 1-2 capsules, 2-3 times a day for 15-20 days.
It may be desired to have one more course in 3-6 months.
1. Mashkovsky M.D. Medicines: Pharmacotherapy for doctors, manual: 2 parts. - Vilnius: ZAO “Gamta”, 1993.
2. Podymova S.D. Liver diseases. - M.: Medicine, 1984. - 480 pages
3. Rakhmanova A.G., Prigozhina V.K., Neverov V.A. Infectious diseases: Manual for general practitioners. - M.-SPb.: Pub. “SSZ”, 1995. - 304 pages
KHAVINSON PROFESSOR, VLADIMIR
At the analysis of Svetinorm® efficiency special attention should be paid to the assessment of the results of biochemical examinations, characterizing aminotransferase activity, pigment and protein-synthesis function of liver. Objectively, most patients after Svetinorm® treatment have noticed stabilization of biochemical indices: bilirubin level, alanine aminotransferase level (table 2). Analysis of immunoglobulins of peripheral blood, being significant criterion of activity of inflammatory process after the course of treatment using Svetinorm®, has resulted in a decrease in IgM level (table 3).
Thus the obtained results testify hepatoprotective properties of Svetinorm® and expediency of its use for complex treatment of acute and chronic liver disorders, in oncological patients after radiation and chemotherapy, and also for prophylaxis of various liver diseases and their complications.
During clinical studies of Svetinorm® there were no side effects, contraindications, complications and drug dependence.
SUPREFORTSuprefort (peptide bioregulator Pancreas) is a peptide bioregulator used to treat and protect the function of the pancreas. As an extract from pancreas Suprefort selectively influence the cells of human pancreatic gland thus improving the functions of the digestive system and maintaining hormonal balance.
Pancreatic peptide Suprefort supports pancreatic health and digestive performance, restores lipid and carbohydeate metabolism and acts as a tissue specific bioregulator to regenerate, repair and restore pancreatic function. Suprefort is a nutritive supplement with natural pancreatic peptides. The pancreas serves many important functions, such as controlling blood sugar and secreting enzymes responsible for digestion. If the pancreas is not kept healthy, it can lead to many different health issues, such as pancreatitis.
Bioregulator Suprefort well tolerated, side effects, complications, contraindications and preparative dependencies when using of Suprefort not identified.
A report of the results of clinical study of the biologically active peptide bioregulator of pancreas origin:
The biologically active peptide bioregulator Suprefort® is a complex of low-molecular peptides with molecular weight up to 10000 Da, isolated from pancreas of young animals - calves aged up to 12 months. Isolated peptides possess tissue-specific action to pancreas cell tissue, thus restoring metabolism and normalizing its functional activity.
Suprefort® is manufactured in the form of capsules, containing 10 mg of active peptides.
Suprefort ® was administered per os 10-15 minutes before meal 1-2 capsules 2 times a day for 10-20 days depending on severity of the pathological process.
The clinical studies of Suprefort ® were carried out at the Medical Center of the Saint Petersburg Institute of Bioregulation and Gerontology in patients with atherosclerosis of various arteries during the period from November 2003 till January 2004.
Deregulation of physiological functions and pathological changes in pancreas result in diseases with signs of nutrition and metabolism disorders.
Consequences of progressive inflammatory process in pancreas are, as a rule, dystrophic processes accompanied with disorders of excretion of digestive pancreatic enzymes, characteristic for chronic pancreatitis. In the presence of disorders of insulin secretion, the patient has symptoms of ‘secondary’ diabetes mellitus.
Diabetes mellitus is one of most widespread endocrine diseases: about 1-2% of Earth’s population has it. Besides there are same amount of people with occult diabetes and genetically predisposed to this disease. The diabetes signs in any single case are integrated reaction to mutual action of multiple factors with various combinations (genetic predisposition, chemical and infectious agents of environment, autoimmune processes, nutrition, physical activity, psychological stresses etc.). Detection of new syndromes (diabetes, caused by formation of antibodies to insulin receptors; diabetes caused by genetic defects of insulin structure etc.) is a reason of constant necessity of addition of disease classification. Potential, latent and asymptomatic forms of the diseases without clinical symptoms require special attention concerning prognosis, prophylaxis and treatment (1, 3, 6, 7, 8).
Treatment of chronic pancreatitis is based mainly on diet and enzyme preparations (pancreatin, pansinorm) etc. (5) Treatment of diabetes mellitus without clinical signs requires diet therapy and phytotherapy (2, 4).
Clinical characteristic of the patients
Distribution of the patients by diagnoses, sex and age is shown in the table 1. Treatment using Suprefort® was carried out in 34 patients (18 male and 16 female) with diagnoses ‘Chronic pancreatitis, latent form’ (12 persons) and ‘Diabetes mellitus II type, latent form’ (22 persons).
The patients with chronic pancreatitis were complaining of the loss of appetite, eructation, meteorism, borborygmus, stool disorders. Two groups of patients were formed using random sampling technique, in these groups the patients have similar sex, age and diagnosis: the basic group included 12 patients (8 men, 4 women), control group - 8 patients (4 men, 4 women).
* Р<0.05 – reliable in comparison with the parameter before treatment
** Р<0.05 – reliable in comparison with the parameter in patients of the control group
In patients of the control group, who have been taking general purpose blood glucose lowering drugs, it was not possible to lower the dosage of the medicines, and in 9 patients (52,9%) the dosage of blood glucose lowering drugs was increased with a purpose of normalization of content of blood glucose.
Thus the results of the clinical study obtained confirm an efficiency of Suprefort® and expediency of its use in complex treatment of the patients with chronic pancreatitis and diabetes mellitus II.
Suprefort® does not result in side effects, complications and drug dependence.
Suprefort® is convenient for administration in hospital, out-patient conditions and at home.
Suprefort® can be used as medical and preventive mean in the form of biological active food additive and in the form of adjunct in combination with any means of symptomatic and pathogenetic therapy, used for treatment of patients with chronic pancreatitis and other diabetes mellitus II.
The biologically active peptide bioregulator Suprefort ® normalizes functional activity of pancreas cells.
Suprefort® is well tolerated by patients at oral administration; it does not result in any side effects and can be widely used as a treatment and prophylactic biologically active food additive for complex treatment of pancreatic function disorders.
Recommended Suprefort® dosage
· In patients with chronic pancreatitis - per os 10-15 minutes before meal 1-2 capsules, 2 times a day for 15 days.
· In patients with diabetes mellitus - per os 10-15 minutes before meal 1 capsule, 2 times a day for 15 days in parallel with blood glucose monitoring.
· It is expedient to carry out another treatment course in 3-6 month if needed.
1. Balabolkin M.I. Diabetes mellitus / Endocrine disorders // Diagnostics and treatment of internal diseases: Manual for doctors. - Edited by F.I.Komarova. - M.: Medicine, 1991. - V. 2. - pages 465-492.
2. Belousov Y.B., Moiseev V.S., Lepakhin V.K. Clinical pharmacology and pharmacotherapy: Manual for doctors. - M.: Universum, 1993. - 398 pages
3. Internal diseases / Edited by A.S. Smetnev, V.G. Kukes. - M.: Medicine, 1982. - 496 pages
4. Yordanov D., Nikolov P., Boychinov Asp. Phytotherapy. - Sofia: Medicine and physical culture, 1972. - 346 pages
5. Mashkovsky M.D. Medicines: Pharmacotherapy for doctors, manual: 2 parts. - Vilnius: ZAO “Gamta”, 1993.
6. Geriatry manual / Edited by D.F. Chebotarev, N.B. Mankovsky. - M.: Medicine, 1982. - 544 pages
7. Teppermen G., Teppermen H. Physiology of metabolism and endocrine system: Translated from English. - M.: Mir, 1989. - 656 pages
Ugolev A.M., Radbil O.S. Digestive system hormones. - M.: Nauka, 1995. - 283 pages
KHAVINSON PROFESSOR, VLADIMIR
The patients of the control group have been taking general purpose medicines. The patients of the main group have been taking Suprefort® in addition to the general purpose medicines - 1-2 capsules, 2 times a day before meal for 15 days.
Diabetes mellitus II in the patients was not accompanied by any clinical signs and was diagnosed on the basis of an increase in glucose level in peripheral blood in view of unbalanced diet.
Control group included 17 patients, who have been taking general purpose medicines. 22 patients of the main group have also been taking Suprefort®. in addition to the general purpose medicines - 1 capsule, 2 times a day before meal for 15 days.
The patient complaints were assessed and compared, general clinical studies of blood and urine were carried out together with blood biochemical test using ‘REFLOTRON’ device, (Boehringer Mannheim, Germany). Duodenal content was examined. Glucose tolerance test was carries out.
It was established that administration of Suprefort® in patients with chronic pancreatitis resulted in increase in appetite and decrease in the rate of dyspepsia.
Laboratory assessment of duodenal content has shown initial decrease in activity of pancreatic enzymes (table 2). After Suprefort® administration there is tendency toward increase in activity of pancreatic enzymes, which correlated with improved clinical symptoms.
Suprefort® in patients with diabetes mellitus II was administered in parallel with glucose tolerance test. It was established that after glucose challenge the patients had characteristic glycemic curve. The patients of the main group have also been taking Suprefort® in addition to the general purpose medicines - 1 capsule, 2 times a day before meal for 10 days. It was shown, that after Suprefort ® administration the test carried out in 2 hours after beginning of the study showed gradual decrease in the glucose level. In 5-10 days after beginning of the treatment course the patients had normal glucose levels. None of the patients had increased dosage of blood glucose lowering drugs, 12 patients (54,5%) were using decreased levels of general purpose medicines and in 7 patients (31,8%) the blood glucose level was below normal values without blood glucose lowering drugs. In 3 patients (13,6%) the parameters remained at the initial level. It is worth noting the stabilization of the blood glucose parameter in the patients of the main group within next 2-3 month after the end of treatment (table 3).
Stamakort Stamakort (peptide bioregulator Stomach Mucas)is a dietary supplement with natural stomach peptides. It normalizes the function of the gastric mucosa by reducing its peptide deficiency and restoring protein synthesis inside its cells. Improves the performance of the STOMACH by normalising the digestive functions, helping to prevent gastric ulcers and polyps. It also helps to prevent heartburn, belching and the feeling of heaviness in the stomach.
STAMAKORT is a natural peptide complex obtained from the stomach of young animals. This complex is highly effective in restoring and maintaining the functions of the digestive system. It works by direct action on the cells of the digestive system, stimulates metabolizm and protein synthesis, thus restoring the optimal functionality of the stomach. Stamakort prevents from the age-related alternations.
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Copyright © 2005 - 2017