VOL. 2, Art. 16 (pp. 57-65 ) // Маy, 2001
Registration certificate 98 /207/6 1 JULY 1998
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Composition and forms of administration
Historic and conceptual prerequisites
DSIP, biological role
DSIP distribution in the organism
Appearance of "deltaran" preparation
DSIP stressprotective activity and mechanisms of its realization
Deltaran sleep-inducing effect
Deltaran application prospects in opiate narcomania and chronic alcoholism
Deltaran and cardio-vascular pathology
Deltaran in neurological practice
Deltaran application in extremal situations
Deltaran administration in oncological practice
Deltaran application in other pathological states
COMPOSITION AND FORMS OF ADMINISTRATION:
DELTARAN is a synthetic nonapeptide structurally analogous to its endogenous prototype. Deltaran is a mixture of synthetic endogenous nonapeptides, the so-named Delta-sleep inducing peptide ( 1 weight part), and the amino acid glycine (10 weight parts). Delta-sleep inducing peptide consists of the following amino acid sequence: tryptophan-alanin-glycine-glycine-aspartate-alanin-serine-glycine-glutamine.
Deltaran is produced in ampoules as a white odourless lyophilized powder soluble in water. Each ampoule contains 0.3mg of delta-sleep inducing peptide and 3mg of glycine. The preparation is intended for intranasal application.
DELTARAN should be dissolved in 1 ml [~10-12 drops] of distilled water at room temperature just before application and then applied one drop at a time in the middle part of each nostril allowing 10-20 minute intervals between doses. The middle part of the nose contains olfactory nerve terminal radicals, or neural patches, which are known to have no synapses en route to the CNS.
After intranasal application the preparation reaches thalamic nuclei in approximately 1.5-2 minutes. The stabilizing effect is evident as early as 3 minutes and up to 1.5 hours depending on a person's endogenous peptides level.
HISTORIC AND CONCEPTUAL PREREQUISITES:
The origins of research of the Delta Sleep inducing peptide-the substance on which "Deltaran" is based-date back to 1977 when a group of Swiss scientists, studying one of the most mysterious phenomenon of the human psychology - sleep, succeeded in singling out a bioactive substrate which affected the delta-phase of sleep in experiments with crossed circulation in rabbits.
Actually, the historic roots of this discovery date back to the 1941 when H.R.Croxatto et Croxatto R. first revealed a new class of biologically active substrates. Unexpectedly, and contrary to the former views, in vitro studies showed that fragments of large biologically active protein molecules with already known characteristics possess absolutely new independent effects. At that time, such information could hardly be interpreted. However, that discovery prompted a series of additional research works. After many years of research and experimental studies concerning the biological activity of peptides and their fragments, scientists of different countries came to a new comprehension of homeostasis-maintenance system regulation in the human organism. It was established that biologically active peptides are, in their essence, mediators of the vast majority of regulatory systems. Several thousand substances which take part in signal transmission in the nervous, immune, endocrine, paraendocrine and other vitally important systems were singled out and characterized. It was determined that many of these substances arise as the result of trypsin -like enzymes action and are subsequently secreted in cells. The majority of these then interact with specific receptors of the target cell thus causing a cascade of reactions in the cell. The biological function of this group of substances was thoroughly studied and later described in quite a number of reviews and monographs.
The so-called neurotrophic factors (NTF) deserve special attention among
all these substances both in connection with their significance in the
organism and also in view of the subject of our interest (DSIP).
During embryogenesis and the postnatal period, NTF takes part in
differentiation, maturation and ensuring survival of peripheral and
central nervous system cells. NTF take part in nervous tissue
cytoarchitectonics creation, in cells phenotype formation and
also in programmed neuronal death suppression. In an adult organism,
NTF are responsible for nervous system cell differentiation, plasticity,
and survival; NTF also participate in reparation of disorders due to brain
and peripheral nervous system impairment and also caused by neurodegenerative
diseases. Neurotrophic factors have proven to be essential in immune
and endocrine systems interaction. According to Levy-Montalchiny,
NTF in this interaction is a kind of a "watch" molecule able to switch
on local- as well as system-defense processes in response to harmful influence.
NTF modulate neuro-immune-endocrine functions which are of uppermost
importance for homeostasis maintenance. Quite a number of substances were found to stimulate induction and NTF polypeptide chains, including simple amino acid chains -oligopeptides, and synthesis intensification.
It turned out, however, that unlike the vast majority of biologically active peptide fragments, oligopeptides act according to molecule - target-cell scheme. To date, more than 300 such peptides have been singled out, however until 1993, there had been no profound investigation into their structure and functional significance. It has subsequently been determined that their structure and properties are highly tissue specific. The molecular mechanisms of their action have not yet been fully identified. Nevertheless, acquired knowledge of the biological effects of these substances has allowed for the development of a new homeostasis regulation scheme. Their biological significance is believed to include separate cell homeostasis maintenance, preventing its accidental alteration, as well as homeostasis regulation of the entire organism which will be touched on below in examples of DSIP mechanism of action. The peptide regulatory system is phylogenetically more aged than nervous and endocrine systems as, most likely, similar mechanisms maintain homeostasis of the unicellular organisms as well. In a multi-cellular organism, the peptide regulatory system may act on a cellular, tissue or system level depending on the situation.
DSIP is just one of these vitally important oligopeptides exhibiting largely unknown molecular mechanism of action.
DSIP, BIOLOGICAL ROLE:
In the 1960s, the Shonenberg-Monje research group, proceeding from the assumption that initiation, depth and length of sleep phases can, most likely, be explained by the existence of a corresponding complex mechanism, conducted a series of systematic studies to disclose a sleep factor. In crossover circulation studies in rabbits they found that low frequency electrical stimulation of the donor's thalamus intralaminar nuclei increases the duration of delta waves both in the donor and in the recipient electroencephalogram; on the contrary, high frequency stimulation brings about an analogous decrease in delta waves duration. Hence, the authors supposed that there ought to be some sleep substance and later on in 1977 they singled out and described tryptophan-alanin-glycine-glycine-aspartate-alanin-serine-glycine-glutamine nonapeptide which was subsequently named the Delta-sleep inducing peptide (DSIP).
Intensive study of this particular substance undertaken afterwards by various research groups has shown that DSIP is present in quite a number of CNS structures, different organs, tissues and liquid mediums in both free and connected forms. DSIP is able to reduce locomotor activity, affect temperature control processes, circadian rhythms and also exerts influence upon electrical-physiological neuronal reactions in various brain structures. It brings about nalokson-dependent analgesia, relieves clinical evidence of alcohol and opiate dependence, and substantially enhances stress resistibility. DSIP was shown to affect the release of pituitary hormones and to exert powerful nalokson-dependent influence on metionin-enkephaline release in the brain.
One of the most impressive features of DSIP characterizing its multifunctional physiological effects is its vivid anti-stress and adaptability activity. Thus, DSIP, injected intravenously into peripheral blood at a dose of 100-200 mg/kg in the course of experiments, substantially increased animals' survival rates in cases of acute stress and, in changing ion Ca transport in sarcoplasmic reticulum, prevented major cardiovascular disturbances. It has also been noted that DSIP possesses antimetastatic oncoprotective properties and has an ability to diminish adverse effects in the course of chemotherapy and radiotherapy. Its antiepileptic activity together with its aptitude to decrease the severity and the length of abstinence syndrome of different etiology, to relieve 'cravings' due to alcohol or narcotic dependence treatment and to smooth out the signs of depression of different genesis are of major clinical importance.
DSIP DISTRIBUTION IN THE ORGANISM:
DSIP distribution in various organs and tissues of different species of animals and man has been determined from radioimmunochemical and immunohistological studies carried out by a number of both foreign and Russian researchers.
According to data obtained by various authors the largest concentration of
DSIP has been found in the thalamus and a slightly less
amount in the hypothalamus and hippocampus.
The most probable areas of DSIP localization are in neurons of the
rostral caudal nerve (which binds the most important olfactory
part of the brain cortex with the lateral part of hypothalamus), neurons
of the main nerve ganglion, tonsil, septum and thalamus. The peptide is present in significant sensory systems including visual, olfactory and tactile and also in parts of the brain connected with various internal organs. DSIP, most likely, is synthesized in brain cells and then it is actively transported.
DSIP was found to be present in membrane fraction extracted from the rat brain. In experiments, it was found that DSIP discharge is stimulated by depolarization and DSIP level of discharge did not depend on Ca ion concentration changes in the medium, which might be due to quite another mechanism of its secretion than that which is known for other neuromediators and neurotransmitters. Membrane- bound aminopeptidaza which chips off N-end triptophan from the DSIP molecule has been revealed in the brain.
It has been discovered that DSIP biosynthesis takes place in adrenal glands.
It has been further determined that there are DSIP - immunoreactive cells
in the fore-part of hypothalamus and in the central periventricular area, hence, it follows that DSIP participate in neurohormonal regulation. There are also grounds to assume that it might act as a neuromodulator responsible for vision and orientation.
A high level of DSIP has been found in kidneys, spleen, gastrointestinal
tract, and pancreatic gland. In blood plasma DSIP has been revealed in both free and bound forms. It is likely that the bound form of DSIP is a kind of physiological reservoir from which a free peptide can afterwards be released.
A study of circadian rhythm of DSIP content in humans has shown that maximum levels are attained at nighttime. In rats the highest level is observed at the moment of change of the light part of a day to the dark with a dip at nighttime. In human beings the dip takes place just before noon. In rats seasonal variations of DSIP levels have also been established.
In liquor mainly a free fraction of DSIP has been discovered that perhaps might be due to the lack of linking proteins in liquor.
Both forms of DSIP are present in milk. In foremilk a substantially higher level of DSIP, about 6 times larger than in milk, has been estimated. In newborns DSIP is apparently absorbed in the gastrointestinal tract and then it penetrates through the hematoencephalic barrier.
Chronic alcohol consumption brings about DSIP content decrease in rats brain in comparison with the animals who refused to drink ethyl alcohol. The same peculiarities are true for the people.
Blood plasma DSIP levels in patients with insomnia were reduced. After intravenous injections of the peptide, sleep became normal.
In schizophrenics, DSIP levels in spinal fluids goes down to 80%, in patients with depression correspondingly to 85 %. According to other research, the fall of DSIP level is even to 50-56 % .
It has been shown that parenteral injection of DSIP and its analogues affect CNS processes. Thus, DSIP injected intravenously to mammals brought about EEG activity change, sleep normalization in case of insomnia, change in body temperature, locomotive activity, memorizing process, and modulation of sleep phases.
DSIP penetrates through hematoencephalic barrier in both directions, however, if the DSIP concentration is low, this process is inhibited, which is not typical for other neuropeptides. Speed of penetration into various brain structures depends on the method of peptide administration.
APPEARANCE OF "DELTARAN" PREPARATION:
Based upon the promising results of the research works mentioned above, further work was enacted in order to find a medicinal form of this endogenous substrate. The problem of protection of the substrate's end molecules was of essential importance for the researchers as the usual duration of the substrate's biological half-life is no longer than a few minutes due to the presence of specific aminopeptidases in the organism. This problem has been successfully resolved by a group of Russian scientists from the Shemjakin Biological Chemistry Institute in Moscow under the leadership of academician Vadim T. Ivanov.
A group of researchers headed by I.A. Prudchenko and Inesa I. Michaljeva succeeded in synthesizing quite a number of slightly modified analogues and later on their effects and activity were thoroughly studied. Finally, two different structures: linear and cyclic were chosen (it is noteworthy that in vivo a molecule of endogenous DSIP acquires a form of a semicircle). In spite of the fact that sleep-inducing effect of the endogenous DSIP seemed rather doubtful due to discrepancy of data obtained, the assessment of the chosen molecules' characteristics after their stabilization against proteolysis has proved that their sleep-inducing activity was strongly pronounced.
In the mid-1990s, DELTARAN, based upon it's proven lack of toxicity and promising research results, was temporarily registered as a food supplement in the Russian Federation. After a further series of experimental and clinical studies, DELTARAN was registered with the Russian Pharmacological Committee [No. 98/207/6] in July 1998. The Comcon Scientific Research Center, made up of the primary researchers involved in the project, was registered and subsequently obtained full rights to the manufacture, distribution and further investigation the preparation.
Currently, there are no true analogous to this preparation in the world. A preparation Acea 1024 has been registered by firm Ciba-Gelgy, and a Clinalfa preparation was registered by the firm Hoffmann La Roshe. Acea 1024 has a far less spectrum of activity, is not actually a direct DSIP derivative, and contains some non-endogenous substances for the human organism; therefore, it might cause a number of adverse reactions, including allergic. DELTARAN, being an endogenous substrate, does not bring about any untoward reactions and its therapeutic diapason is actually boundless. In comparison with DELTARAN, Clinalfa has more limited application (narcology and sleep disturbances), the route of administration (intravenous) is less convenient and, moreover, it is at least three times as expensive as DELTARAN (1 dose of Clinalfa costs $45).
DSIP STRESSPROTECTIVE ACTIVITY AND MECHANISMS OF ITS REALIZATION:
One of the most significant features of DSIP multifunctional physiologic
activity is its strongly pronounced stress-protective and adaptability activity.
Stress is an adaptation syndrome; it was described more than 50 years ago as the universal reaction of an organism from either damage or the threat of damage.
Stress, a necessary mechanism of adaptation and survival of organism, ensures mobilization of entire ensemble of reactions which safeguard survival in extreme conditions. However, this physiological reaction is limited and can be depleted bringing about significant morphological damage to the organism. Endogenous DSIP levels in humans are produced in decreasing amounts after ~35 yrs. of age thus reducing the continued effectiveness of the stress response.
Neuroendocrine, metabolic, immune, cardiovascular and other disturbances have been described in detail in numerous publications on the subject (Meerson, Selje, Dilman and others). Experimental and clinical data give evidence of direct damage to a number of subcortical nuclei as a result of stress.
This fact is of vital importance due to our recently extended comprehension
of the mechanisms of both the stress and distress reactions.
The classical conception concerning the importance of
the hypothalamic-pituitary-adrenal axis has been supplemented by
knowledge that glucocorticoid secretion is mainly regulated by
neurosecretory neurons of the hypothalamus--paraventricular nucleus.
are also unquestionable data stressing the significance of amygdala in
thebehavioral and cardiovascular stress response. It is now understood
that striate body nuclei also affect the hypothalamic-pituitary-adrenal
axis linking together amygdaloid nuclei and the hippocampus with brain
systems responsible for vital homeostatic functions. Glutamate-containing
neurons also participate in regulation. As a rule, all the above mentioned
structures stimulate hypothalamic-pituitary-adrenal axis response on stress stimulus.
The hippocampus, prefrontal cortex and lateral parts of the septum are
the major sources of inhibiting influences (secreted glucocorticoids
also have a direct inhibitory effect ). As a matter of fact, inhibitory
neurons most often contain gamma aminobutyric acid.
Consequently, it becomes obvious that disorder in regulatory structures leads to an inadequate stress response and results either in its failure, sometimes incompatible with survival, or in its transition into distress. It is well accepted these days that stress-distress reactions are of major importance in the pathogenesis of acute as well as chronic diseases.
What is the reason for neuronal death during stress if their normal action is so vitally important for an organism? How do biochemical processes and cell membrane structures, including those of the neurons, change in response to stress factor action?
"Catecholamines excitation" leads to tissue respiration stimulation in
mitochondria. It has been found that hexokinase, which is a key enzyme
responsible for dextrose utilization in the brain, possesses a
specific peculiarity: it may exhibit changeable intracellular
localization. 90% of hexokinase cell activity normally relates to
mitochondria; during stress, the amount of hexokinase in mitochondria
decreases by 10% and more. Oxidation and phosphorylation become
separate, succinic dehydrogenase, which oxidize succinic acid, is
activated and metabolic processes, which provide tricarboxylic acid cycle
with succinic acid inflow, also become more intensive. As a result,
the energy supply increases, but at the same time it leads to a phenomenon
of "hyperreduction". In these conditions, excessive amounts of superoxide
radicals are generated. Lipase activation due to catecholamines
results in an increase of free fatty acids amount. These two
circumstances together with increased Ca 2+ influx into the cell create
favourable conditions for activation of lipid peroxide oxidation by Ca-dependent enzymes.
An increase in the amount of free radicals might well happen as a
result of a monoamine oxidase (MAO)-A and-B distribution alteration. Usually MAO-A is inside brain cells mitochondria; during times of stress its activity goes down, it appears in cytoplasm, and then these two portions of MAO-A in mitochondria and in cytoplasm nearly equalize; as a result the volume of reactions catalyzed by this enzyme dramatically increases and it brings about a rise of peroxide remains.
Activated tissue oxygen might appear in the process of oxidation of adrenaline
surplus due to stress into adrenochrome and also as a result of flavo- and ubisemichinones formation.
So long as superoxide radicals are usual metabolites of living cells
normally utilizing oxygen in the course of their metabolism, there are
protective enzymes, namely superoxidedismutase (SOD) which keep the peroxide radicals concentration permanent. The study of SOD content in different tissue cells during stress has revealed concentration and activity decrease in various but definite periods after the stress factor influence which correlated with the type of tissue under investigation as well as with the character of a stress factor. That is why, lipid peroxide oxidation caused by an enhanced amount of peroxide radicals, free fatty acids and Ca-dependent enzymes is not adequately counteracted.
Intensification of lipid peroxide oxidation inevitably leads to mitochondria membranes deformation and destructurization which in their turn not only change membrane ionic permeability but also worsen its connection with membrane related enzymes (MAO, hexokinase, creatin phosphokinase and others). Cells membrane structure changes as well. Microglia scavenger-receptors react in response to membrane structure alteration. Microglia activization leads to inflammatory reactions classical cascade development in the major brain structures what causes various neuro -degenerative changes including immediate death of neurons due to apoptosis.
CNS, unfavourably affected by stress reaction, loses its integrity necessary for realization of a whole complex of reactions vitally important for organism survival what brings about hardly eliminated homeostasis changes right up to polyorganic insufficiency in case of extraordinary stress (trauma, infectious process and so on).
Recently obtained data confirm that CNS degeneration caused by stress is one of the main mechanisms of aging process.
What is the role of DSIP in these processes? As mentioned above, its stress protective activity was studied over the course of many years. In experiments it has been shown that DSIP prevents cardiovascular disorders, improves cold and hypokinetic stress adaptation.
According to publications, it is most likely that DSIP's modulating effects and the coordinating all functional CNS links are brought about with the help of classic neuromediatory systems: adrenergetic, serotonin and GABA gamma aminobutyric acid. In 1990 Menjerizkiy proved that GABA content in brain structures increase after DSIP parenteral injection. Radioimmunological analysis has shown that DSIP-like substances are intracellular, mainly, mitochondrial and that DSIP easily penetrates hematoencephalic barrier.
A brilliant research, fulfilled by the psychical health Scientific Center
of the Scientific Research Institute of the Brain of the Russian Medical
Science Academy together with the Bioorganic Chemistry Institute of the
Russian Academy of Science and the Gorkiy Medical High School (Chvatova,
Dovedova and Michaljeva, 1987), has shown that DSIP considerably influence
MAO-A, MAO-B and hexokinase enzymes activity and their intracellular distribution in acute stress. DSIP administration not only prevented MAO-A activity decrease in mitochondria but, on the contrary, increased its activity 2-4 times in comparison with the control. MAO-B activation, which is typical for stress, also decreased due to DSIP.
In stress associated with hypoxia characteristics of oxidative
phosphorylation in mitochondria change substantially so that the adenosine diphosphate (ADP) phosphorylation speed obviously decreases and phosphorylation respiration slightly slows down. Preliminary DSIP administration completely prevents these changes.
Hypoxic stress leads to definite adenine nucleotide content changes. ADP
and ATP concentrations no doubt diminish though AMP concentration
on the contrary increases. Guanine nucleotides also undergo changes so that
GTP concentration sharply decreases by 79% and GDP concentration
simultaneously grows. Following DSIP preliminary administration to animals
exposed to hypoxia ADP and ATP concentrations approximate starting
level, though AMP concentration does not differ very much. GTP content evidently changes, its amount increases, although the final level proves to be lower than in intact animals.
Hexokinase activity study has shown that DSIP counteracts HK activity and distribution changes due to stress. DSIP administration at the time of stress completely prevents HK exit from mitochondria. Mitochondria membrane ability to bind with HK decreases three-fold in stress; DSIP preliminary administration preserves this ability close to normal levels. These data confirm, that DSIP administration exerts direct protective influence upon brain tissue mitochondria.
Stress-induced brain serotonin content in animals either intact or those after DSIP administration has also been the subject of this study. It has been found out that hypoxic stress brings about a 1.5 times increase in brain serotonin.; DSIP administration decreases its content nearly to norm.
It has also been found that DSIP administration at the time of hypoxic
stress prevents the increase of blood dextrose level (which normally doubles in animals exposed to stress) stabilizing it at normal level, while at the same time exhibits no influence on blood dextrose content in animals not under stress.
The details of DSIP biochemical action attract intensive attention
because of its particular significance in a variety of mechanisms and
interrelations of endogenous regulati of the organism's stress response
which might be a major precondition to its possible clinical application
in quite a number of pathological states as well as in cases of physical,
phychoemothional and intellectual overstrain.
It is important to emphasize that DSIP is an absolutely endogenous substrate. Therefore "DELTARAN", which in fact is a DSIP derivative and biologically and biochemically is its structural analogue, is not an alien substance for the human organism. This structure is similar for the human, vertebrates and other animal organisms as well. The molecule is phylogenetically unchangeable, nonspecific and, hence, does not carry any allergic information. Moreover, its amino acid chain is so short that it is even a labour and scientific-intensive problem to receive antibodies for experiments and therefore succeeding in it becomes itself a scientific achievement.
Adding DSIP from outside into the organism we just make up for this substrate deficiency, either absolute or functional, and assist neurons in charge function maximum adequately under existing stress of any genesis.
"DELTARAN" neither stimulates the nervous system, nor it is a sedative preparation. It simply optimizes CNS functioning under difficult conditions of strain and overstrain.
DELTARAN SLEEP-INDUCING EFFECT:
In spite of the fact that DSIP was discovered as a delta-sleep inducing peptide in rabbits, its sleep-inducing action was doubtful for a long while due to the contradictory results obtained in experiments. Neither peptide parenteral administration, nor its direct application into brain ventricles have proven to exhibit any influence upon sleep duration and phases.
However, further studies concerning its distribution and function in organisms have resulted in understanding that administered endogenous substrate preparation is promptly destroyed by endogenous peptidases. It has turned out that its short half-life period in organism which is no more than just a few minutes is preconditioned by a specific amino peptidase influence.
Only DSIP molecules modification increases their anti-amino peptidase stability and brings about an obvious sleep-inducing effect in experiments which depends on the route of administration and on the method by which their end molecules were protected. In experiments, the duration of the effect lasted up to 8 hours after the administration.
The results obtained have allowed to consider that there are three possible variants after either endogenous or modified DSIP administration:
1) sleep-inducing action;
2) aggregation /formation of a complex together with protective protein carrier;
3) degradation due to proteases influence.
As only partly protected analogous can be destroyed by carboxipeptidase, it leads to their substantially delayed degradation which causes a marked sleep-inducing effect in experiment.
The way of DSIP influence upon sleep has not yet ultimately been studied. There are some data that reveal DSIP's affect on serotonin- and GABA - mediated transmission in the brain. Moreover, it has been shown that endogenous DSIP participates in regulation of quite a number of peptide hormones: it inhibits thyroid stimulating hormone, corticotrophin, and somatoliberin release, stimulates luteinizing hormone, somatoliberin and growth hormone. It is a common knowledge, that GABA is a "slow sleep mediator" (Steriade M.,1992). Somatoliberin has an ability to prolong paradoxical and, to some extent, slow sleep. Thus, metabolically stable DSIP analogues, which imitate endogenous DSIP modulatory and releasing/inhibitory function, can fulfill their action modulating the above mentioned mediators and hormones release.
DELTARAN clinical application has shown complete correlation with experimental data. All pilot studies concerning the clinical use of DELTARAN have noted its sleep-inducing effect as the most prominent and stable. As was mentioned above, many people suffering from insomnia and other sleep rhythm and duration disorders, have, in fact, shown a reduced endogenous DSIP level and that is why exogenous analogue administration brings about sleep normalization. Normalizing effect is obtained only if there are sleep disorders and, the more the initial pathology, the more the visible effect. While DELTARAN does not influence normal rhythm of activity and rest in people without sleep disorders, it markedly increases a person's endurance and efficiency in the necessity to stay awake at night and early morning hours.
Sleep-inducing effect can be observed in 1-2 days following intranasal application at a dose 3-6 mg per day. The preparation can be recommended for outpatients for sleep disorders correction.
DELTARAN APPLICATION PROSPECTS IN OPIATE NARCOMANIA AND CHRONIC ALCOHOLISM:
Potential medicinal application in patients with opiate narcomania and chronic alcoholism have their source in its stress protective characteristics, as well as in peculiarities of its influence upon major neurons. Obviously, this idea was of particular interest for the researchers and clinical physicians.
Thus, Dick, Tissot and others, in 1984, studied DSIP effectiveness for
stopping opiate narcomania abstinence syndrome. The preparation was administered 4-6 times a day in a course of 3-6 days. In 97% of the cases authors succeeded to cease signs of abstinence in a vary short time.
A number of researchers have shown, that chronic alcohol abuse leads
to endogenous DSIP brain content decrease both in humans and animals.
Mayskiy and his co-authors have found that endogenous DSIP level in animals
predisposed to alcohol abuse decreased more than 1.5 times after a long
history of excessive alcohol consumption. DSIP blood plasma level in those
with insomnia has also turned out to be lowered. DSIP levels in people
suffering from depression is also diminished by 56 - 85% depending on the
study one views.
These data lead to the supposition that DSIP application might be effective for stopping abstinence syndrome in patients with either chronic alcoholism or opiate narcomania in both of which distress is one of the leading pathogenetic factors as well as for the further treatment and rehabilitation of the patients with the above mentioned pathology.
Further laboratory and clinical trials have completely confirmed this idea.
In a wide scale study conducted by Mayskiy A.I. and his collaborators from the narcomania medicine research prophylaxis and treatment Laboratory of the Russian Pharmacology Institute together with the psycho-pharmacology laboratory the Scientific Research Institute of the Medical Science Academy
(НИИЭПиТ АМН СССР) and the Semipalatinsk Medical Institute pharmacology
department, it has been demonstrated that DSIP has influence upon
alcohol motivation in rats and mice in a free choice situation. It has turned out that DSIP at doses of 100 mg/kg decreases ethanol consumption after 3 and 10 months of abuse by 54-44%, respectively, and, what is more, the effect not only overstays DSIP withdrawal but even causes further alcohol consumption decrease. Some other preparations (antabus, phenasepam and so on) which are commonly used for chronic alcoholism treatment do not maintain any effect after their discontinuation, moreover, they cause tolerance and dependence and bring about an additional strain on the liver that might be important in cases of long-lasting alcoholism. The results seem to be much the same in intraperitoneal as well as in intranasal ways of administration.
DSIP effect on the intensity of withdrawal syndrome after morphine
discontinuation has also been assessed. It has been noted that morphine abstinence reduces by 67% due to peptide in animals.
It has been shown that DSIP administration to alcohol abusing monkeys at
doses of 300 mg per animal, caused stimulation of emotionally-positive
forms of behavior, inhibition of aggressive reactions and profound
sleep-inducing effect. It has also been found that DSIP administration
to intact as well as to those with chronic alcoholism animals in case
of acute emotional stress results in a vivid stress-protective effect,
prevents after-stress psychotic depression and behavior deficiency.
Overdosage is not possible (see above). Patients do not develop addictions to it. DELTARAN is compatible with all drugs and methods of treatment, it strengthens their action, lessens their total dose and counteracts adverse reactions.
Below are the results of DELTARAN application for alcoholism and opiate narcomania.
In 1994 in the "Siberian clinic" (Director Bochan N.A.) together with the Scientific Research Institute of the Russian Medical Science Academy (Director- the Russian Medical Science Academy academician Semke V.Y) a clinical study of DELTARAN preparation effectiveness for stopping inclination for alcohol and relieving abstinence syndrome in cases of associated forms of alcoholism was completed. The study was carried out on 45 patients with the second stage of alcoholism using a double blind method with placebo. The preparation was used in a complex treatment of abstinence syndrome as well as in a follow-on treatment of alcohol drive at doses recommended by the Pharmacology Scientific Research Institute of the Russian Medical Science Academy. A comparative study of clinical dynamics was done in conformity with the Scientific Research Institute of the Russian Medical Science Academy and according to a special assessment scale.
In 72% of the cases a more rapid reduction of vegetative-asthenic syndrome due to abstinence syndrome in comparison with the control group was noted. In the course of further treatment, the drug exerted profound influence on primary attraction to alcohol by the way of thymoleptic normalization and vegetative stabilization.
Similar results were obtained during the clinical trials of DELTARAN for the treatment of alcoholism in Odessa, Ekaterinburg and Moscow.
Clinical trials for stopping opiate abstinence syndrome have been conducted in the narcology State Scientific Centre of the Russian Ministry of Public Health under the leadership of professor A.G. Vrublevskyi. 27 patients with opiate narcomania were investigated. 23 patients received the preparation intranasally as a stand-alone treatment in doses of 0.3-1.2 mg per day. The results were assessed by dynamics of 104 abstinence syndrome signs on the basis of 4 mark scale.
The effect of the drug was obvious in just 15-20 minutes after intranasal administration. It is known that the preparation strongly affects somatovegetative symptoms. Such symptoms of opiate abstinence as sweating, lacrimation, rhinitis and fever quickly ceased. DELTARAN relieved anxiety, decreased signs of psychical desadaptation by reducing the degree of pathological attraction to narcotics. The duration of abstinence syndrome treatment was approximately 3-10 days. The preparation has been found to be effective and was recommended for the complex treatment of opiate withdrawal syndrome.
Very good results have been obtained in Ekaterinburg during the clinical studies conducted mutually with the Regional Clinical Hospital and the Ekaterinburg Medical Institute (psycho-pharmacology department) devoted to the treatment of opiate withdrawal syndrome and to the further course of
treatment. 98 patients, among them 49 patients with opiate and 49 persons with poly-narcomania, have been investigated over a 1.5 year period. Before the study, all patients applied to different medical institutions and received standard therapy apropos of narcomania.
DELTARAN was administered intranasally at doses of 0.6 mg per day from the first day of admission to the hospital. A reduction of vegeto-vascular and psychotic symptomocomplex in comparison with a control group as well as a decrease of attraction to narcotics were observed both during the treatment of abstinence syndrome and in the course of the following DELTARAN treatment. In two cases there were no signs of abstinence at all, though, according to the former patients' experience, previously the withdrawal syndrome was very severe. DELTARAN administration led to a marked improvement of sleep.
The period of remission in patients who received DELTARAN was much longer than that in a control group. The maximum period of remission was 18- and 1- month correspondingly.
Breakdown and resumption of narcotic intake did not cause usual sensations, there were no signs of euphoria, 2 patients reported about dizziness, nausea, vomiting, as if they received narcotic for the first time. It might be due to opiate receptors renewal of normal perceptibility in this group of the patients, however, it should be further investigated.
In case of breakdown the patient was recommended to take DELTARAN not constantly but only at the time of "craving". A considerable reduction of craving for narcotics has been noted.
All the above mentioned data let make following conclusions:
1. DELTARAN is effective in complex treatment of abstinence syndrome both in case of alcoholism and opiate narcomania. Sometimes it can be administered as a stand-alone drug.
2. DELTARAN is effective in a follow-up course of treatment of alcoholism and narcomania, as it reduces the primary pathological cravings for narcotic and relieves vegeto- asthenic and depressive syndrome.
3. DELTARAN is effective in treatment of alcoholism and narcomania combined with post-traumatic encephalopathy.
4. DELTARAN might, possibly, restore genetically determinated perceptibility of the opiate receptors.
DELTARAN AND CARDIO-VASCULAR PATHOLOGY:
As has been already shown, DSIP actually normalizes almost every component of the stress response. At present, there is no doubt that stress reaction and its exhaustion are of great importance in pathogenesis of cardiovascular, in particular, acute diseases. These ideas have been thoroughly studied and developed in the works of Meerson F.Z. and his colleagues.
It should be added to the above mentioned that harmful effects of stress
on the condition of ion-transporting miocardial systems: Na, K-ATP of
the sarcolemma and Ca -ATP of the sarcoplasmic reticulum as a result of POL. At the same time it has been shown that, besides the above mentioned effects, the activity of the catalase which is one of the myocardial cell protective enzymes counteracting POL rise sharply decreases (by 22%). The degree of its decrease correlates very well with the loss of the effectiveness of Ca transportation systems. The speed of Ca transport falls down critically at the time of stress. The addition of exogenous Ca results in an additional 30% inhibition of this process what proves the failure of sarcoplasmic reticulum to remove Ca from myoplasm at the time when it is especially necessary. It leads to the further Ca -pump inhibition which results in the so- called vicious circle.
It is a common knowledge, that numerous biochemical alterations caused by stress, especially ionic transport system disorder, result in severe, sometimes fatal arrhythmia and also dramatically decrease miocardial contractility.
DSIP application appears to be very promising for patients with cardiovascular problems, and initial results tend to bear this out.
According to experimental works, DSIP administration at the time of stress not only raises animal's steadiness against all kinds of stress but also counteracts their death due to cardiovascular disorders and possesses antiarrhythmic activity.
Study of ionic transport system disorders and possibilities of their
correction and prophylaxis has shown that DSIP application during
stress brings about considerable catalase activity increase (see above),
invariability of Ca transport velocity; addition of exogenous Ca does not
inhibit the speed of Ca transport as it is usual for stress but, on the
contrary, it grows by more than 40%. All this proves considerable
improvement of Ca-transport system effectiveness. In stress,
Ca myoplasm level primarily inevitably increases, DSIP usage gives
the possibility to promptly compensate the surplus of unbound Ca 2+ in
DSIP protective activity is rather high as far as stress aggravation at the time of its administration not only causes Ca transport systems damage but, on the contrary, results in their greater effectiveness. The speed of transport increases by 30% and, as it has already been mentioned, Ca high concentrations do not cause any inhibition, the effectiveness of counteracting POL enzymes: catalase and superoxidismutase increases.
DSIP stabilizes both miocardial contracting function and electric activity thus preventing fatal rhythm disorders.
These experimental data have been confirmed by a number of clinical trials. On the basis of the St.Petersburg Pokrovskyi hospital cardiological department under the leadership of L. M. Kukuy, Ph.D, DELTARAN was used in patients with a severe, worsening development of ischemic heart disease on the background of hypertonic disease II-III degree, in patients of elder age group with ischemic heart disease and also in patients with myofascial trigger pathology.
To verify the results, the number of heart attacks, their severity, ECG changes before DELTARAN administration, after the first day of taking and at the end of the course of treatment have been taken into consideration. The course of treatment was 7-10 days long, on the first day patients received 2 ampoules intranasally and then 1 ampoule once a day in the morning.
In a group of young and middle-aged patients with ischemic heart disease rapid stabilization of their state, stopping of angina pectoris, and mood improvement were noted. Patients easily, and without any after-effects, endured in many relations complicated coronarographic research. According to Holter's monitoring, there were neither group extrasystoles, nor ECG-signs of transitory myocardial ischemia in the course of the first day. Normalization of the heart rate and a two-fold decrease of the frequency of supraventricular extrasystoles were reported. Variation range of cardiocycles duration diminished as a result of the central regulation strengthening. Regulatory systems strain index markedly changed, it grew up to 338 + 40 (normal value is 220 +25) which speaks to the participation of antistress humoral mechanisms in the health state stabilization.
In a group of elderly patients with ischemic heart disease substantial reduction of complaints connected with clinical manifestation of polyorganic disorders, usually described in this patients group, has been found. Their general feelings and sleep stabilized.
In a group of patients with myofascial pathology deliverance from splitting painful syndrome has been much faster, vegetative disorders remission ( such as dizziness, noise in the ears, scapulo-brachial syndrome) has been more prompt.
No complications related to DELTARAN application have been noted.
Positive results have also been received during DELTARAN preparation
clinical trials on the basis of the 4th and 5th
departments (acquired valvular disease) of the Novgorod Specialized
Clinical Cardiosurgery hospital. The preparation was tested in a double,
blind placebo-controlled study in patients with acquired valvular disease,
who had been operated on with an application of artificial circulation.
The preparation did not much influence arrhythmia most likely because of
significant organic and anatomic defects in the origin of rhythm disorders.
The application of the preparation has turned out to be very effective before and after the operation in cases of sleep disturbance. The drug administration has proved to be highly effective for the treatment of asthenia, psychic slowing-down, apathy and so on. It has also been found that the preparation exerts influence upon extrapyramidal disorders.
In view of very hopeful results (effectiveness in 70 % of the cases) clinical trials in the above mentioned hospital have been continued up to the present time and the range of indications has been enlarged.
It should be stressed once more that, in contrast to other stress protective treatments commonly used in patients with the above mentioned pathologies such as benzo-diazepines, gamma-hydroxybutyric acid and others, DELTARAN does not cause an immediate sedative effect and in patients without sleep disorders it does not affect their sleep; on the contrary, the more sleep and psycho-emotional disturbance, the more its hypnotic activity. In contrast to other preparations it has no toxicity even at doses 1000 times more than therapeutic. No side effects have been reported. The effectiveness of the preparation has been unchangeable throughout the whole course of treatment, the patients do not develop addictions to it.
The drug is safe and effective in cardiological out-patients treatment as well. From 7 to 15 day courses of treatment, depending on the severity of the disease, are recommended. In elderly patients more prolonged (up to a month) course of therapy is desirable because it is necessary not only to receive positive changes but to ensure it as well as the endogenous DSIP level in that category of patients is no doubt decreased. According to average statistical data, doses of the preparation 2 ampoules per day, 1 in the morning and 1 in the evening on the first 1 or 2 days and then 1 ampoule a day, either in the morning or in the evening, are quite enough for most of the patients.
DELTARAN IN NEUROLOGICAL PRACTICE:
DELTARAN application for the treatment of pathological processes of the nervous system seems to be very effective since any pathological process, including neurological, is a source of stress which is more pronounced in case of more central location of the pathological focus and since psycho-emotional stress is an etiopathogenetic factor of a number of neurological diseases.
Quite a number of clinical trials, including complex treatment of neuroborreliosis, multiple sclerosis, and infantile cerebral paralysis have been completed.
DELTARAN preparation study in cases of neuroborreliosis has been
conducted at the Institute for the Human Brain, St.Petersburg under the scientific leadership of V.I. Golovkin, Ph.D.
Neuroborreliosis is a neurological infectious disease caused by a treponema-like spirochaeta (Borrelia recurrentis spirochaeta Obermeieri) which enters the human organism via mite bite. A pathogenic organism spreads in all organs and tissues by lymphogenous, haematogenous or perineural ways and uppermost hits the central nervous system. It leads to a start of an earlier described pathobiochemical cascade with an apoptosis of defected neurons by activated microglia and to a development of the whole organism desadaptation. Moreover, the products of the nervous tissue disintegration, which are unknown for the immune system, become neurospecific antigens which launch autoimmune mechanisms in neuroborreliosis pathogenesis.
The study was conducted with the assistance of a double blind placebo-controlled method with Student's statistic criteria. To verify the results of the study, subjective complaints, neurological and ECG changes, immune system state (determination of lymphocytes sensibilization level against neurospecific antigens) were assessed. The effectiveness of the complex therapy, including DELTARAN, reached 85.5% in comparison with 49.5% in a control group.
Complaints of heightened irritability, sweating, headache, insomnia disappeared most rapidly (within a month). The altered intellectul-mnestic status also improved. It is interesting to note that the maximum
of subjective improvement ensued in 5-6 months after the course of treatment which correlates with the results of the immunological study (see further).
Neurological symptoms dynamics usually began with reflex disorders normalization. In 70% of the patients pathological phenomena disappeared and reflex background smoothed out in a month. Sensitivity restored a bit later. Ataxia was the last to disappear.
EEG data confirm the bio-electric cerebral activity normalization (65%). Slow wave and sharp wave activity ceased (73%) and rapid -slow atypical waves disappeared. Alpha-rhythm became more symmetrical with a more marked regular component. In most of the cases functional load did not cause paroxysmal activity. Spectral analysis data indicated on the disappearance of irritative activity foci in the frontal-temporal areas of the large hemispheres cortex. The above mentioned positive changes usually came true not before a month after the course of treatment.
An immunological state study has revealed a curious phenomenon of immunological inversion: at the time of clinical remission lymphocytes sensibilization to neural tissue increased, however, in 3-6 months lymphocytes sensibilization to neural tissue undoubtedly decreased which obviously spoke of stopping CNS destructive process.
In a control group the above mentioned changes both of the EEG and of the immune state have not been observed.
Thus, DELTARAN at a total course dose of 20 ampoules has turned out to be effective in the treatment of that kind of pathology. The delay of the effect and the immunological state inversion seem to be of particular significance and requires further investigation.
No less promising results have been achieved in multiple sclerosis (MS) treatment which was undertaken on the basis of the professional diseases and general therapy clinic (the Industrial and Marine Scientific Research Centre, St.Petersburg) together with the Human Brain Institute under the leadership of professor Golovkin V.I. Although MS itself exerts a chronic stress influence, at the same time an emotional stress is one of the major factors of its etiopathogenesis (the first ever documented case of MS occurred in Prince August de Este after a nervous breakdown for domestic reasons).
On the whole it is an idiopathic inflammatory disease of the central nervous system with a progressive-remittent development and with periodic worsening due to infectious, psycho-emotional stress and endocrine disorders. MS is accompanied by vegetative reactions instability, meteorological dependence, allergic reactions on the background of immune deficit and changed reactivity.
Tranquilizers and sedatives which are commonly used in the treatment of this disease only worsen the main symptoms, causing ataxia, weakness in feet and, moreover, upset the pelvic functions control. Antidepressants also upset neurotransmitters balance even to a greater degree what worsen cerebellar and extrapyramidal syndromes.
Inclusion of DELTARAN into the treatment of MS brings about marked positive
changes in about 75.6% of cases studied. The first positive
effects appear in the initial days after the start of the therapy and,
the worse the previous intellectual-mnesthic disturbance,
the greater was the observed positive dynamics. The biggest regress of
both objective and subjective symptoms in a 10 days course of DELTARAN
therapy has been observed in 83.3% patients with a syndrome of vegetative
dystonia and with hypotensive type of neuro-circulatory dystonia.
Thus, it has been proved that DELTARAN preparation addition to the treatment of neurological diseases brings about positive dynamics which is inaccessible in case of routine therapy.
The prospects of DELTARAN preparation usage in patients with infantile cerebral paralysis (ICP) have been studied on the basis of the
orthopedic-traumatological rehabilitation department of the St.Petersburg Regional Children hospital (N.I. Serebryakova) and the Laboratory of sensory systems rehabilitation of the Human Brain Institute ( Fjodorov A.B.).
It is common knowledge that congenital (ICP) and acquired cranio-cerebral injury (CCI) and injury of the spinal cord lead to early disability.
The leading pathogenetic factors of the ICP and CCI are hypoxia and local ischemia which lead to initiation of POL processes and to an extensive chain of pathological reactions and therefore to further damage.
In case of ICP, repeated courses of DELTARAN preparation were
administered to 5-14 year old children at doses of 1-2 ampoules a
day intranasally during 5 days. A remarkable positive effect has been
observed in 88.9% cases. Positive clinical dynamics included lowering of muscle tonus, increase of movements volume and muscle force what correlated very well with EEG data .
Topographic mapping before and after treatment has revealed brain neurodynamics changes. Alfa potentials amplitude in the projection of the posterior brain parts (parieto-occipital part) surely increased. Mapping of the spectral rhythm power in the process of treatment showed teta and delta-activity movement from the anterior to the posterior parts of the brain (posterior cerebral associative zone). This brain bioactivity transformation pattern not only proves certain positive effect of the drug, but also confirms participation of the posterior cerebral associative zone which, most likely, is an additional channel of motor afferent information processing in the process of compensation.
Thus, in ICP treatment there are new rather promising prospects.
DELTARAN APPLICATION IN EXTREMAL SITUATIONS:
As extreme factors inevitably lead to the start of stress-response reactions cascade with the subsequent natural development of their exhaustion and distress, the desire to find ways and means for that disorders correction is quite obvious, especially so, because in some professions challenging, demanding, persistent physical, intellectual and psychoemotional strain conditions are their characteristic parts and the result of the professional activity very often depends on the adequacy of stress reaction, as its failure might cause fatal consequences. These consequences might apply not only to professionals themselves but might as well also affect those people whose lives depend on their professional activity. The list of such professions include: air traffic control officers, military and civil pilots, servicemen, professional athletes and so on.
At the present time the activity of the servicemen is affected by three
groups of unfavourable factors which exert essential influence on the quality of their work and on the life duration of the professional service men.
The first group includes natural factors, such as geographical factors, meridional and latitudinal travel, which require adaptation. The second group consists of various factors of surrounding environment: climate, air-gas composition, barometric pressure, noise, vibration, ionizing radiation and so on, the possibility and adequacy of adaptation to which depend both on the factor parameters and on the duration of its persistent action. The third group of factors has to do with the characteristics of professional activity: the change of labor and rest regime, hypokinesia, weightlessness, overstrain, sensory deprivation, monotony, great psycho-emotional strain and so on.
The liquidators of the Chernoble catastrophe make up a particular group. The results of the many years of study of the leading Russian scientific-medical institutions have shown that at the present time, 10 years after the disaster, more than half of the liquidators suffer from progressive asthenic, neurosis-like, depressive, and intellectual-mnesthic disorders usually in combination with vegetative-vascular disturbance. The structure of the disorders and the data of the patients check-up show that the neurophysiological disturbance pathogenesis is determined by cerebral vascular disturbance in conjunction with vegetative, methabolic-endocrinological regulation changes. Signs of early aging due, perhaps, to neuro-degenerative process have been observed. Neurophysiologic changes were represented by diencephalic structure and basal ganglia dysfunction (32%) and irritative-dystrophic changes of the cerebral cortex (66%). Cerebro-vascular insufficiency progress, energy brain tissue
supply decrease, and chronic cerebral structures hypoxia develops. Antioxidative systems of the organism become insufficient.
Since long ago chemo-and pharmaco-correction have been used to improve adaptive resources, for example, shizandra, leuzea, rhododendron and others have long since been known to have tonic qualities. South American Indians chewed bushes leafs containing cocaine and cola. Application of psycho-stimulants, hormonal preparations have recently become popular, although they are far from being safe for patients. Doctors are certainly aware of the severe side effects associated with their use.
The above described features of DELTARAN preparation, created on the basis of DSIP, were of particular importance for the researcher in view of their possible use in these professional groups.
In 1996 a study "Effectiveness of DELTARAN preparation in optimizing an adaptation process at the time of extreme influence" was held in the extreme states physiology Scientific Research Institute, in the Military Medical Academy in St. Petersburg under the leadership of V.N. Zigan, Ph.D.
The study was fulfilled using double blind placebo-controlled methods. The effectiveness was assessed on the basis of the following data: blood pressure and heart rate measurement, psycho-somatic state assessment, psychological investigation with the modified eight-color Lusher test, and anxiety determination according to Spilberg-Chanin. Concentration and steadiness of attention, speed of information processing, and levels of mental capacity for work were the subjects of investigation. Assessment of difference importance was fulfilled according to Student's criteria.
The results confirm that patients who received DELTARAN were not inclined to develop tachycardia, their systolic blood pressure did not increase but, on the contrary, it even decreased slightly, and their diastolic blood pressure did not change. Their sleep normalized, the number of complaints on dizziness and headache was significantly reduced, and the number of people suffering from ringing in the ears went down by 40%. Their psycho-emotional state improved, the anxiety and nervousness level diminished. (It is apropos to remind an experimental work on rats in labyrinth. DSIP application significantly decreased their anxiety level and the number of random unsuccessful wandering, and helped to improve the adequacy of behavioral reactions in the common both of a single animal and of a group.) All this facilitated high enough adequate capacity for work preservation during 7-10 days of military-professional activity.
The preparation was administered once a day, in the morning, at dose 1-2 ampoules. No side effects were reported or observed.
DELTARAN was also studied in field conditions during the military activity
in Chechnya. In extreme situations the preparation showed the above described effectiveness, the number of neuro-psychic adverse reactions were sharply reduced. For wounded personnel, the processes of healing and rehabilitation improved, the frequency of complications was reduced (the data have not been yet published).
Thus, application of DELTARAN preparation on the basis of DSIP is indicated in people whose professional activity is connected with physical and psycho-emotional strain and overstrain, as well as for correction of disorders caused by that kind of activity. In cases of neuro-degeneration process, the drug administration might result in either stabilization or the reverse process development. The recommended doses should be individualized depending on the situation and the initial patient's condition.
DELTARAN ADMINISTRATION IN ONCOLOGICAL PRACTICE:
Tumor growth, due to its significance in the structure of morbidity and mortality, has attracted intensive investigation from many generations of researchers and scientists. It goes without saying that there is an urgent necessity to optimize a complex of treatment of this pathology.
What is the possible role of DSIP and DELTARAN preparation as its derivative in the treatment of oncological diseases?
Oncological processes exhibit extreme physiological and psycho-emotional stress on an organism. Acute and chronic stress states are persistent concomitants of the patient from the moment of diagnosis determination untill death. All the currently available methods of treatment cause various stress reactions which considerably complicate the course of disease, worsen the prognosis and do not allow many patients to complete chemo- and radio- therapy courses. Psycho-emotional state destabilization only worsens the situation.
The role of DSIP as a stabilizing and regulatory factor of adequate stress reaction has already been shown above, although DSIP produce some other possibly useful effects.
In all oncological clinical studies (the N.N. Petrov Oncological Scientific Research Institute, the St. Petersburg Oncology Medical Centre, the St. Petersburg Medical Rehabilitation Centre of the medical post-graduate education Academy, the Children's Oncology and Hematology department of the St. Petersburg Clinical Centre of Advanced Medical Technologies, the Kavezkyi Experimental Pathology, and the Oncology and Radiobiology Institute of the Academy of Science of the Ukraine, Kiev), DELTARAN has shown the following effects: psycho-emotional state improvement, motor activity increase, appetite and sleep improvement, pain threshold increase, which altogether permitted to decrease doses of narcotic and non- narcotic analgesics during a 7-10 days course of intranasal DELTARAN administration at doses 3 mg a day. The difference between the main and the control groups enumerated indices is statistically reliable; the study included a wide range of oncologic pathologies.
In some experimental works it has been found that from the moment of
malignant transformation, tissue factors acquire great
significance in antitumoral resistance formation on an organ or tissue level.
As such, the initial factors of tissue neuro-humoral reactions, which affect tissue trophicity and cells functional activity, are the regulatory basis of intercellular interaction and can substantially modify malignant tumors relapsing process (see above information on DSIP and neuro-trophic factors). Moreover, according to experimental works, DSIP takes part in circulation regulation and directly influences repair (most likely, by means of neuro-trophic factors secretion stimulation).
In the Scientific Technical Centre "MEDICINE", a group of researchers led by K.P. Balizkyi succeeded in showing that the deviation of a number of neuro-humoral factors, which takes place locally during tumor growth (adrenergic mechanisms exhaustion, serotonin and anticholinesterase level increase, sharp increase of thyroxin level and insulin level decrease) tend to normalize due to DSIP use. Thus, serotonin concentration substantially reduced, anticholinesterase activity decreased by 40-60%, catecholamine level normalized, thyroxin did not exceed normal values and insulin content increased 2-3 times.
DSIP modifying influence upon tissue neuro-humoral factors was followed
by a noteworthy decrease of a number of animals with relapses and it also
inhibited the progress of existing relapses and metastatic spreading. The greatest metastatic spreading inhibition and relapse frequency was observed at dose 50 mkg/kg . Its antimetastatic effect is, most likely, due to system activity.
The importance of immune competent cells in development,
in inhibition, or elimination of the spread of cancer can scarcely be
exaggerated. It is well known, that quite a number of brain nuclei,
in particular arcuate and posterior hypothalamic, essentially influence
the immune response and their damage causes a great deal of immunological disorders.
DSIP prevents the lesion of these zones and , thus, lessens the degree of immunological deficit.
According to modern understanding, the macrophage population together
with natural killers-lymphocytes (NK-cells) are of the most importance on
the stage of the initial tumor growth, including initial metastatic spreading.
As is generally known, macrophages are regarded as cell effectors of an organism's natural resistance and are extremely important in tumor and antimicrobic immunity. It is established that the macrophage population is heterogeneous. Depending on their function, they can be divided into two groups: macrophage-helpers and macrophage-suppressors. There are also macrophage cells with characteristics similar to cytotoxic cells. Activated macrophages even destroy tumor cells.
Lymphocytes- natural killers (NK), were for the first time described as a separate cell population more than 15 years ago. Numerous data confirm that there is a direct correlation between the NK activity level and their ability to destroy tumor cells and inhibit metastasis growth. Needless to say, NK activity decreases in the process of tumor growth and metastatic spreading. Aggressive antitumor chemo- and radio- therapy results in further NK suppression.
The increase of functional activity both NK-cells and peritoneal, alveolar and spleen macrophages has been vividly proven in the experimental work of the Scientific Research Centre "MEDICINE". As is known, the activity of these cells exactly correlates with their content of adenosine which is a natural activity inhibitor. In the process of tumor growth, the adenosine level in these immune competent cells sharply increases. DSIP administration at dose 50 mkg/kg resulted in adenosine-desaminase, which is a key enzyme of adenosinolysis, increase in 1.5-4 times, thus bringing about functional activity rise. Molecular mechanism of such effect might be explained by interaction of superficial NK receptors with neuropeptides. It might very well be that DSIP affects NK activity, making macrophages increase interferon and other small oligopeptides such as neuro-trophic factors (in particular, leukocytes growth factor) synthesis. Moreover, it is not excluded that DSIP might exert influence on other various cytokines formation which in their turn also affect immune response.
These data, based upon very important experimental work, have been indirectly confirmed during the clinical trials at the Children's Oncology and Hematology department of the Advanced Medical Technologies Centre, led by candidate of medical science M.B. Belogurova.
In children with malignant tumors who received intensive polychemotherapy, severe myelosupression developed (besides, tumor growth itself is due to immune cells inhibited activity on various levels). Leukopenia often leads to infectious complications which are the major cause of death of the patients receiving antitumor treatment.
It is common practice to use various hemopoietic growth factors (such as granulocytic colony-stimulating factor, neipogen, granocyt, leukomax) to shorten the period of aftercytostatic cytopenia. The course of such therapy not only brings about other additional side affects but at the same time is very expensive.
In this study children with severe pancytopenia received intranasal DELTARAN at dose 3 mg per day on the 1-2 day of cytopenia.
Together with essential improvement of psychoemotional state, a more rapid normalization of leukocytes number was noted in children who received the preparation. The average duration of leukopenia in the main and in the control groups was respectively 8.2+ 0.5 and 13.2 + 0.8 days. It should be stressed that in the group of patients who received DELTARAN, profound leukopenia lasted more than 10 days in 25 % of the children; in the control group, leucopenia with a duration of more than 10 days was registered in the overwhelming majority of patients. Thus, in a control group of children, infectious complications were significantly more frequent requiring intensive antibiotic and antimycotic therapy and, hence, the intervals between the courses of specific chemotherapy increased.
DELTARAN is recommended for application as a component of complex tumor diseases therapy as it has a positive influence on the development of pathological process and on the amount of complications which are inevitable side effects of the specific treatment. The dosages varied depending on the age, body weight and on the severity of the state.
DELTARAN APPLICATION IN OTHER PATHOLOGICAL STATES:
Taking into account all of the biological effects of DSIP mentioned above, it is reasonable to suppose that its application would be sensible in other situations which cause strain or overstrain of the homeostasis regulatory systems. DSIP stabilizes the work of major neurons due to its positive effect on their functional activity and gives the possibility to increase regulatory effectiveness, especially in cases of extremely severe pathological processes which involve a wide range of vital functions maintenance systems in morbid syndrome. Experimental and clinical data show that the DSIP effect is more pronounced the more severe the case.
Deltaran was prescribed to children aged 1 to 14 years old in very grave condition in the Children's Burn Centre (A.I. Grigorjev) of city hospital N1. All children had surface burn of at least 47% and thereafter were in a state of burn shock and had septicotoxemia. The doses of the preparation varied from 3 to 9 mg depending on the area and burn depth.
A substantial improvement of all the patients psychoemotional state was observed: their sleep and appetite normalized, asthenic syndrome was relieved, and fear of bandaging lessened. The terms of healing and transplant-taking were significantly reduced. The manifestation of depression after the end of treatment was far less vivid.
There has been an attempt to use DELTARAN for the treatment of autoimmune thiroiditis (Ekatherinburg). The preliminary results show that at the time of DELTARAN administration hormonal tests tended to normalize, autoantibodies titer notably decreased. Although the number of patients is not enough to summarize the results, the preliminary indications are hopeful.
In the Ekatherinburg Regional Clinical hospital DELTARAN was used in
patients with serious cranio-cerebral trauma who had been admitted to
the neuro -surgery department in extremely grave condition. The medical
prognosis was very poor, their trauma was, in fact, incompatible with life.
DELTARAN was administered in very high doses from the moment of
admission (up to 15 mg a day). Out of 6 patients only one died, the rest were discharged from the hospital with minimal levels of disturbance after the trauma (detailed data has not yet been published).
Although more than 300 similar peptides with tremendous biological potential have been preliminarily identified, their mechanisms of actions are not yet understood.
DELTARAN is a representative of a new class of parapharmaceuticals based upon regulatory peptides and has proven effective in the treatment of many and varied pathologies, including serious ones. Clinical trials should be continued and expanded in order to ascertain the indications for clinical application and further develop knowledge of the molecular mechanisms in action.